New Organ: Up to $15,000 For Social Network Engagement

The New Organ Prize is a technology prize aimed at speeding development of tissue engineered complex organs, founded by the Methuselah Foundation. To win, a competitor must build a complex organ from a patient's own stem cells, transplant it, and have it function for two years - without making use of present stepping stone technologies such as decellularization that still require a donor organ. Start with cells and end up with patient-matched organs: that is the vision.

One of the projects currently undertaken by the New Organ volunteers is the New Organ 100 initiative, focused on crowdsourcing the first stage of prize fundraising, raising awareness, and building support in the large community of organ donors, organ recipients, and their supporters.

Anyone can join in, create a fundraising page, and persuade their friends to help out; fundraisers compete with one another in rankings of number of donors and amount raised. This is an expansion into the world of social networking, and the New Organ Prize can be found on a variety of social sites:

As matters proceed, the New Organ Prize continues to attract matching donations and incentives. The latest is an offer by investor Michael Matula: for every like or share on Facebook, or follower on Twitter, he will donate $1 to the prize fund - up to $15,000. In an ideal world, every reader here would think enough of the initiative to head on over and donate a modest amount, or start a fundraiser and talk a few friends into supporting the initative. If you're not up for that, however, then consider stretching your mouse fingers so far as to like the New Organ 100 page.

Measuring Impaired Autophagy With Aging in the Pancreas

Autophagy is the important collection of processes that break down damaged cellular components and unwanted metabolic byproducts. More autophagy improves the health of the organism and extends longevity, while less autophagy leads to the reverse. Boosted autophagy appears to contribute strongly to a number of life-extending interventions, including calorie restriction, and researchers have achieved such goals as reverting aged liver function to youthful levels by increasing the effectiveness of autophagic processes. Unfortunately, autophagy declines with age as the cellular components that carry out the process become damaged and overwhelmed by metabolic waste products. Here researchers measure the impact of reduced autophagy with age in the pancreas: "Type 2 diabetes is characterized by a deficit in β-cell function and mass, and its incidence increases with age. ... Impaired or deficient autophagy is believed to cause or contribute to aging and age-related disease. Autophagy may be necessary to maintain structure, mass, and function of pancreatic β-cells. In this study, we investigated the effects of age on β-cell function and autophagy in pancreatic islets of 4-month-old (young), 14-month-old (adult), and 24-month-old (old) male Wistar rats. We found that islet β-cell function decreased gradually with age. Protein expression of [autophagy markers] exhibited a marked decline in aged islets. The expression of Lamp-2, a good indicator of autophagic degradation rate, was significantly reduced in the islets of old rats, suggesting that autophagic degradation is decreased in the islets of aged rats. [Markers] of mitochondrial and nuclear DNA oxidative damage exhibited strong immunostaining in old islets. Analysis by electron microscopy demonstrated swelling and disintegration of cristae in the mitochondria of aged islets. These results suggest that β-cell and autophagic function in islets decline simultaneously with increasing age in Wistar rats, and that impaired autophagy in the islets of older rats may cause accumulation of misfolded and aggregated proteins and reduce the removal of abnormal mitochondria in β-cells, leading to reduced β-cell function. Dysfunctional autophagy in islets during the aging process may be an important mechanism leading to the development of type 2 diabetes." Reversing the decline in autophagy by restoring lysosomal function is a part of the SENS vision for rejuvenation biotechnology.


The Point of Slowing Aging

This abstract encapsulates the point made by advocates of slowing aging through metabolic manipulation by drugs or other means - that it is a far better approach than the present dominant methodologies of treating various end-stages of aging separately, and by patching over the symptoms rather than treating root causes: "Atherosclerosis, hypertension, obesity, diabetic complications, cancer, benign prostate hyperplasia, Alzheimer and Parkinson diseases, age-related macular degeneration, osteoarthritis, osteoporosis, and seborrheic keratosis are strongly associated with aging, implying a common underlying process. Each disease is treated separately and, in most cases, symptomatically. Suppression of aging itself should delay or treat all age-related diseases, thus increasing healthy life span and maximal longevity. But, is it possible to slow down aging? Recent evidence indicates that the target of rapamycin signaling pathway is involved in cellular senescence and organismal aging. Preclinical and clinical studies demonstrated the therapeutic effects of rapamycin in diverse age-related diseases. One simple reason why a single drug is indicated for so many age-related diseases is that it inhibits the aging process."


From a Recent Symposium on Cryonics and Dementia

Cryonics is the low-temperature preservation of the deceased, as rapidly as possible after death so as to preserve the fine structure of the brain before it can be damaged or decay. The body, or at least the head, are also preserved - but that is largely incidental to the real purpose, which is to store the mind encoded in the structure of neural tissue. For so long as that mind exists in low-temperature storage it has time to wait out progress in technology, the dawn of an age of medical molecular nanotechnology, and advanced tissue engineering capable of restoring that brain to live in a new body. If you have the technology to de-vitrify a brain whilst maintaining its mind, so the thinking goes, then building a body from stem cells is pretty straightforward by comparison.

In any case, my point here is the the focus of cryonics is the brain, its structure, and the mind. Threats to the fabric of the mind are of greater importance than threats to the rest of the body in this way of looking at the world, as there exist a range medical conditions that can destroy your mind well prior to death, placing you just as far beyond help as if you burned to death, were lost at sea, or simply buried. Earlier this month, the folk of the Institute for Evidence Based Cryonics hosted a symposium on cryonics and dementia. Here is a report:

The recent symposium on cryonics and brain-threatening disorders was a major success. On Saturday, July 7, 2012, around 30 people attended the first ever symposium on dementia and cryonics in Portland, Oregon. The symposium started with a brief introduction by Institute for Evidence Based Cryonics President Aschwin de Wolf, who emphasized why people with cryonics arrangements have a clear interest in understanding and avoiding dementia. The first speaker, Chana de Wolf, introduced the audience to the topic of adult neurogenesis, the two areas in the brain where it occurs, and how little we still understand about it. Aubrey de Grey then talked about the SENS approach to rejuvenation and how some emerging damage repair bio-technologies might be able to also reverse neurodegenerative diseases such as Alzheimer's disease. Cryonics Institute President Ben Best followed Aubrey's presentation with a technical introduction about the pathophysiology of Alzheimer's disease and the treatments that are currently being investigated.

There is also a main symposium page with links to slides and a video of some of Aubrey de Grey's presentation.

A Comparative Cellular and Molecular Biology of Longevity Database

Researchers recently announced a database of interesting material on the biology of longevity - one of a growing number of publicly available online databases in this field: "Discovering key cellular and molecular traits that promote longevity is a major goal of aging and longevity research. One experimental strategy is to determine which traits have been selected during the evolution of longevity in naturally long-lived animal species. This comparative approach has been applied to lifespan research for nearly four decades, yielding hundreds of datasets describing aspects of cell and molecular biology hypothesized to relate to animal longevity. Here, we introduce a Comparative Cellular and Molecular Biology of Longevity Database [as] a compendium of comparative cell and molecular data presented in the context of longevity. This open access database will facilitate the meta-analysis of amalgamated datasets using standardized maximum lifespan (MLSP) data (from AnAge). The first edition contains over 800 data records describing experimental measurements of cellular stress resistance, reactive oxygen species metabolism, membrane composition, protein homeostasis, and genome homeostasis as they relate to vertebrate species MLSP."


Modest Success in a Cancer Vaccine Trial

German researchers trialing a generally applicable cancer vaccine technology find that it improves on chemotherapy, but remains a long way from a cure. Still, this is generally how matters proceed: first results are only first results, and much improvement lies ahead. "Researchers [have] published the results of two clinical studies using the kidney-cancer vaccine IMA901 ... It is composed of ten synthetic tumor-associated peptides (TUMAPs), which activate the body's own killer T-cells against the tumor. Unlike chemotherapy, this process targets the body's immune responses and mobilizes them to attack the cancer. The studies show that this active immunization against cancer can be successful and extend the life of a patient for longer than even the latest chemotherapy techniques - with far fewer side-effects. ... All of the medications previously used have brought about a clear improvement in reducing tumor growth in cancer of the kidneys, but they did not lead to the desired extension of the patient's life and certainly did not cure the patient. ... The study shows that in kidney-cancer patients with documented T-cell reactions against two or more tumor-associated peptides, the immune reaction and clinical progress were clearly linked. That confirms the hypothesis that cancer treatments can be further developed by broadly activating the immune system against various target structures on the surface of the tumor. ... The principle applied here - of active immunization against cancer antigens previously identified in cancer cells - can be used against practically all types of cancer. ... researchers have published similarly successful clinical studies in the case of bowel cancer [and] prostate cancer. Immatics is currently carrying out studies on treatments for glioblastoma [a common and malignant brain tumor] and further studies for treating liver cancer and ovarian carcinoma are in the pipeline."


Papers on Pharmaceutical Innovation and Longevity Gains

Earlier this year, I noted a paper by Frank Lichtenberg that correlates life expectancy with the pace of introduction of new drugs - both of which are metrics that can be measured fairly well, and are fairly well recorded over the past few decades. So we see the expected result: one fairly general measure of the pace of progress in medicine is linked to longevity, most likely indicating that more rapid development of new medicine leads to longer lives, even when that medical progress is largely old-style drug discovery and commercial development. Here, I'll point out a few other papers along the same lines by the same author, one recent and the others from past years:

Pharmaceutical Innovation and Longevity Growth in 30 Developing and High-income Countries, 2000-2009

We examine the impact of pharmaceutical innovation, as measured by the vintage of prescription drugs used, on longevity, using longitudinal, country-level data on 30 developing and high-income countries during the period 2000-2009. We control for fixed country and year effects, real per capita income, the unemployment rate, mean years of schooling, the urbanization rate, real per capita health expenditure (public and private), the DPT immunization rate, HIV prevalence and tuberculosis incidence.

Life expectancy at all ages and survival rates above age 25 increased faster in countries with larger increases in drug vintage. The increase in drug vintage was the only variable that was significantly related to all of these measures of longevity growth. ... Pharmaceutical innovation is estimated to have accounted for almost three-fourths of the 1.74-year increase in life expectancy at birth in the 30 countries in our sample between 2000 and 2009, and for about one third of the 9.1-year difference in life expectancy at birth in 2009 between the top 5 countries (ranked by drug vintage in 2009) and the bottom 5 countries (ranked by the same criterion).

What to take away from this: even under the outright terrible systems of regulation that presently exist in most countries with advanced medical research communities, regulation that greatly slows progress and increases costs, the great utility of biotech research and development still filters through to this degree. Imagine how much better off we'd all be if there were no massive government agencies devoted to slowing down and blocking progress in medicine!

The older papers provide some more numbers to further flesh out the picture sketched by Lichtenberg and his colleagues. Medical progress is good - we should have more of it:

Pharmaceutical innovation and the longevity of Australians: a first look (2008)

We examine the impact of pharmaceutical innovation on the longevity of Australians during the period 1995-2003. Due to the government's Pharmaceutical Benefits Scheme, Australia has much better data on drug utilization than most other countries. We find that mean age at death increased more for diseases with larger increases in mean drug vintage. The estimates indicate that increasing the mean vintage of drugs by 5 years would increase mean age at death by almost 11 months. The estimates also indicate that using newer drugs reduced the number of years of potential life lost before the ages of 65 and 70 (but not before age 75). During the period 1995-2003, mean age at death increased by about 2.0 years, from 74.4 to 76.4. The estimates imply that, in the absence of any increase in drug vintage, mean age at death would have increased by only 0.7 years. The increase in drug vintage accounts for about 65% of the total increase in mean age at death.

Pharmaceutical Innovation, Mortality Reduction, and Economic Growth (1998)

We perform an econometric investigation of the contribution of pharmaceutical innovation to mortality reduction and growth in lifetime per capita income. In both of the periods studied (1970-80 and 1980-91), there is a highly significant positive relationship across diseases between the increase in mean age at death (which is closely related to life expectancy) and rates of introduction of new, priority (as defined by the FDA) drugs. The estimates imply that in the absence of pharmaceutical innovation, there would have been no increase and perhaps even a small decrease in mean age at death, and that new drugs have increased life expectancy, and lifetime income, by about 0.75-1.0% per annum.

The connection between wealth and longevity is strong. For a deeper historical perspective, you might look back at these posts:

A Single-Issue Political Party for Longevity Science

In a number of countries one plausible path to advocacy for a cause is the establishment of a single issue political party - see, for example, the original Green Party or Pirate Party as successful examples of the type in Europe. The Russian longevity science community is beginning to take this approach: "On July 19, we made the first step towards the creation of the Longevity Party. The initiative group of 10 people gathered together in Moscow to establish the first political party aimed at extending human lifespan using technological advances. ... Among these 10 people were Mikhail Batin, Alexey Turchin, Leonid Kaganov and Elena Milova. This is the very first step in the long and hard process of legally registering a political party. I believe this is one of the most important things that happened in the past few years in fighting aging. Nowhere in the world ever before have people expressed their desire to live longer in the form of a political movement. ... The main goal of the Longevity Party is to increase human lifespan so that people could live for as long as they would like to and remain young and healthy. We would like to achieve this goal by promoting scientific research and technological advances in regenerative medicine, genetics of aging and longevity, neuroscience, computer modeling of biological processes and other areas of life extension. ... The next big thing we need to do is to finalize the Program of the Party. Then we have to have at least 2 people in 42 regions of Russia as representatives of the Party and have the founding meeting after which the Party can be registered and eventually appear in the voting ballots. Our goal is to influence the authorities to support life extension technologies and increase funding for research aimed at improving people's health and extending longevity."


FDA Reaches to Regulate (i.e. Block) Simple Stem Cell Therapies

The FDA seems to be succeeding in the courts with regard to shutting down the few groups in the US trying to offer first generation stem cell therapies, and placing a heavy burden of regulation upon them. This most likely means that for another decade or so the only realistic way to access most of the present variety of stem cell therapies will continue to be medical tourism: "It's official: stem cells are drugs. At least, that's the opinion of the US district court in Washington DC, which has ruled that the Food and Drug Administration (FDA) has the authority to regulate clinics offering controversial stem cell therapies. Treatments in which stem cells are harvested from bone marrow and injected straight back into the same patient are deemed part of routine medical practice - not regulated by the US government. But if the cells are subjected to more than 'minimal manipulation', the FDA maintains that the therapy becomes a 'drug', which must be specifically approved for use. It was on this basis that in 2008 the FDA began moves to shut down Regenerative Sciences, a clinic in Broomfield, Colorado, that treats orthopaedic problems using a stem cell therapy called Regenexx. ... Regenexx consists of mesenchymal stem cells, which give rise to tissues including bone and cartilage, taken from a patient's bone marrow and grown in culture for about two weeks. Centeno has published a series of case reports describing its use to treat joint problems - but no controlled clinical trials. ... Regenerative Sciences challenged the FDA's authority to regulate its activities, setting the stage for a legal fight. In 2010, the FDA sought an injunction to take Regenexx off the market. This has now been granted in the court's ruling. Christopher Centeno, medical director of Regenerative Sciences, vows to appeal. 'This is really round one. Our position remains that a patient's cells are not drugs.'"


An Interview With David Gobel, Methuselah Foundation CEO

The Methuselah Foundation is presently launching the New Organ 100, one part of a long term initiative to accelerate development of tissue engineered complex organs. An interview with CEO David Gobel was recently published at Motley Fool.

So You Wanna Live Forever?:

Borders: What is "life extension" -- and what does the Methuselah Foundation have to do with it?

Gobel: There are two kinds of life extension, one based on statistics and one based on one's own particular, non-statistical life. In each case, Life Extension means being healthier and living longer than: a) humans maximally have lived historically as a species (i.e. 120 years); and b) living a longer and healthier life than one individually would otherwise be likely to achieve without thoughtful intervention and new life extending technologies. For example, my mom lived to be 81, and had cancer surgery, knee replacements, insulin and a bunch of other interventions that didn't exist when when she was younger. My estimate is that medical advances added 19 happy years to her life...a huge personal dividend. We want to significantly extend the quality and quantity of that dividend so that 90 becomes the new 40.

By promoting extension of the statistical healthy lifespan, Methuselah has been a major influence on the public and scientific community's perception of the acceptability and value of increasing the maximum human lifespan and health-span. Starting in 2003 via the Methuselah Mouse Prize (four winners to date) and the tireless work of Methuselah volunteers - notably, Dr. Aubrey de Grey - the concept of engineering the delay of the human "expiration date" went from a ridiculous sci-fi fantasy to a non-controversial goal that serious scientists can now pursue without destroying their careers. The only controversy today is not if it will happen, but how soon it will happen.

On the second point of personal longevity, Methuselah has initiated a New Organ Prize that will incent the creation of something blindingly obviously needed. New parts for people. If a car can run perfectly well as if it had just come off the assembly line 110 years after being built because of replacement parts, why should humans be second class citizens to cars? Why should the 30,000 people who need new hearts at any given time be stuck with death as the likely outcome when your old corvair can easily get a rebuilt fuel pump? It is completely ridiculous, and we intend to do all we can to end the horror of the "Dialysis Matrix," for those needing kidneys currently suffer year after year in silence. So, New Parts For People is our current focus, because no one dies statistically - we die one unique and irreplaceable person at a time. Often because we just need a new part.


Borders: What is the most promising research avenue for the near term?

Gobel: Several directions: First, there is the switch from trying to slow aging by trying out various drugs, which is the essence of the old approach to all human medicine, to the rational design of biotechnologies to precisely repair or work around each of the causes of aging. As outlined by Aubrey de Grey and others in the Strategies for Engineered Negligible Senesence (SENS), we already know with a fair degree of surety exactly which of the many cataloged biochemical and cellular changes that accompany aging are in fact the root causes of degeneration, frailty, and death. We also know enough about how to revert these changes to be developing the necessary biotechnologies for the task. This is a straightforward research and development plan, or at least as straightforward as research can ever be; progress here at the present time is largely a matter of raising more funding and convincing more of the research community to give up the old drug development line, going nowhere fast, and join the better party.

Secondly, the field of stem cell medicine, encompassing tissue engineering, regenerative medicine, and so forth, offers the prospect of replacing worn body parts and cell populations, or even restoring them in situ without surgery. ... It is even a promising matter that cell therapies are hampered by the damaged environment of the old body: Because so much of regenerative medicine is most beneficial to the old, that large industry will be increasingly steered in the direction of understanding how to reverse that environmental damage - how to restore the broken signaling and damaged stem cell niches that lead to poor regenerative capacity in the elderly.

A Review of Skeletal Muscle Mitochondria in Aging

An open access paper: "Aging is characterized by a progressive loss of muscle mass and muscle strength. Declines in skeletal muscle mitochondria are thought to play a primary role in this process. Mitochondria are the major producers of reactive oxygen species, which damage DNA, proteins, and lipids if not rapidly quenched. Animal and human studies typically show that skeletal muscle mitochondria are altered with aging, including increased mutations in mitochondrial DNA, decreased activity of some mitochondrial enzymes, altered respiration with reduced maximal capacity at least in sedentary individuals, and reduced total mitochondrial content with increased morphological changes. However, there has been much controversy over measurements of mitochondrial energy production, which may largely be explained by differences in approach and by whether physical activity is controlled for. These changes may in turn alter mitochondrial dynamics, such as fusion and fission rates, and mitochondrially induced apoptosis, which may also lead to net muscle fiber loss and age-related sarcopenia. Fortunately, strategies such as exercise and caloric restriction that reduce oxidative damage also improve mitochondrial function. While these strategies may not completely prevent the primary effects of aging, they may help to attenuate the rate of decline."


Towards Functional Blood Vessels Grown From Fat Cells

Another of the numerous different efforts to build blood vessels from a patient's own cells: "Researchers have grown small blood vessels in a lab using stem cells from fat gathered through liposuction. Such cultured blood vessels might someday play a role in transplant operations, including heart bypass surgery. ... Many more steps are involved before heart surgery patients can benefit from this technique. ... First, we will need to make a fully functional vessel. Ours works, but does not yet achieve physiological mechanical properties. [Then] we will need to show that stem cells obtained from old, sick people can also be used to make a functional vessel and that this works in an animal model. ... All in all, [we] are still five to 10 years away from seeing this being tested in people. ... For the study, researchers using liposuction extracted adult stem cells from fat and turned them into smooth muscle cells. Adult stem cells are considered to be undifferentiated, which means they hold the potential to morph into specialized cell types. ... The extracted cells were 'seeded' onto a very thin collagen membrane. As they multiplied, researchers rolled them into tubes with the diameter of small blood vessels (3 millimeters). In three to four weeks, they were able to grow usable blood vessels."


Archon Genomics X PRIZE Gains a Competitor

The genomics prize offered by the X PRIZE foundation is of interest to the aging research community because it aims to sequence a great deal of genetic data from centenarians:

The Archon Genomics X PRIZE [is] an incentivized prize competition that will award $10 million to the first team to rapidly, accurately and economically sequence 100 whole human genomes to a level of accuracy never before achieved. The 100 human genomes to be sequenced in this competition will be donated by 100 centenarians (ages 100 or older) from all over the world.

As noted by the press in the past few days, this prize initiative has gained an entrant:

A genome-sequencing contest announced six years ago finally has its first entrant: Life Technologies Corp.'s Ion Torrent, which on Monday said it was entering the fray. The Archon Genomics X Prize will award $10 million to the first team that sequences the complete genomes of 100 people aged 100 or older in 30 days or less, for no more than $1,000 each, and with an error rate of no more than 0.0001 percent.

No one else has been game since the contest was announced in 2006, when it would have taken 33 years and $100 million to do 100 genomes, estimates Ion Torrent founder and CEO Dr. Jonathan Rothberg. In January, the company said its Ion Proton Sequencer was ready to sequence a complete human genome in a day at a cost of $1,000.


"All the numbers work," said Rothberg. "We'll have eight Protons (sequencers) running at a dedicated facility with about a dozen people, and we'll be able to sequence up to 100 billion bases every two hours."

That raw data must be assembled into their order on the 23 human chromosomes, a task analogous to putting the pages of the New York City phone book into the right sequence. The assembly process will take Ion Torrent most of the 30 days it has under X Prize rules.


Other companies have until May 31, 2013 to enter the ring. The countdown will start on September 5, 2013, when a judge from the foundation will deliver vials containing the DNA of 100 centenarians to each sequencing team. Each will have until October 4 to determine the 100 genome sequences, with the winner determined by accuracy.

There is a certain amount of showmanship inherent in all research and technology prizes, part and parcel of attracting interest, raising funds, and educating the public, but it's hard to argue with a system that gets the job done. Research prizes, including the original X PRIZE for suborbital flight and the Methuselah Mouse Prize, have a long history of success in spurring development, accelerating fundraising, and creating a new cycle of progress in industries that were previously resting on their laurels.

A Review: Physical Activity Increases Life Expectancy

An open access review: "Physical activity reduces many major mortality risk factors including arterial hypertension, diabetes mellitus type 2, dyslipidemia, coronary heart disease, stroke, and cancer. All-cause mortality is decreased by about 30% to 35% in physically active as compared to inactive subjects. The purpose of this paper was to synthesize the literature on life expectancy in relation to physical activity. A systematic PubMed search on life expectancy in physically active and inactive individuals was performed. In addition, articles comparing life expectancy of athletes compared to that of nonathletes were reviewed. Results of 13 studies describing eight different cohorts suggest that regular physical activity is associated with an increase of life expectancy by 0.4 to 6.9 years. Eleven studies included confounding risk factors for mortality and revealed an increase in life expectancy by 0.4 to 4.2 years with regular physical activity. Eleven case control studies on life expectancy in former athletes revealed consistently greater life expectancy in aerobic endurance athletes but inconsistent results for other athletes. None of these studies considered confounding risk factors for mortality. In conclusion, while regular physical activity increases life expectancy, it remains unclear if high-intensity sports activities further increase life expectancy."


Regenerating Bone With Scaffolds and Gene Therapy

Another group working on bone regeneration: "researchers have developed an innovative scaffold material (made from collagen and nano-sized particles of hydroxyapatite) which acts as a platform to attract the body's own cells and repair bone in the damaged area using gene therapy. The cells are tricked into overproducing bone producing proteins known as BMPs, encouraging regrowth of healthy bone tissue. This is the first time these in-house synthesised nanoparticles have been used in this way and the method has potential to be applied to regenerate tissues in other parts of the body. ... Previously, synthetic bone grafts had proven successful in promoting new bone growth by infusing the scaffold material with bone producing proteins. These proteins are already clinically approved for bone repair in humans but concerns exist that the high doses of protein required in clinical treatments may potentially have negative side effects for the patient such as increasing the risk of cancer. Other existing gene therapies use viral methods which also carry risks. By stimulating the body to produce the bone-producing protein itself, using non-viral methods these negative side effects can be avoided and bone tissue growth is promoted efficiently and safely."


Biochemistry (Moscow)'s Issue on Programmed Aging

Leonid Gavrilov was kind enough to point the Gerontology Research Group list in the direction of a recent open access issue of Biochemistry (Moscow). It's in English and the focus is on what the editors call "phenoptosis," a term that means programmed aging.

Some debate continues within the scientific community over the degree to which aging is programmed, which aspects of aging are programmed, and whether it is fair to call the body's characteristic responses to accumulated stochastic damage a form of programmed aging. Patterns of gene expression clearly change in fairly defined ways with aging, for example, and it is well known that stem cell populations decline and become less active - but is that just a reaction to levels of damage, or something else? This feeds into discussion over strategy when it comes to how to approach development of therapies for aging. Is it sufficient to repair all cellular and molecular damage caused by the operation of metabolism, because all forms of programmed aging are just reaction to that damage? Or even after researchers realize the SENS vision of rejuvenation biotechnology, would they then have to build further genetic therapies to block forms of decline that proceed independently of damage? From my view of what is known, I think the evidence leans more towards the former than the latter situation - and either way, we should still be working to realize rejuvenation biotechnology.

In any case here is an excerpt from the open access papers in Biochemistry (Moscow) Volume 77(7):

What Is "Phenoptosis" and How to Fight It?

Aging of an organism can be defined as a balanced decay of many physiological functions with age, leading to gradually increasing risk of death. The key question is: what is the cause of such a decay of body functions? Two main views on this problem have been competing in biology for a long time - an optimistic and a pessimistic one. The first approach believes aging to be the final stage of our ontogenetic program; this assumption implies the possibility of canceling aging by switching off this stage. The second approach considers aging to be an inevitable result of the functioning of a complex living system: the accumulation of errors and damage in its biomolecules, depletion of "life force", operation of certain genes that used to be originally useful but became harmful with age, etc.

It is obvious that if the pessimistic hypothesis is true, then any attempts to fight the process of aging are doomed to failure: all of us are destined to get broken like an old car. One of the leading gerontologists of the XX century, Alex Comfort, stated though that it is difficult to believe a horse and a carriage age in the same way. Nevertheless, the majority of gerontologists still oppose the theory of programmed aging. It is only very recently that certain data have been obtained providing direct support for the optimistic concept. These data allow us to understand how these age-activated biochemical mechanisms of the decay of body functions might have appeared in the course of evolution.

Interestingly, this is the exact opposite of the way I see the situation. We are actually in a far better situation as the damaged car than as an entity that undergoes programmed aging. If the SENS view and the reliability theory view of damage as the source of aging are correct, then we already well understand how to fix things: we have a detailed list of the damage modes, and a detailed list of plans to deal with them. When it comes to programmed aging, however, there is nothing in the field that even begins to amount to that level of clarity. It's exactly the same problem as for attempts to slow aging through genetic and metabolic manipulation: it requires understanding and safely producing new long-term working states in human metabolism - an undertaking of massive proportions. In contrast the just-repair-the-damage approach requires that researchers revert known age-related changes in human metabolism to restore it to the state it held when young. No new working state, but rather keep the metabolism that is already known to work and repair it every so often.

But you should peruse the whole issue: many interesting arguments are put forward.

Assessing mTOR Signaling in Human Aging

The target of rapamycin (TOR) gene is widely studied by researchers working on the mechanisms of aging and enhanced longevity provided by calorie restriction. Here a team pull in more data from human populations: "Interventions which inhibit TOR activity (including rapamycin and caloric restriction) lead to downstream gene expression changes and increased lifespan in laboratory models. However, the role of mTOR signaling in human aging is unclear. We tested the expression of mTOR-related transcripts in two independent study cohorts; the InCHIANTI population study of aging and the San Antonio Family Heart Study (SAFHS). ... 8 genes were robustly associated with age in both cohorts. Genes involved in insulin signaling (PTEN, PI3K, PDK1), ribosomal biogenesis (S6K), lipid metabolism (SREBF1), cellular apoptosis (SGK1), angiogenesis (VEGFB), insulin production and sensitivity (FOXO), cellular stress response (HIF1A) and cytoskeletal remodeling (PKC) were inversely correlated with age, whereas genes relating to inhibition of ribosomal components (4EBP1) and inflammatory mediators (STAT3) were positively associated with age in one or both datasets. We conclude that the expression of mTOR-related transcripts is associated with advancing age in humans. Changes seen are broadly similar to mTOR inhibition interventions associated with increased lifespan in animals. Work is needed to establish whether these changes are predictive of human longevity and whether further mTOR inhibition would be beneficial in older people." It is worth recalling that we humans are unusually long-lived for mammals of our size; it is certainly possible that we evolved to consistently use some of the same mechanisms that are only turned on with calorie restriction in smaller mammals.


Modifying Old Heart Stem Cells to Boost Regenerative Capacity

The stem cell research community is increasingly headed in the direction of finding ways to reverse or work around the age-related decline in regenerative capacity, driven by changes in stem cells and their niches: "Since patients with heart failure are normally elderly, their cardiac stem cells aren't very healthy. We modified these biopsied stem cells and made them healthier. It is like turning back the clock so these cells can thrive again. ... Modified human stem cells helped the signaling and structure of the heart cells, which were biopsied from elderly patients. Researchers modified the stem cells in the laboratory with PIM-1, a protein that promotes cell survival and growth. Cells were rejuvenated when the modified stem cells enhanced activity of an enzyme called telomerase, which elongates telomere length. Telomeres are 'caps' on the ends of chromosomes that facilitate cell replication. Aging and disease results when telomeres break off. ... There is no doubt that stem cells can be used to counter the aging process of cardiac cells caused by telomere degradation. ... The technique increased telomere length and activity, as well as increasing cardiac stem cell proliferation, all vital steps in combating heart failure. While human cells were used, the research was limited to the laboratory. Researchers have tested the technique in mice and pigs and found that telomere lengthening leads to new heart tissue growth in just four weeks. ... Modifying aged human cardiac cells from elderly patients adds to the cell's ability to regenerate damaged heart muscle, making stem cell engineering a viable option."


A Database of Genes Related to Calorie Restriction

The family of sites created by researcher João Pedro de Magalhães and colleagues has grown to include a number of interesting resources, such as the AnAge database of life span information for long-lived species, and a list of people and companies working on aging or longevity science. The latest addition is GenDR, a resource for genes associated with longevity induced through calorie restriction:

Dietary restriction (DR), limiting nutrient intake from diet without causing malnutrition, retards age-related degeneration and extends lifespan in multiple organisms. DR induces multiple changes, yet its underlying mechanisms remain poorly understood. To facilitate research on the genetic and molecular mechanisms of DR-induced life-extension, we developed GenDR, a database of genes associated with DR. GenDR includes two datasets: 1) genes inferred from experiments in model organisms in which genetic manipulations cancel out or disrupt the life-extending effects of DR; 2) genes robustly altered due to DR, derived from a meta-analysis of microarray DR studies in mammals.

Understanding the genetic basis of DR is of great importance not only to the biology of ageing but to understand how diet can influence ageing, longevity, health and age-related diseases. Pharmaceutical interventions that target DR-associated genes are also an emerging area with huge potential. For more information on DR and its potential, please refer to a recent review.

While you are browsing, you might consider following one of the header links through to the Digital Ageing Atlas, which is another interesting resource database:

The Digital Ageing Atlas is a portal of changes covering different biological levels. There are currently portals for both humans and mice. The idea is to integrate molecular, physiological and pathological age-related data and create an interactive portal that serves as the first centralised collection of ageing changes and pathologies.

There is much that could be done to expand upon these databases and the sites and tools that present the data, but I think we'll see that happen in the years ahead. The trend is definitely towards open access to scientific knowledge, and a part of that open access will be dedicated tools and presentation layers that make searching for information and learning an easier prospect.

Enhanced Energy Metabolism Contributes to Extended Lifespan Through Calorie Restriction

Here is an open access paper that looks at some of the mechanisms of calorie restriction in nematode worms - and you'll note that PEPCK-C manipulation, shown to extend life and improve health in mice, also works in the same way in this lower species: "Caloric restriction (CR) markedly extends lifespan and improves the health of a broad number of species. Energy metabolism fundamentally contributes to the beneficial effects of CR, but the underlying mechanisms that are responsible for this effect remain enigmatic. A multidisciplinary approach that involves quantitative proteomics, immunochemistry, metabolic quantification and lifespan analysis was used to determine how CR, which occurs in the C. elegans eat-2 mutants, modifies energy metabolism of the worm, and whether the observed modifications contribute to the CR-mediated physiological responses. A switch to fatty acid metabolism as an energy source and an enhanced rate of energy metabolism by eat-2 mutant nematodes was detected. Lifespan analyses validated the important role of these previously unknown alterations of energy metabolism in the CR-mediated longevity of nematodes. As observed in mice, the over-expression of the gene for the nematode analogue of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C) caused a marked extension of lifespan in C. elegans, presumably by enhancing energy metabolism ... We conclude that an increase, not a decrease in fuel consumption, via an accelerated oxidation of fuels in the TCA cycle is involved in lifespan regulation; this mechanism may be conserved across phylogeny."


Identifying Genetic Changes that Reduce Stem Cell Aging

Here researchers note a genetic alteration that reduces age-related changes in one stem cell population: "Upon aging, the number of hematopoietic stem cells (HSCs) in the bone marrow increases while their repopulation potential declines. Moreover, aged HSCs exhibit lineage bias in reconstitution experiments with an inclination towards myeloid at the expense of lymphoid potential. The adaptor protein Lnk is an important negative regulator of HSC homeostasis, as Lnk deficiency is associated with a 10-fold increase in HSC numbers in young mice. However, the age-related increase in functional HSC numbers found in wild type (WT) HSCs was not observed in Lnk-deficient animals. Importantly, HSCs from aged Lnk null mice possess greatly enhanced self-renewal capacity and diminished exhaustion, as evidenced by serial transplant experiments. In addition, Lnk deficiency ameliorates the aging-associated lineage bias. Transcriptome analysis revealed that WT and Lnk-deficient HSCs share many aging-related changes in gene expression patterns. Nonetheless, Lnk null HSCs displayed altered expression of components in select signaling pathways with potential involvement in HSC self-renewal and aging. Taken together, these results suggest that loss of Lnk partially mitigates age-related HSC alterations."


Video from the Genetics of Aging and Longevity Conference

The Science for Life Extension Foundation helped organize the 2nd International conference on the Genetics of Aging and Longevity, held back in April in Moscow. Thanks to the Foundation staff, video from the conference is starting to make its way to a YouTube channel. Here are a couple of the videos already posted; you might want to keep an open eye for others as they arrive.

Dr. Bartke reported the first evidence that mutation of a single gene can significantly extend lifespan in a mammal, and [has] extensively characterized the phenotype of long-lived Ames dwarf mice, identifying several mechanisms that are likely to explain or contribute to their delayed aging and greatly prolonged longevity.
[The] research of Dr. Reis focuses on the molecular genetics of longevity and age-associated diseases, using both previously defined mutations and gene mapping. He managed to extend the lifespan of a nematode worm, C.elegans, 10-fold by only one mutation in the age-1 gene.

Adding More Data to the Role of Nuclear DNA Damage in Aging

We accumulate random nuclear DNA damage - mutations - as we age. This is understood to increase the risk of cancer, as the more mutations that occur the greater the chance that one will be of the rare type that can spawn a cancer, but there is some debate over the degree to which nuclear DNA damage contributes to aging itself. Here researchers add some more data to the picture: "Hundreds of mutations exist in leukemia cells at the time of diagnosis, but nearly all occur randomly as a part of normal aging and are not related to cancer, new research shows. [Researchers] have found that even in healthy people, stem cells in the blood routinely accumulate new mutations over the course of a person's lifetime. And their research shows that in many cases only two or three additional genetic changes are required to transform a normal blood cell already dotted with mutations into acute myeloid leukemia (AML). ... The study is the first to investigate how often mutations typically develop in healthy stem cells in the blood. ... In recent years, [researchers] have sequenced the genomes of 200 patients with AML to try to understand the mutations at the root of the disease. Without fail, each patient's leukemia cells held hundreds of mutations, posing a conundrum for scientists, who have long believed that all the mutations in a cancer cell are likely to be important for the disease to progress. ... But we knew all of these mutations couldn't be important. It didn't make any sense to us that so many mutations were present in all the cells in the tumor. ... Every person has about 10,000 blood stem cells in their bone marrow, and the researchers found that each stem cell acquires about 10 mutations over the course of a year. By age 50, a person has accumulated nearly 500 mutations in every blood stem cell. ... Mutations are known to develop in cells as we age, but no one had any idea how many mutations occur in blood stem cells and how frequently they develop. These random, background mutations occur during cell division and are unrelated to cancer. Our DNA can tolerate a huge number of these hits without any negative consequences. But if a cancer-initiating event occurs in one of these stem cells, it captures the genetic history of that cell, including the earlier mutations, and drives leukemia to develop. ... scientists were surprised to see that the total number of mutations varied by age, not by whether a patient had leukemia. Thus, a healthy person in his 40s had just about the same number of mutations in his blood stem cells as a leukemia patient of the same age had in his cancer cells."


Possible Early Antibody Therapy for Alzheimer's Disease

From the MIT Technology Review: "Alzheimer's patients given a drug that is already used to treat immune disorders saw their condition stabilize in a small study presented at a conference this week. Study participants were given the compound - known as intravenous Ig, or IVIg - for three years. During this period, they showed no signs of further cognitive decline or memory loss. ... All participants in the study had mild to moderate Alzheimer's disease. Only four received the optimal dose of IVIg over three years. These patients showed no decline from their baseline state in cognition, memory, daily functioning, or mood - all expected effects of the disease. Patients who initially received a placebo but were later switched to IVIg treatment declined more slowly while receiving the drug. IVIg [contains] a mixture of antibodies isolated from the pooled plasma of blood donated by healthy people. The assumption is that this blood by-product contains antibodies from the healthy donors that attack the damaged proteins in Alzheimer's patients. ... such results [should] inspire a large number of scientific studies aimed at identifying the functional ingredients in the immune mixture, so that others could potentially develop a synthetic form. ... I really do hope that it turns out to work, because then it gives a good platform to start finding out what components are in there, What is it in the IVIg - is it selective antibodies against beta-amyloid, against tau, or something else?"


More Press for the 2045 Initiative

You'll no doubt recall the 2045 initiative backed by an enthusiastic high net worth Russian individual, which appears so far to be the opening stages of a serious long-term effort to convert a fraction of that net worth into the technologies needed for artificial, non-biological bodies capable of indefinitely supporting a human brain - and after that to move on to brain emulation and mind uploading.

I commented on this vision last year:

To my eyes, the most interesting aspect of this Russia 2045 initiative is that, unlike any other serious proposal I'm aware of, their focus is on getting out of biology and into machine bodies as rapidly as possible. ... In essence, this is a course to throw away as much of the body as possible as soon as possible - a path based on a different set of preconceptions about difficulty and efficiency on the road leading to an artificial brain hosting a once-biological human mind.

I'm of the opinion that this is not the most optimal path towards the defeat of aging, based on my understanding of the relative difficulty of building a full-featured neural interface and life support system for the brain versus realizing rejuvenation biotechnology that can repair the biological chassis we have now - even leaving aside the issue that an uploaded or emulated copy of your mind is just a copy of you, not you. In the long run we will all be wholly artificial, of course, but it seems premature to be aiming for that now versus after the advent of molecular nanotechnology and the capacity to build functional replacements for biological components (e.g. blood cells, brain cells, and so forth) that are better than the original. It is, however, very important for the general future of engineered longevity to have a diversity of approaches, disagreement, and enthusiastic people with resources and vision. At the very least, in a world in which artificial bodies are being developed with the stated goal of preventing people from aging to death, it becomes that much easier to gather support for work on the biotechnologies that can repair the damage of aging.

In any case, the 2045 Initiative is back in the press again, and here are a couple of items:

Russian Mogul to 'Forbes' Billionaires: Limitless Lifespans Can Be Yours

First up is the development of robots that can be controlled by the human mind. After that, and ideally within 10 years, Itskov wants to develop robots that can actually host a flesh-and-blood human brain, via surgical transplant. In twenty years time, things get even more interesting: Itskov anticipates "uploading" the contents of the human brain into a robot, yielding eternal life via artificial body. By 2045, he'd like to replace those 'bots entirely - with holograms. Since February, Itskov has stayed plenty busy working on his "Avatar" plan ... With a lab of scientists reportedly already working on the program in Russia, Itskov has now branched out to the U.S, with plans to open a San Francisco office this summer and host a futurity conference - called Global Future Congress - in New York later this year.

His next step: Itskov has published an open letter to the world's richest people, urging them to back the initiative - and consider volunteering themselves as potential avatars. "I urge you to take note of the vital importance of funding scientific development in the field of cybernetic immortality and the artificial body. Such research has the potential to free you, as well as the majority of all people on our planet, from disease, old age and even death."

Billionaires: Russian Mogul Wants to Upload Your Brains Into Immortality

Earlier this year, a Russian media mogul named Dmitry Itskov formally announced his intention to disembody our conscious minds and upload them to a hologram - an avatar - by 2045. In other words he outlined a plan to achieve immortality, removing the human mind from the physical constraints presented by the biological human body. He was serious. And now, in a letter to the members of the Forbes World's Billionaire's List, he's offering up that immortality to the world's 1,266 richest people.


"Currently you invest in business projects that will bring you yet another billion," Itskov writes. "You also have the ability to finance the extension of your own life up to immortality. Our civilization has come very close to the creation of such technologies: it's not a science fiction fantasy. It is in your power to make sure that this goal will be achieved in your lifetime."

This last note is absolutely true with regard to the SENS vision of rejuvenation biotechnologies as well: the wealthiest people in the world have it in their grasp to build a way out of aging for everyone, given that the baseline medical technologies would probably cost in the ballpark of a billion dollars and ten years to demonstrate in laboratory animals. Yet so far, they are not showing much interest - wealth doesn't grant vision, sadly, so we should all be pleased when a high net worth visionary does turn up, even if he's not working to our own favored plan of action.

Rapamycin Versus Macular Degeneration

A commentary on testing rapamycin as a therapy for age-related macular degeneration (AMD): "Although neovascular AMD only accounts for less than 15% of the overall age-related macular degeneration, it is responsible for over 80 percent of the severe vision loss cases. ... It was reported in 2004 that rapamycin (trade name sirolimus) treatment significantly reduced the extent of neovascularization [induced] in adult mice ... In an advance online publication this year [Kolosova et al] presented exciting results that rapamycin could actually prevent AMD-like retinopathy in an aging rat model that more closely resembles human AMD pathology. They investigated the effect of rapamycin on spontaneous retinopathy in senescence- accelerated OXYS rats. OXYS rats were treated orally with either 0.1 or 0.5 mg/kg rapamycin, which was given together with food. Rapamycin was found in a dose-dependent manner to reduce the incidence and severity of retinopathy, and attenuated AMD disease progression. Some histological abnormalities associated with retinopathy were notably reduced ... significantly, rapamycin prevented destruction of ganglionar neurons in the retina. Rapamycin did not exert any adverse effects on the retina in control disease-free Wistar rats, suggesting that it is safe."


Testing Blanket Blood Pressure Medication in Older People

What happens if everyone in later years regularly takes common blood pressure and cholesterol medications, even if healthy? Researchers have been running trials: "Results of a randomised trial [show] that a four-component Polypill given to people aged 50 and over to reduce their risk of heart attack and stroke, the most common causes of death worldwide, achieved large reductions in blood cholesterol and blood pressure, the main causes of these two diseases. ... The results observed in the trials had been accurately predicted in an earlier paper [before] any Polypill had been made. The Polypill, a tri-layered tablet, contains three blood pressure lowering medicines and a statin for lowering cholesterol. This was given to people without a history of cardiovascular disease aged 50 or more. They experienced a 12 percent reduction in blood pressure and a 39 percent reduction in LDL cholesterol (the 'harmful' cholesterol), achieving levels typical of people aged 20 years. ... The health implications of our results are large. If people took the Polypill from age 50, an estimated 28 percent would benefit by avoiding or delaying a heart attack or stroke during their lifetime; on average, those who benefit would gain 11 years of life without a heart attack or stroke. ... This is the first trial in people selected on the basis of age alone without the need for a medical examination or tests - setting the scene for the prevention of first heart attacks and strokes in the general population without requiring a medical examination or special tests. ... Our trial shows that the predicted effects of the Polypill can be achieved in practice. The expected impact on preventing what is now the world's leading cause of death is large - about a two-thirds reduction in heart attacks and strokes."


Chimeras for Xenotransplantation

Progress in decellularization is one of the reasons that xenotransplantation of animal organs into people may become a going concern. Decellularization is the chemical removal of cells from a donor organ, leaving behind the intricate structure of the extracellular matrix and chemical cues that instruct cells how to populate the organ; there have been some successes in past years in using decellularization to form and transplant comparatively simple structures, such as tracheas. It should be possible to take a pig's heart, strip out the of all pig cells, and repopulate it with a human recipient's cells; porcine and human organs are similar enough that the use of pigs as an organ source has been considered for some time. Adding decellularization to the technology platform may provide a way to establish a low-cost source of donor organs on demand that will arrive prior to the ability to grow entire complex organs from a patient's own cells.

Another possible approach is outlined in a recent Signals post, which is to grow actual human organs in animals:

Hiromitsu Nakauchi has a vision for regenerative medicine. In this vision, he sees a renewable source of human organs for transplantation that are grown within the bodies of farm animals. Here's how it works: pluripotent stem cells would be injected into an early animal embryo that is not capable of generating a specific organ. As the animal embryo develops, the human pluripotent cells would differentiate into the missing organ. This human organ would then be removed and transplanted into a patient.


In 2010, Nakauchi published a report in Cell describing the generation of a rat pancreas in a mouse ... Normal rat pluripotent stem cells were injected into a mouse embryo in which a key gene involved in pancreas development had been deleted (leaving the mouse incapable of forming a pancreas) and indeed rat pluripotent stem cells were able to generate a functioning rat pancreas in the mouse.

This month in the American Journal of Pathology, Nakauchi's group published the generation of kidney from induced pluripotent stem cells in a mouse lacking a key kidney developmental gene using the same technology.

At the ISSCR meeting earlier this month in Yokohama, Japan, Nakauchi described his work translating this technology to large farm animals. Using two transgenic pig lines, normal, fluorescent orange pig pluripotent stem cells were injected into a pancreas incompetent pig embryo. The result: a chimeric pig with a fluorescent orange pancreas.

In Japan (and many other countries), pluripotent stem cells cannot legally be injected into another embryo for the generation of chimeras, thus the long-term goal of generating interspecies chimeras between human and pig could not be tested. Nakauchi told the audience that he would need collaborators from other countries to perform these experiments.

This seems like a promising line of work, though it remains to be seen how well it competes with the evident enthusiasm in the research community for direct construction of new organs from a patient's cells. One might suspect that is one of those applications of science that is doomed to be tied up in knee-jerk politics and regulation, however, attacked by people who have few objections to farming gene-engineered animals for meat as soon as it starts to make any headway.

Nanoscale Scaffolds and Stem Cells for Cartilage Repair

Via EurekAlert!: "tissue engineers have used tiny, artificial fiber scaffolds thousands of times smaller than a human hair to help coax stem cells into developing into cartilage, the shock-absorbing lining of elbows and knees that often wears thin from injury or age. ... Rather than just patching the problem with short-term fixes, like surgical procedures such as microfracture, we're building a temporary template that mimics the cartilage cell's natural environment, and taking advantage of nature's signals to biologically repair cartilage damage. ... Unlike skin, cartilage can't repair itself when damaged. For the last decade, [researchers have] been trying to better understand the development and growth of cartilage cells called chondrocytes, while also trying to build scaffolding that mimics the cartilage cell environment and generates new cartilage tissue. This environment is a 3-dimensional mix of protein fibers and gel that provides support to connective tissue throughout the body, as well as physical and biological cues for cells to grow and differentiate. In the laboratory, the researchers created a nanofiber-based network using a process called electrospinning, which entails shooting a polymer stream onto a charged platform, and added chondroitin sulfate [to] serve as a growth trigger. After characterizing the fibers, they made a number of different scaffolds from either spun polymer or spun polymer plus chondroitin. They then used goat bone marrow-derived stem cells (a widely used model) and seeded them in various scaffolds to see how stem cells responded to the material. ... compared to cells growing without scaffold, these cells developed into more voluminous, cartilage-like tissue. ... The investigators then tested their system in an animal model. They implanted the nanofiber scaffolds into damaged cartilage in the knees of rats, and compared the results to damaged cartilage in knees left alone. They found that the use of the nanofiber scaffolds improved tissue development and repair as measured by the production of collagen, a component of cartilage. The nanofiber scaffolds resulted in greater production of a more durable type of collagen, which is usually lacking in surgically repaired cartilage tissue."


Linking Oxidative Stress With Age-Related Immune Decline

Mitochondrial damage is one of the reasons that levels of damaging oxidative compounds rise in the body with age - known as oxidative stress. At the level of molecular machinery, having reactive molecules flying around in large numbers will cause important mechanisms to break down more often. It is generally thought that increased oxidative stress contributes to a range of dysfunctions, and here researchers link it with immune system decline: "Aging is known to affect immune function, a phenomenon known as immunosenescence ... Our study has uncovered several ways in which aging can worsen the body's overall ability to mount an effective immune response. ... All cells generate chemicals called free radicals as a normal part of metabolism. These highly reactive, unstable molecules can readily damage proteins, lipids and other cellular components ... Cells keep 'oxidative stress' in check by producing several enzymes that are scavengers of free radicals. But in aging, increased production of free radicals coupled with cells' decreased production of antioxidant enzymes cause a buildup of damaged proteins and other molecules that can be toxic to cells. The current study is the first to examine whether age-related oxidative stress compromises the function of a type of immune cell called dendritic cells. ... When you are exposed to viruses or bacteria, these cells engulf the pathogens and present them to the immune system ... [Researchers] isolated dendritic cells from aging mice and found that oxidation-damaged proteins had accumulated in those cells and had caused harmful effects. For example, oxidatively modified proteins hampered the function of endosomes, the cell's organelle where pathogens are inactivated. When the mice were injected with a potent antioxidant in the abdominal cavity daily for two weeks, some of the effects of oxidative stress were reversed. This finding has implications for designing vaccines or therapies for humans, especially the elderly, whose weakened immune systems increase their susceptibility to infections and cancer, and reduces vaccine effectiveness. ... Many elderly people respond very poorly to vaccination, so perhaps a cycle of therapy with antioxidants before vaccination might improve their immune response to vaccines."


Calorie Restriction Increases Neurotransmitter Levels in Flies

Calorie restriction improves pretty much every established measure of health and slows pretty much every established measure of aging in a wide range of species, our own included. If people cared more about longevity, then everyone would be a calorie restriction practitioner - no presently available medical technology can do as much for a basically healthy individual as simply eating less while still obtaining all necessary micronutrients. As it is, however, only a comparatively small number of people seem able to evaluate future benefits to health and life expectancy as being more rewarding than the consumption of additional calories here and now. Which is too bad, but that's the human condition for you.

Research into the biochemical mechanisms of calorie restriction, its relationship with our variable metabolism, and the way in which variations in metabolism determine natural longevity all continues apace. There has been a steady stream of new discoveries over the past ten years, a growing catalog of specific ways in which ingesting fewer calories improves the operating biology of a range of species. Here is an interesting new addition to that list:

Flies on the low-calorie diet showed a 100 percent increase in the release of brain chemicals, which are called neurotransmitters, from their neurons. These chemicals carry signals from one nerve cell to another across gaps called synapses. The brain has millions of synapses that are believed to be the critical structures required for normal brain function. Diseases such as Parkinson's harm them irreparably.

Furthermore the chemicals were secreted at critical locations. "Diet restriction increased the neurotransmitters released at synapses called neuromuscular junctions," Dr. Eaton said. "These synapses, which form on muscle, transmit nerve impulses from the brain to muscles, resulting in movement. If neuromuscular junctions degenerate, resulting in the release of less neurotransmitter, then muscle activity diminishes. This is observed in diseases such as myasthenia gravis and amyotrophic lateral sclerosis (ALS)."

The observation that diet could directly affect the amount of neurotransmitter secreted by the neuron was a novel observation that had not been seen previously. "People have seen that diet has effects on the nervous system, but the nuts and bolts of what it is doing to neurons have not been established," Dr. Eaton said. "We believe we have shown a novel and important effect."

It remains to be seen how this will translate into mammals - there doesn't appear to be a great deal of literature out there on calorie restriction and neurotransmitters, and what does exist may or may not be particularly relevant to this finding, as it seems to largely focus on the brain itself rather than its connections to other bodily systems. There are a lot of different neurotransmitters, and a lot of locations in the nervous system where they can behave in different ways or produce different results.

Alcor Donates to Brain Preservation Prize, is Declined

These things happen: "How well does cryopreservation (with current methods) work? Is the process sufficiently preserving personal identity-critical information stored in the brain? Are there any alternatives that might be as good or better? Although the Alcor Library already contains evidence that, under good conditions, we are preserving neural connections (the totality of which is now sometimes being referred to as the 'connectome'), more evidence is desirable. The Brain Preservation Foundation is offering a $100,000+ Brain Preservation Technology Prize in order to stimulate the scientific evaluation of such technologies as cryopreservation and chemopreservation (aldehyde or other chemical fixation followed by embedding in solid resin). The goal of the prize is to lead to 'the development of an inexpensive and reliable hospital surgical procedure which verifiably preserves the structural connectivity of 99.9% of the synapses in a human brain if administered rapidly after biological death.' ... A few days ago, Alcor announced that it would contribute $10,000 to the Brain Preservation Foundation toward the costs of testing both cryopreservation and chemopreservation. The Foundation has declined our donation because of concerns that it might be perceived as influencing the judges' decisions. Even though Alcor was not a competitor for the prize, we can understand the Foundation's concern. We will instead look for other ways to validate existing cryopreservation methods, as well as continue to improve them."


A Profile of Kenneth Hayworth, Brain Preservation Prize Founder

From the Chronicle of Higher Education: "By 2110, Hayworth predicts, mind uploading - the transfer of a biological brain to a silicon-based operating system - will be as common as laser eye surgery is today. ... While a graduate student at the University of Southern California, he built a machine in his garage that changed the way brain tissue is cut and imaged in electron microscopes. The combination of technical smarts and entrepreneurial gumption earned him a grant from the McKnight Endowment Fund for Neuroscience, a subsidiary of the McKnight Foundation, and an invitation to Harvard, where he stayed, on a postdoctoral fellowship, until April. To understand why Hayworth wants to plastinate his own brain you have to understand his field - connectomics, a new branch of neuroscience. A connectome is a complete map of a brain's neural circuitry. ... He looks at the growth of connectomics - especially advances in brain preservation, tissue imaging, and computer simulations of neural networks - and sees something else: a cure for death. In a new paper in the International Journal of Machine Consciousness, he argues that mind uploading is an 'enormous engineering challenge' but one that can be accomplished without 'radically new science and technologies.' ... to Hayworth, science is about overturning expectations: 'If 100 years ago someone said that we'd have satellites in orbit and little boxes on our desks that can communicate across the world, they would have sounded very outlandish.' One hundred years from now, he believes, our descendants will not understand how so many of us failed for so long to embrace immortality. In an unpublished essay, 'Killed by Bad Philosophy,' he writes, 'Our grandchildren will say that we died not because of heart disease, cancer, or stroke, but instead that we died pathetically out of ignorance and superstition' - by which he means the belief that there is something fundamentally unknowable about consciousness, and that therefore it can never be replicated on a computer."


Does Anyone Really Care About Living Longer?

One of the little things that's quite clear from even a brief examination of human nature:

Regular exercise can extend life, but 90% of humanity would rather die than submit to a daily workout. ... Last week, an international conference in Brazil heard from scientist Professor Frank Booth, who gave a talk about how the lack of physical activity can be shown to significantly reduce lifespan. The current USA guidelines for physical activity are 30 minutes a day for somebody over 20 years old, but he reported that over 90% of people do not do this amount and are shortening their life as a result.

Human psychology is hardwired to discount future rewards, a thing called time preference. The future reward that is an increased chance of being alive in sixty years tends to have a lower value for most people than, say, substituting a video game or nap for exercise right now. Sad but true. So there is more gaming, less exercise, and shorter lives on balance. Time preference is pretty good in the environment in which we evolved, but becomes increasingly less helpful the more civilized and technologically enabled that environment becomes.

So equally, if low-cost life-extending therapies existed - along the lines of the rejuvenation biotechnologies proposed by the SENS Foundation - and not using them was viewed as something akin to failing to brush your teeth, then many of the same people who skip exercise would make the effort to head to the clinic every few years and thereby live longer. Social pressure also enters into value judgments, a cost to be measured alongside others. It is entirely possible that people of future years will be using longevity medicine for reasons that have little to do with their own longevity; after all, they will still be operating with the same time preference as we do. Being alive sixty years in the future has a small value for the average human being.

This is one of the reasons why so very many people make themselves more sick than they have to be, and die younger than they might have. They didn't take care of themselves, despite knowing that they could do a better job. Separately, but a part of the same pattern of psychology, today there exists the realistic prospect of building actual, working means of rejuvenating the old. The path to achieving that end is just about as clear, straightforward, and well defined as medical research can ever be. We know what needs to be fixed, and there are numerous proposals for ways to fix it. But the public at large is not yet rallying to this cause.

A cynic might say that they never will, and cite human nature as outlined above. Fortunately, it isn't necessary to persuade everyone. Even a sizable minority will be enough. We can point to successful minority support for research and development in many age-related diseases, for example - large research communities work on the common conditions of aging, despite that fact that everything said about aging and the value of life in the future applies there. There are ways around the basic problem of time preference as it applies to raising support for the medicine of human longevity. We just have to keep working away at it, just like the pioneers who built successful research communities for cancer, heart disease, dementia, and many other conditions that plague the old.

An Example of an Early Targeted Cancer Therapy

One of the ways in which new means of targeting therapies to specific cells in the body - such as cancer cells - will arrive in the clinic more rapidly is for their developers to use existing approved drugs. That isn't necessarily the way to build objectively better therapies, but it will cost far less to run the regulatory gauntlet: "researchers have developed a novel system to simultaneously deliver a sustained dose of both an immune-system booster and a chemical to counter the cancer's secretions, resulting in a powerful therapy that, in mice, delayed tumor growth, sent tumors into remission and dramatically increased survival rates. The new immunotherapy incorporates well-studied drugs, but delivers them using nanolipogels (NLGs), a new drug transport technology the researchers designed. The NLGs are nanoscale, hollow, biodegradable spheres, each one capable of accommodating large quantities of chemically diverse molecules. The spheres appear to accumulate in the leaky vasculature, or blood vessels, of tumors, releasing their cargo in a controlled, sustained fashion as the spherule walls and scaffolding break down in the bloodstream. For the recent experiments, the NLGs contained two components: an inhibitor drug that counters a particularly potent cancer defense called transforming growth factor-β (TGF-β), and interleukin-2 (IL-2), a protein that rallies immune systems to respond to localized threats. ... The current study targeted both primary melanomas and melanomas that have spread to the lung, demonstrating promising results with a cancer that is well-suited to immunotherapy and for which radiation, chemotherapy and surgery tend to prove unsuccessful, particularly when metastatic." It's worth remembering that the medicine presently available in the clinic is not really available because it is better for patients, but rather because it is better at getting past regulatory hurdles - these two properties sometimes overlap, but are not the same at all.


Progress in Building Muscle Tissue For Transplant

Researchers are making progress towards building useful muscle tissue from scratch, suitable for transplant: "exercise is a key step in building a muscle-like implant in the lab with the potential to repair muscle damage from injury or disease. In mice, these implants successfully prompt the regeneration and repair of damaged or lost muscle tissue, resulting in significant functional improvement. ... For the study, small samples of muscle tissue from rats and mice were processed to extract cells, which were then multiplied in the lab. The cells, at a rate of 1 million per square centimeter, were placed onto strips of a natural biological material. The material, derived from pig bladder with all cells removed, is known to be compatible with the body. Next, the strips were placed in a computer-controlled device that slowly expands and contracts - essentially 'educating' the implants on how to perform in the body. ... The next step was implanting the strips in mice with about half of a large muscle in the back (latissimus dorsi) removed to create functional impairment. While the strips are 'muscle-like' at the time of implantation, they are not yet functional. Implantation in the body [prompts] further development. ... The scientists compared four groups of mice. One group received no surgical repair. The other groups received implants prepared in one of three ways: one was not exercised before implantation, one was exercised for five to seven days, and one had extra cells added midway through the exercise process. The results showed that exercising the implants made a significant difference in both muscle development and function. ... The implant that wasn't exercised, or pre-conditioned, was able to accelerate the repair process, but recovery then stopped. On the other hand, when you exercise the implant, there is a more prolonged and extensive functional recovery. Through exercising the implant, you can increase both the rate and the magnitude of the recovery."


Trehalose Boosts Autophagy, Reduces Neurodegeneration

Trehelose is known to be involved in yeast life span, and given in the diet can extend life in nematode worms. In animals closer to we humans, it has been show to stimulate autophagy, the collection of processes by which cells recycle damaged components and remove the unwanted build-up of metabolic byproducts. More autophagy seems to be an unqualified good, and shows up as a mechanism of action by which healthy life span is extended via calorie restriction (CR), exercise, and drugs that aim to mimic some of the biochemical changes caused by CR and exercise. This all makes sense: if damaged components are removed from cells more rapidly, they have less time to cause further damage themselves. The system as a whole is better maintained. So there is some impetus in the research community to develop the means to enhance autophagy in humans.

I noticed one small portion of that line of work today - an open access study in mice that used trehalose to stimulate greater levels of autophagy, and showed a reduction in the level of degeneration expected in their brains. Like many animal studies, the mice here were engineered to develop a form of neurodegeneration comparatively rapidly, so as to provide a model for assessment of possible treatments at a lower cost:

The accumulation of insoluble proteins is a pathological hallmark of several neurodegenerative disorders. Tauopathies are caused by the dysfunction and aggregation of tau protein and an impairment of cellular protein degradation pathways may contribute to their pathogenesis. Thus, a deficiency in autophagy can cause neurodegeneration, while activation of autophagy is protective against some proteinopathies. Little is known about the role of autophagy in animal models of human tauopathy.

In the present report, we assessed the effects of autophagy stimulation by trehalose in a transgenic mouse model of tauopathy, the human mutant P301S tau mouse ... Autophagy was activated in the brain, where the number of neurons containing tau inclusions was significantly reduced, as was the amount of insoluble tau protein. This reduction in tau aggregates was associated with improved neuronal survival in the cerebral cortex and the brainstem. We also observed a decrease of p62 protein, suggesting that it may contribute to the removal of tau inclusions. ... Our findings provide direct evidence in favour of the degradation of tau aggregates by autophagy. Activation of autophagy may be worth investigating in the context of therapies for human tauopathies.

Pleasantly, the authors paid some attention as to whether providing mice with trehalose causes inadvertent calorie restriction, something that plagues the studies of incautious researchers. The effects of calorie restriction are very strong, and if your prospective treatment happens to make the mice in your study eat less - well, those mice will usually do better than their counterparts, all other things being equal. But here:

Water consumption of the three groups (no treatment, sucrose-treated and trehalose-treated) was similar. Sucrose and trehalose had no impact on the animals' weights or coat aspects, suggesting that the health of the mice was similar among the three groups.

Trehalose, Calorie Restriction, and Longevity in Yeast

You might recall that a few years ago, researchers extended life in nematode worms by feeding them trehalose. Here, scientists link normal abundances of trehalose in yeast cells with the longevity induced by calorie restriction: "Our recent investigation of how a lifespan-extending caloric restriction (CR) diet alters the metabolic history of chronologically aging yeast suggested that their longevity is programmed by the level of metabolic capacity - including trehalose biosynthesis and degradation - that yeast cells developed prior to entry into quiescence. To investigate whether trehalose homeostasis in chronologically aging yeast may play a role in longevity extension by CR, in this study we examined how single-gene-deletion mutations affecting trehalose biosynthesis and degradation impact (1) the age-related dynamics of changes in trehalose concentration; (2) yeast chronological lifespan under CR conditions; (3) the chronology of oxidative protein damage, intracellular ROS level and protein aggregation; and (4) the timeline of thermal inactivation of a protein in heat-shocked yeast cells and its subsequent reactivation in yeast returned to low temperature. Our data imply that CR extends yeast chronological lifespan in part by altering a pattern of age-related changes in trehalose concentration. We outline a model for molecular mechanisms underlying the essential role of trehalose in defining yeast longevity by modulating protein folding, misfolding, unfolding, refolding, oxidative damage, solubility, and aggregation throughout lifespan." Trehelose stimulates autophagy in higher animals, the all-important set of mechanisms that recycle damaged cell components, so one would expect it to be beneficial there as well.


Mitochondrial Haplotypes Correlate With Dementia Risk

Some mitochondrial DNA lineages are objectively better than others, as demonstrated by correlations with longevity in humans. Here is a correlation with dementia risk, which might be superficially explained by a greater ability to power fuel-hungry neurons, or greater resistance to mitochondrial damage over time: "Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be a major cause of abnormal reactive oxidative species production in AD or increase neuronal susceptibility to oxidative injury during aging. The purpose of this study was to assess the influence of mtDNA sequence variation on clinically significant cognitive impairment and dementia risk in the population-based Health, Aging, and Body Composition (Health ABC) Study. We first investigated the role of common mtDNA haplogroups and individual variants on dementia risk and 8-year change on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) among 1,631 participants of European genetic ancestry. Participants were free of dementia at baseline and incidence was determined in 273 cases from hospital and medication records over 10-12 follow-up years. Participants from haplogroup T had a statistically significant increased risk of developing dementia and haplogroup J participants experienced a statistically significant 8-year decline in 3MS, both compared with common haplogroup H. [Other variants were] associated with a significant decline in DSST score [or] 3MS score."


New Organ 100 Announced by the Methuselah Foundation

The Methuselah Foundation formally launched the New Organ initiative earlier this year: a research and technology prize aimed at speeding up tissue engineering of replacement organs. Today the Foundation announced the New Organ 100:

Today, 3,000 people will die from organ failure, many due to the lack of replacement organs. In the U.S. alone, over 100,000 are stuck on a waiting list, and many more can't even get on a list.

We need a revolution in medicine, and we need it as soon as possible.

Regenerative medicine is coming of aging. Significant breakthroughs are beginning to happen, but the funding to move the science and technology forward remains woefully inadequate.

The Methuselah Foundation is announcing today the New Organ 100 to kickstart a visible, popular movement with a singular purpose: make regenerative medicine famous to achieve whole organ manufacturing within 10 years.

We invite you to be among the initial 100 New Organizers, the seeds of the movement who each make the same pledge: give $10 a month toward raising the New Organ Prize, and ask 10 friends and family to do the same.

The goal of the New Organ Prize is simple: to stimulate progress while demonstrating the rising demand for greater R&D funding. 100% of gifts go toward growing the prize. Every gift is matched by donors to support the New Organ Fund, which funds our operations and investments in startups advancing critical technologies, such as Organovo's 3D bioprinter and Silverstone Solutions' kidney-matching software.

Lee Downing was one of the lucky ones. When he got on the waiting list for a liver transplant, it was only 4,000 people long. After his transplant in 1988, he regained his health completely. He's been actively promoting organ donation ever since, working hard to enable others to receive the git of life that he was blessed with.

And after 24 years in the trenches, he's never felt as optimistic as he does now:

"It's pretty simple. We've tried everything, and we still haven't succeeded. I believe we need a revolutionary change in our approach to transplantation, and New Organ is it. Without it, more people are going to die, and even more people are to be added to the waiting list. The New Organ Prize, where modern medicine and state-of-the-art technology merge, may be the most significant impact we can make on the current paradigm of transplantation. It's going to safe lives."

No one has ever used a prize to build a movement for social change ... until now.

Will you join us?

The Methuselah Foundation has been steadily gearing up to focus attention on the big goals in tissue engineering for some years now. It's is worth remembering that the Foundation was one of the early investors in organ printing development company Organovo, for example - and the leaders of Organovo are prominently featured as sponsors and advocates in the New Organ 100 campaign.

If you agree with the New Organ goals - tissue engineered organs in the clinic, as fast as possible - then join in, spread the word, and donate.

Discussing Rapamycin

A piece by author David Stipp gives an overview of the past few years of research into the effects of rapamycin: "The first strong evidence that a drug could slow aging in mammals came out in 2009 when scientists reported that chronically feeding doses of rapamycin to mice significantly extended their average and maximum lifespans. Yet rapamycin, a drug used to help prevent rejection of transplanted organs, causes multiple side effects in people, including elevated triglycerides and cholesterol, increasing the risk of heart disease; moderate immune suppression, perhaps increasing infection risks; and low blood platelet levels, which raises the specter of dangerous bleeding. In recent years another especially surprising and troubling side effect has come to the fore: Chronically taking large doses of rapamycin induces 'insulin insensitivity' in both rodents and humans, leading to rising blood sugar and potentially to type 2 diabetes. How do we reconcile such adverse effects with the drug's unprecedented ability to boost healthy aging and longevity, at least in mice? Some telling insights on this burning issue were recently published in two reports on rapamycin's effect on insulin and blood sugar: a mouse study that revealed a probable mechanism behind the effect and a theory paper suggesting that the purported diabetes risk has been overblown."


PGC-1alpha Versus Huntington's Disease

Via ScienceDaily: researchers "have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington's disease (HD). ... It's a lead we can vigorously pursue, not just for Huntington's disease, but also for similar neurodegenerative conditions like Parkinson's disease and maybe even Alzheimer's disease. ... In HD, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central nervous system cells. ... [Researchers] focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function. ... It's all about energy. Neurons have a constant, high demand for it. They're always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity. ... the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha, [and] elevated levels of PGC-1alpha in a mouse model of HD virtually eliminated the problematic misfolded proteins. ... PGC-1alpha influenced expression of another protein vital to autophagy - the process in which healthy cells degrade and recycle old, unneeded or dangerous parts and products, including oxidative, damaging molecules generated by metabolism. For neurons, which must last a lifetime, the self-renewal is essential to survival. ... Mitochondria get beat up and need to be recycled. PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEB. ... If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time."


The World of Aging Science Must Up-End, Change, Renew Itself

It is unfortunate that popular culture, that ongoing conversation of countless threads that lies at the center of our diverse society, is so focused on drugs and pills as the sum of all medicine - anything that is consumed, and so especially when it comes to influencing the pace of aging. It is a terribly wrong, horribly damaging viewpoint, but one that is relentless propagated by the loudest voices, coincidentally also those who gain the most in the short term by creating a culture of customers for their products. When the world thinks of medicine for aging in terms of pills and potions, it shuts the door on support for real rejuvenation biotechnology, such as the detailed plans for development advocated by the SENS Foundation and others.

Part of the process of building the true medicine of rejuvenation - which will look like gene therapies, tailored cell alterations, engineered enzymes to strip away harmful metabolic side-products, and so on - is obtaining the support and at least superficial understanding of the public at large. That is still very much lacking, and some fraction of the blame for that can be pinned on the short-sighted idiots of the "anti-aging" marketplace who propagate lies and myths about aging and what can be done about it in order to sell products that do next to nothing. They have spent so much time and effort on this over the past decades that they have shaped the visions of popular culture to follow their message - and that harms us all by stripping away possible support for meaningful research and development, and making it harder to create that support.

The vast majority of commentary on aging, science, longevity, and what can be done about it is garbage at worst, and interesting but ultimately irrelevant to the future of our lives at best. Into the latter half falls work on calorie restriction mimetics such as metformin and rapamycin. They simply don't do enough to worth sinking billions of dollars into further research and development - though of course that research and development will happen anyway, regardless of my opinions on the matter. There are far better paths ahead than tinkering with compounds and genes that have modest effects, on a par with calorie restriction, and potentially serious side-effects to go along with that.

If results are what matter - and I think they are the only measure worth considering given the pace of death caused by aging - then world of aging and longevity research should focus on the SENS vision of targeted, deliberate repair of specific forms of damage, and move on from the tired old model of patching the end results of damage by trying a lot of compounds to find some that sort of do something beneficial. Nor should research spend their time on the comparatively new approach of trying to slow down the pace at which damage accumulates - again by trying a bunch of compounds to find some that sort of do something beneficial.

There are now far more effective paths forward for the treatment of aging than the approaches undertaken in past decades when biotechnology and the state of knowledge was too poor to do better. The world of aging science must up-end, change, become quite different. The SENS Foundation and the network of research groups working on related matters are doing the right thing. Big Pharma, the calorie restriction mimetic developers, the people searching for longevity genes or gene therapies to slow aging - they are heading down a side-path that will do little beyond generating new knowledge. Our lives will not be greatly lengthened by their efforts, as we will be old by the time that they produce therapies with modest effects on human life span by slowing down the pace at which damage accumulates. Ways to slow aging are of little value to those already aged. Our healthy lives will be significantly extended only by the successful development of methods of rejuvenation - of damage repair, ways to actually reverse the toll of aging on cells and systems.

Which, conveniently, are planned out and proposed in some detail.

Alzheimer's Disease Considered as Synaptic Imbalance

From Maria Konovalenko: "I met Dr. Bredesen during the Buck Advisory Council meeting at the Buck Institute for Research on Aging in Novato, California on May 21. [The] Advisory Council consists of influential individuals who can contribute to Buck Institute's mission of advancing aging research. A very interesting crowd. ... Dale Bredesen opened the mini conference with his report on Alzheimer's research. The majority of scientists envision this horrible degenerative process as accumulation of toxic molecules, namely amyloid beta and tau proteins. Amyloid beta forms plaques between the cells and tau protein tangles inside the cells. These toxic proteins disrupt the functions of our neurons. ... So, Dr. Bredesen views Alzheimer's disease differently - as an imbalance between synaptic maintenance and synaptic reorganization. The thing is that for our brain to function properly we need to form connections between our neurons, and also we need to break down those connections that we no longer need. According to Dale Bredesen, this balance disrupts, it shifts towards synaptic reorganization, we loose our memory, face the horrors of loosing our consciousness and eventually we die. ... So how can we preserve this balance? Dr. Bredesen's lab studies the underlying mechanisms of neurodegeneration. There were able to find out that one of the things that contributes to the balance shift is the change in APP cleavage. APP is amyloid precursor protein. It is concentrated in synapses of our neurons. APP can break down into either two, or four parts. When it breaks down into 2 parts those proteins are sAPP alfa and CTF alfa. This is a 'good' combination. However, during aging amyloid precursor protein cleavage shifts towards the 'bad' combination, which is sAPP beta, Amyloid beta, Jcasp and C31. This is the shift in balance that leads to the onset of disease. The shift can be restored. The mouse strain that has one mutation that leads to not having APP to break down to Jcasp and C31 proteins leads to restoring memory in mice. But the most exciting thing is that Dr. Bredesen is testing a drug that shifts the APP cleavage balance back to normal."


Investigating the Mechanisms of Rheumatoid Arthritis

Researchers examine possible molecular mechanisms for rheumatoid arthritis in a paper published earlier in the year: "Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory and destructive joint disorder that affects tens of millions of people worldwide. Normal healthy joints maintain a balance between the synthesis of extracellular matrix (ECM) molecules and the proteolytic degradation of damaged ones. In the case of RA, this balance is shifted toward matrix destruction due to increased production of cleavage enzymes and the presence of (autoimmune) immunoglobulins resulting from an inflammation induced immune response. Herein we demonstrate that a polyclonal antibody against the proteoglycan biglycan (BG) causes tissue destruction that may be analogous to that of RA affected tissues. The effect of the antibody is more potent than harsh chemical and/or enzymatic treatments designed to mimic arthritis-like fibril de-polymerization. ... The specific antigen that causes the RA immune response has not yet been identified, although possible candidates have been proposed, including collagen types I and II, and proteoglycans (PG's) such as biglycan. We speculate that the initiation of RA associated tissue destruction in vivo may involve a similar non-enzymatic decomposition of collagen fibrils via the immunoglobulins themselves that we observe here ex vivo."


The Importance of Inflammation in Aging

As noted numerous times in the past here at Fight Aging!, chronic inflammation is a bad thing. Aging is the accumulation of damage, and the evidence strongly suggests inflammation to be a mechanism by which many different medical conditions cause damage and reduce life expectancy - such as autoimmune diseases, for example. Even the presence of excess visceral fat tissue appears to raise the risk of age-related disease and lower life span through boosting levels of inflammation. Furthermore, as you get older, and even in the best of circumstances and health, the immune system itself starts to fall into a malfunctioning state in which it causes ever greater levels of inflammation - thus producing ever more damage while at the same time failing to do its job.

Markers of inflammation correlate well with mortality rates, which is well worth keeping in mind given just how easy it is to slip into a lifestyle that greatly raises levels of inflammation.

So avoid inflammation as best you can. The easiest and some of the best tools are calorie restriction and exercise, both of which do far more for a generally healthy individual than any presently available medical technology. But not everyone has the luxury of being able to be a generally healthy individual: those suffering auto-immune disorders like rheumatoid arthritis are going suffer increasing inflammation and a lowered life expectancy until a cure arrives. So the future of health has to be as much about technological progress as it is about better using the tools that are to hand today.

Here are a couple of open access papers as a reminder of the bad things that inflammation does to you - and, for most of the younger members of the audience, via the agency of that surplus visceral fat tissue you happen to be carrying around.

Inflammation in Aging: Cause, Effect, or Both?

Aging is a progressive degenerative process tightly integrated with inflammation. Cause and effect are not clear. A number of theories have been developed that attempt to define the role of chronic inflammation in aging ... However, no single theory explains all aspects of aging; instead, it is likely that multiple processes contribute and that all are intertwined with inflammatory responses.


While there does not appear to be a "cure" for the complex process of aging, it should be possible to facilitate successful aging, namely, aging without significant loss of cognitive or physical function and relatively free of disease. There are lifestyle factors and potential interventions that can slow specific processes primarily through reduction or prevention of chronic inflammation and therefore forestall aging itself.

Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice

Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease.


We found that a systemic immune challenge during late gestation predisposes [mice] to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines [and] significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. ... Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.

Infections mean inflammation, of course - one of the many reasons that people exposed to a large burden of infectious disease tend not to live as long as their peers. They become more burdened by damage, from the disease process and from the inflammation that attends it, with each infection. One of the reasons that we live longer than our ancestors is that we are better at controlling and evading infectious disease: not just the diseases that kill people in youth, but the diseases that are survived.

Investigating Precursor Ogliomers in Alzheimer's Disease

The focus of research on Alzheimer's disease begins to shift away from amyloid plaques: "Cell death in the brain causes one to grow forgetful, confused and, eventually, catatonic. Recently approved drugs provide mild relief for symptoms but there is no consensus on the underlying mechanism of the disease. ... We don't know what the problem is in terms of toxicity. This makes the disease difficult to cure. ... Accumulations of amyloid plaques have long been associated with the disease and were presumed to be its cause. These long knotty fibrils, formed from misfolded protein fragments, are almost always found in the brains of diseased patients. Because of their ubiquity, amyloid fibrils were considered a potential source of the toxicity that causes cell death in the brain. However, the quantity of fibrils does not correspond with the degree of dementia and other symptoms. New findings support a hypothesis that fibrils are a by-product of the disease rather than the toxic agent itself. This paradigm shift changes the focus of inquiry to smaller, intermediate molecules that form and dissipate quickly. These molecules are difficult to perceive in brain tissue. ... For decades, it was believed that fibrils were a toxic species, but increasingly researchers are looking at small, soluble precursor forms of the fibrils, known as oligomers. ... These oligomers may be toxic by inserting themselves into membranes and causing a damage to the membrane. The membrane is critical for the cell viability."


An Epigenetic Contribution to Osteoarthritis

An example of the study of epigenetics starting to deliver targets for therapy: "scientists used human tissue samples to discover that those with osteoarthritis have a signature epigenetic change (DNA methylation) responsible for switching on and off a gene that produces a destructive enzyme called MMP13. This enzyme is known to play a role in the destruction of joint cartilage, making MMP13 and the epigenetic changes that lead to its increased levels, prime targets for osteoarthritis drug development. ... To make the discovery, [researchers] compared the extent to which DNA methylation was different in cartilage from patients suffering from osteoarthritis and healthy people of similar age. They found that at one small position, the gene for MMP13 had less DNA methylation in diseased patients. Then they confirmed that reduced methylation of this gene increases levels of the destructive enzyme MMP13. ... We've already seen how epigenetics has advanced our approach to cancer. Now we're seeing it with other diseases ... This study not only lays the groundwork for a new understanding of osteoarthritis, but also shows that the old 'either/or' nature v. nurture argument is outdated: epigenetics teaches us that nature (the daily wear and tear of joints) regulates nurture (the genes in our cartilage) to cause arthritis."


Close to the Establishment of an Australian Cryonics Provider

Provision of cryonics services, the low-temperature preservation of the mind's structure on death, is a 40-year-old concern. It is presently the only chance at a longer life available to the vast numbers of people who will age to death prior to the advent of rejuvenation biotechnology of the sort envisaged at the SENS Foundation. In a better world than the one we presently live in, cryonics would already be a world-wide and massive industry, preserving tens of millions of people every year - saving them from oblivion, and giving a chance at a long and interesting future in an age with the technology to restore a preserved person to active life. Sadly this is far from the case. The long term success of providers outside the US has yet to be achieved, for example, as has the sort of growth needed to turn this into a truly robust and competitive industry.

But there are signs of progress, such as the establishment and continued existence of Russian cryonics provider Kriorus, and more spin-off technology development ventures like 21st Century Medicine. Another group worthy of notice is Stasis Systems Australia:

Stasis Systems Australia (SSA) is a non-profit organisation formed to build and operate Australia's first cryonic storage facility. ... We are currently putting together a group of ten investors to build the facility, and have nine so far. We intend to commence operations in 2013. As of 15 May 2012, we are incorporated as a not-for-profit company in New South Wales. If you would like to be part of this venture please get involved, and if you would like more information, contact us.

Statis Systems Australia was in the press of late, as they look closer to launch:

Not-for-profit company Stasis Systems Australia is celebrating a key milestone of 10 investors, each paying $50,000 for the privilege of having their body stored when they die. Now the company is looking for a suitable location to build their super-cool facility, possibly in South Australia or New South Wales.

Co-founder Mark Milton said he had been talking to both SA Health and the NSW Health Department and had received a sympathetic and supportive hearing. More than 250 people have been cryonically preserved around the world, and close to 2000 more have signed contracts with overseas providers, he said.

Their optimism is still a long way from becoming reality, because scientists can so far only freeze and then revive single cells - not whole organs and certainly not whole people. And Australians interested in cryopreservation were at a distinct disadvantage, having to travel overseas when sick or risk having the procedure done here and then "thawing out" on the way over. "The logistical reason more than anything else is what prompted me to get together with Peter Tsolakides, who is the other founder, to get together and try and figure out whether it was feasible," Mr Milton said.

This is apparently an outgrowth of the Cryonics Institute community, and we can hope that this initiative proceeds well. Diversification is important as a key component of growth, and geographical diversification is definitely one of the options.

Exercise Beneficial in Elderly

Here is yet another study showing that exercise in the elderly produces benefits large enough to power a massive drug industry were they caused by a pill - yet most people fail to take advantage of the free advantages bestowed by regular exercise: "Aging and physical inactivity are 2 factors that favour the development of cardiovascular disease, metabolic syndrome, obesity, and diabetes. In contrast, adopting a habitual moderate exercise routine may be a nonpharmacological treatment alternative for neuroendocrine aging disorders. We aimed to assess the effects of moderate exercise training on the metabolic profiles of elderly people with sedentary lifestyles. Fourteen sedentary, healthy, elderly male volunteers participated in a moderate training regimen for 60 min/day, 3 days/week for 24 weeks at a work rate equivalent to their ventilatory aerobic threshold. ... Blood samples for analysis were collected at 3 intervals: at baseline (1 week before training began), and 3 and 6 months after training. The training promoted increased aerobic capacity (relative VO2, and time and velocity to VO2max) and reduced serum α-MSH after 3 months of training when compared with the baseline data. In addition, serum thyroid hormone (T3 and T4) was reduced after 6 months of training compared with baseline levels. Our results demonstrate that a moderate exercise training protocol improves the metabolic profile of older people, and metabolic adaptation is dependent on time." You will recall that lower thyroid hormone levels are associated with longevity in humans.


No Difference in Reprogrammed Cells From Old and Young Mice

In the last couple of years there have been promising indicators to suggest that age is no barrier to producing useful cells for therapy from a patient. Here is another: "Advanced age is associated with decreased stem cell activity. However, the effect of aging on the differentiation capacity of induced pluripotent stem (iPS) cells into cardiovascular cells has not been fully clarified. We investigated whether iPS cells derived from young and old mice are equally capable of differentiating into vascular progenitor cells, and whether these cells regulate vascular responses in vivo. iPS cells from mouse embryonic fibroblasts (young) or 21 month-old mouse bone marrow (old) were used. Fetal liver kinase-1 positive (Flk-1+) cells, as a vascular progenitor marker, were induced after 3 to 4 days of culture from iPS cells derived from young and old mice. ... purified Flk-1+ cells were directly injected into ischemic hindlimbs of nude mice. Revascularization of the ischemic hindlimb was significantly accelerated in mice transplanted with Flk-1+ cells derived from iPS cells from either young or old mice, as compared to control mice ... The degree of revascularization was similar in the two groups of ischemic mice injected with iPS cell-derived Flk-1+ cells from young or old mice. [The] properties of iPS cells derived from old mice are essentially the same as those of iPS cells from young mice, suggesting the functionality of generated iPS cells themselves to be unaffected by aging." It should be noted that while old cells seem to work just as well, the aged environment of the patient's body does present an obstacle to the benefits of cell therapies.


The All or Nothing Progress of Longevity Science

Competition drives progress, but put enough humans into any field and the successful groups will start to form cartels in order to keep their leading position without having to compete as hard for it. It is inherent in the human condition that we self-sabotage very well and very aggressively just as soon as we achieve enough success to feel somewhat elevated over our less fortunate peers. Who can even begin to guess how many opportunities have been wasted, how much potential technological progress has been lost thanks to these urges?

The world of technology is now remarkably flat. The majority of the amenities of modern technology are available to the majority of the world: the descendants of peasants can fly for the same cost as the bloodlines of kings, cars and mobile phones are ubiquitous, and holding vast wealth doesn't in fact give a person any great and massive advantage over the middle class - or even the poor in wealthier regions - when it comes to the variety of available medical technology. Every new advance moves rapidly from being comparatively expensive, faulty, and scarce to being comparatively cheap, reliable, and widespread - whether we are talking about air conditioning or heart surgery, though the pernicious effects of regulation slow down the applications of biotechnology to a crawl in comparison to other lines of technological progress.

One of the defining features of our age is the degree to which the very wealthy and the very connected use the same technologies as the rest of us. When new technology is developed we all win - it doesn't matter which research or development group got there first, because we will all have access soon enough. What does matter is how soon that new technology arrives, and that is a function of the size and level of competition in the research and development communities. Michael Batin has this to say, machine translated from the Russian:

In most types of social interactions, people want to be the first. In sport, business, politics, the most coveted, the most honorable place - this place is number 1. This behavior is due to our neurophysiology, our genetics. Often, the winner takes all. During the war, or fight a duel to win - means to survive.

But, in the fight against aging is a totally different situation. We will survive, if any other scientist, institution or fund wins [in the fight against] aging. Yes, these [strangers get] the glory, money and women. At the same time everyone else interested in the victory over the aging gets a chance to live. No amount of money can [be] compared with the value of life. When you're alive, you have the opportunity to achieve whatever you want. When a person is dead, for him [nothing] is possible.

When we see someone [doing better than us to] extend the life of an animal model [and struggle] with aging, [he benefits us] because he can give us life. The more people who are trying to find a cure for old age, the greater our chances of survival, [and] for the return of youth to radical life extension.

The larger the community, the more healthy competition, the better the outcome and the faster the progress towards the end goal. When it comes to the biotechnology of rejuvenation we will either all win together or we all lose together - there is little in the way of middle ground in technological progress. That result is entirely determined by how fast we can create this sort of future medicine, such as that outlined in the SENS proposals.

Considering Mitochondrial Dynamics in the Context of Aging

A herd of mitochondria exists in every cell, producing the ATP necessary to power that cell. Damage to mitochondria is important in aging, but how damage progresses in a cell's mitochondrial population is complicated by the fact that these are not completely discrete and static entities. They multiply like bacteria (fission), can merge with one another (fusion), and can also exchange individual components of their molecular machinery - so damage can be both passed around or mitigated depending on circumstances. Here researchers build models to better understand this dynamic: "Mitochondria are organelles that play a central role as 'cellular power plants'. The cellular organization of these organelles involves a dynamic spatial network where mitochondria constantly undergo fusion and fission associated with the mixing of their molecular content. ... Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging ... We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the 'mitochondrial infectious damage adaptation' (MIDA) model according to which a deceleration of fusion-fission cycles reflects a systemic adaptation increasing life span."


Stem Cell Transplant Explored as Alzheimer's Disease Therapy

Work on stem cell transplants in rats is outlined here: "Alzheimer's disease (AD) has been called the disease of the century with significant clinical and socioeconomic impacts. Epidemiological studies point out that AD affects 5% of the population over 65, and, parallel with increasing lifespan, the incidence of disease will rise dramatically. Clinically AD is characterized by a progressive learning capacity impairment and memory loss, especially memories of recent events ... Adult neural tissues have limited sources of stem cells, which makes neurogenesis in the brain less likely. Stem cells transplantation seems to be a promising strategy for treatment of several central nervous system (CNS) degenerative diseases such as AD, amyotrophic lateral sclerosis (ALS), and Parkinson's disease ... The present study aims to evaluate the effect of bone marrow mesenchymal stem cells (MSCs) grafts on cognition deficit in chemically and age-induced Alzheimer's models of rats. ... Two months after the treatments, cognitive recovery was assessed ... Results showed that MSCs treatment significantly increased learning ability and memory in both age- and [chemical]-induced memory impairment. Adult bone marrow mesenchymal stem cells show promise in treating cognitive decline associated with aging and [nucleus basalis magnocellularis] lesions."


A Lack of Biotechnology is the Only Limit on Human Longevity

Are there limits on human longevity? Sure. Few people will make it past a hundred years of age in the environment of today's medical technology - but today is today, and the technology of tomorrow will be a different story. If you want to talk about longevity and mortality rates, you have to qualify your position by stating what sort of applied biotechnologies are available. Longevity is a function of the quality and type of medicine that is available across a life span.

It so happens that most of the advances in medicine achieved over the course of human history, the vast majority of which have occurred in the past fifty years, have solved problems that killed people early in life. Infectious disease, for example, is controlled to a degree that would have been thought utopian in the squalor of Victorian England. The things that kill older people are a harder set of challenges: great progress has been made in reducing mortality from heart disease in the past few decades, for example, but that is just one late stage consequence of the complex array of biochemical processes that we call aging.

The point of this discussion? It is that tremendous progress in medicine, including the defeat or taming of many varied causes of death and disability, has not greatly lengthened the maximum human life span as experienced in practice. The research community hasn't really started in earnest on the work on rejuvenation biotechnology that will achieve that end - the story of medicine to date has been work on other line items, or largely futile attempts to patch over the failure modes that lie at the end of aging.

There are things that need to be fixed that currently limit human life span. Since aging is only an accumulation of damage, there is in fact a gentle trend towards extended life as a result of general improvements across the board in medicine - perhaps one year of additional life with every five years of technological progress at the present time. On average, people with access to the modern environment of technology and support are suffering biological damage at the level of cells and molecular machinery more slowly across their lives. But this incidental life extension is slow going indeed.

Given this history of medical progress you will find many life science researchers and advocates who view the human life span as bounded - they look to past progress and extrapolate to assume that future progress can only carry on improving things within the existing human maximum life span. In other words that more and more people will live in good health closer to that maximum, but that the maximum is set in stone. There's even a name for this goal, "compression of morbidity".

This is a ridiculous view when considered in the light of reliability theory and aging, but it is widely held and therefore something that advocates for rejuvenation biotechnology must work to dismiss. The future of medicine in the next few decades is not about gaining a decade of life with no hope of pushing out human life span beyond 120 years - it is about building the alpha versions of medical technologies that can provide indefinite healthy life spans through periodic repair of the known forms of cellular and molecular damage that cause aging. But unless many more people come to understand this point, there will continue to be the same lack of support for research that will lead to radical change in the relationship of medicine and aging. Advocate and gerontologist Aubrey de Grey touches on these issues in a recent editorial:

Is there a biological limit to longevity?

Gerontologists and demographers have argued about this for a long time, with the balance of opinion heavily influenced by the changes seen in the wealthiest nations' "survival curves" - graphs showing, broadly speaking, the proportion of an initial population that survived to a given age. Until a couple of centuries ago, these curves looked very much like radioactive decay curves, because one's chance of dying at any given age was pretty much the same. As medicine emerged and we became protected from most infectious diseases, the curve became more rectangular, implying a biological limit that most people were getting fairly close to.


So, why am I exercised about this? Simply because the belief in a biological limit to longevity is very often elided into a belief in a medical limit. And unfortunately, this inference is being taken seriously by influential observers and commentators, with all that that entails for public policy going forward.


Technology is about transcending what nature has created. To say that the biological limits to longevity are any kind of evidence of what we can do with medicine is a mixing of apples with oranges of the most egregious nature. And the reason it matters, of course, is that those who have not the time or intellect to see through it have the power to dissipate society's enthusiasm for attacking aging, by reinforcing the age-old belief that it is as immutable as the heat death of the universe. The result is a delay in the defeat of aging with medicine, the unnecessary loss of life and the unnecessary perpetuation of the untold suffering caused by aging. This cannot be allowed.

We must clarify, loud and clear, that medicine is about transcending biology.

Just so.

Nitric Oxide and Aging Blood Vessels

Nitric oxide levels are a possible target for therapies aimed at some of the signs of aging in blood vessels: "Many disorders emerge with advancing aging, and cardiovascular diseases (CVD) are a major cause of morbidity and mortality in the elderly. The term vascular aging encompasses all the structural and functional alterations in the blood vessels with progressive aging. Both smooth muscle cells and intima layers are affected. These vascular changes lead to endothelial dysfunction, arterial stiffness in consequence of intense remodeling and calcification, impaired angiogenesis, greater susceptibility to vascular injury and atherosclerotic lesions. The mechanisms underlying vascular aging are complex and involve multiple pathways and factors ... In this complex scenario, vascular function depends on the balanced production/bioavailability of nitric oxide (NO), which is maintained by the normal activity of endothelial nitric oxide synthase (eNOS). On the other hand, excessive amount of NO produced by inducible nitric oxide synthase (iNOS) up-regulation contributes to vascular dysfunction. Evidence obtained from experimental models indicates that decreased NO bioavailability as well as increased reactive nitrogen species (RNS) production contributes to aging-associated vascular dysfunction. ... Pharmacological modulation of NO generation and expression/activity of NOS isoforms may represent a therapeutic alternative to prevent the progression of cardiovascular diseases."


Suggesting a Test of Rapamycin and Metformin Together

Rapamycin extends life in mice through mechanisms similar to those of calorie restriction, but has serious side-effects - though researchers are working to separate the positive mechanisms from the undesirable negative mechanisms. Metformin is also thought to be a calorie restriction mimetic drug, but the evidence for it to extend life in mice is mixed. Here, researchers suggest trying both drugs at the same time in the hopes that metformin blunts some of the side-effects of rapamycin: "Treatment with rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1) can increase mammalian life span. However, extended treatment with rapamycin results in increased hepatic gluconeogenesis concomitant with glucose and insulin insensitivity through inhibition of mTOR complex 2 (C2). Genetic studies show that increased life span associated with mTORC1 inhibition can be at least partially decoupled from increased gluconeogenesis associated with mTORC2 inhibition. Adenosine monophosphate kinase (AMPK) agonists such as metformin, which inhibits gluconeogenesis, [might] be expected to block the glucose dysmetabolism mediated by rapamycin."


Possible Uses for a Working T-Cell Vaccine Platform

T-cell vaccines are a comparatively new approach to steering the immune system to perform tasks normally left undone, such as clearing out persistent herpesviruses. It is a reminder that the heading of immune therapy covers a very wide range of possible technologies, not all of which are even on the drawing board yet, and it will be an important part of the longevity science toolkit in the years to come.

An introduction to T-cell vaccine research can be found at the Technology Review:

All existing vaccines rouse the body into creating antibodies that attach to the surface of infecting microbes and flag them for destruction. But pathogens that live inside our cells, such as the viruses, bacteria, and other microbes that cause AIDS, malaria, herpes, and chlamydia, can evade this surveillance. ... In order to deal with those types of pathogens, oftentimes we have to stimulate what we call cellular immunity. Unlike antibody immunity, which recognizes pathogens directly, cellular immunity has to recognize the infected cell and get rid of your own infected cells.

But activating cellular immunity - and the family of infection-fighting cells known as T cells that drive it - is challenging. The trial-and-error method used to develop antibody-based vaccines has not worked for T-cell vaccines. Despite years of academic and industry work, and even clinical trials, there are no T-cell vaccines for infectious disease on the market.


A Cambridge, Massachusetts, biotech company called Genocea thinks its high-throughput method could change that. The company will begin its first clinical trial later this year, when its experimental herpes vaccine will be the first test of its claims.

The first and most straightforward way in which a working T-cell vaccine platform might be used to extend life expectancy is as a therapy to clear out the common herpesvirus known as cytomegalovirus (CMV). Most of the population carries strains of CMV by the time they reach old age, and it is thought that CMV plays a role in progressive immune system disarray:

Most people are exposed to this mild persistent herpesvirus over the course of their life; it causes few obvious symptoms, but over time more and more of your immune system resources become uselessly specialized to fight it. An immune cell dedicated to remembering the signature of CMV is unavailable for other uses - and eventually you run out of cells to protect you from new threats, destroy cancers, and clear out senescent cells. This process is one part of the frailty and increased risk of death and disease that comes with old age.

But there are other many other potential uses as well. A more mature T-cell vaccine platform could lead to an array of targeted cell destruction therapies. Destroying cells is, after all, one of the tasks that immune cells have evolved to carry out. A way of rapidly generating new, reliable, and selective methods to destroy very specific cell populations will be helpful in a very wide range of therapies designed to hold back the depredations of aging. For example, such a therapy might be used to cull the unwanted cells that clog up the immune system and degrade its effectiveness - including the memory cells uselessly devoted to persistent CMV strains.

Equally there are cancer cells, senescent cells (if researchers can figure out a better way of reliably identifying them from their surface chemistry), and all sorts of other cells we'd be better off without. Destroying them will repair some of the harms of aging caused by their presence. The most cost-effective way to get rid of them all is via some form of versatile technology that can be quickly adapted to new targets - and it's a fair bet that the first forms of that technology will involve learning how to manipulate the immune system to get the job done. Why reinvent the wheel when you can use what already exists?

Calorie Restriction Boosts Stem Cell Function

It is known that calorie restriction increases stem cell capacity in aging, thereby helping to maintain tissues for longer. From Extreme Longevity, a recent commentary on the mechanisms involved: "Like it or not food lovers, the single most effective known means of extending animal lifespan is through reducing daily caloric intake. Though not definitively proven in humans, the success of this intervention has been demonstrated in myriad species in more than 50 years of research. ... A protein called mTOR is responsible for this effect. mTOR combines with two other proteins to mediate several important cellular processes. These include translation of mRNA into protein, mitochondrial activity, and autophagy. Caloric restriction inhibits mTOR activity which leads to longer lifespan. The new studies [convincingly] demonstrate that reduction of mTOR activity causes preservation of stem cell health. They increase in abundance and proliferative potential. One study shows this occurs in intestinal cells, and the other in muscle cells. In the instestinal cell study, the authors showed that it was actually supporter cells called Paneth cells that aided the health of stem cells when they were taken from calorie restricted animals. They further showed this effect was mediated by mTOR inhibition and that it was achieved by increasing the activity of another protein called Bst1, important in cell proliferation. In the muscle study, calorie restricted animals had greater muscle stem cell proliferative capacity too. And this effect was also seen when the stem cells were transplanted into non calorically restricted animals, suggesting the microenvironment or niche around the stem cells was key. ... taken together, the two studies indicate that preserving and enhancing stem-cell function in multiple tissues is one of the ways in which calorie restriction slows the ravages of aging."


Discussing IGF-1 and Heart Health in Mammals

An open access commentary: "The mammalian heart must maintain its structural and functional integrity for decades, yet the response to damage in this vital organ is remarkably inadequate and often results in heart failure. Moreover, patients with chronic heart failure show profound metabolic changes, leading to peripheral abnormalities in addition to an initial cardiac impairment. Several evidences have suggested a relationship between the IGF-1 system and cardiovascular disease. Many cardiovascular risk factors, such as sedentary lifestyle, diabetes, smoking, oxidized low-density lipoprotein, obesity, psychological distress and reduced coronary flow reserve, have been associated with reduced IGF-1 levels. Conversely, human studies indicate that increased levels of IGF-1 are characterized by a decreased incidence of heart failure and mortality in elderly individuals. Nevertheless, the fact that IGF-1 can act either as a circulating hormone or as a local growth factor has confounded previous analyses of animal models in which transgenic IGF synthesized in extra-hepatic tissues was released into the circulation. Locally acting mIGF-1 isoform improves muscle regeneration and counters muscle wasting associated with diseases, including sarcopenia, muscular dystrophy and ALS. By contrast, circulating IGF-1 isoforms have been implicated in the restriction of lifespan and have contrasting effects on the heart when expressed as transgenes, variously promoting cell survival, or inducing prolonged hypertrophy with pathological consequences."


An Engineering Approach to Extending Lifespan in Nematodes

If more life science researchers thought like engineers, we might see faster progress towards extended healthy longevity. One of the marks of pure engineering versus pure science is the willingness to pursue development of working solutions in the absence of full knowledge of the underlying principles. Both the Romans and the early British industrialists built superb bridges in the absence of a full understanding of structural and material science, not by chance but because they could deliberately and carefully use empirical knowledge to work around their ignorance of deeper scientific laws. So too there is much more room for empiricism in the development of medicine, and in longevity science in particular, than is presently practiced. In the scientific world, the favored next step following a demonstration of extended life in laboratory animals is to figure out every detail of how it works rather than explore the possibility of building a therapy - but both paths could be explored in parallel.

In any case, here are results from a group of life science engineers, working with nematode worms:

We have taken an engineering approach to extending the lifespan of Caenorhabditis elegans. Aging stands out as a complex trait, because events that occur in old animals are not under strong natural selection. As a result, lifespan can be lengthened rationally using bioengineering to modulate gene expression or to add [components from other species].


We overexpressed five genes that act in endogenous worm aging pathways, as well as two genes from zebrafish encoding molecular functions not normally present in worms. For example, we used zebrafish genes to alter mitochondrial function and innate immunity in ways not normally available to C. elegans and extended worm lifespan by ~40%. Next, we used a modular approach to extend lifespan by 130% by combining up to four components in the same strain. These results provide a platform to build worms having progressively longer lifespans.

This project is conceptually similar to using engineering to increase the useful lifespan of a primitive machine (1931 Model T) using both parts from the model T as well as parts from a more advanced machine (2012 Toyota Corolla). Our results open the door to use engineering to go beyond the constraints of the C. elegans genome to extend its lifespan by adding non-native components.

Tinkering with metabolism and genes to slow aging isn't my favored approach for extending healthy longevity - it is a poor path in comparison to efforts aimed at repairing accumulated damage - but I am very much in support of the attitude displayed by the authors quoted above. The research community could do with a whole lot more of that sort of mindset.

On Osteoarthritis

This open access review paper discusses what is known of osteoarthritis: "Half of all persons aged over 65 suffer from osteoarthritis (OA). As a matter of fact, age is the most prominent risk factor for the initiation and progression of OA. The common explanation for this is the cumulative effect of mechanical load over the years, resulting clinically in 'wear and tear' and pathologically in cartilagepathogenesis and progression of OA. Not only cartilage, but also subchondral bone, menisci, muscles as well as fat, and synovial tissues play an important role, notably in the early phase of OA. Therefore, OA has been referred to as a 'whole joint disease.' Despite a higher complexity, this concept has not only improved our understanding of the disease but also indicates potentially new treatment strategies. ... Inflammation in form of cellular infiltration of synovial tissue or subchondral bone and expression of inflammatory cytokines is more and more recognized as trigger of OA. It has been demonstrated that joint movement can exhibit anti-inflammatory mechanisms. Therefore physical activity or physiotherapy in the elderly should be encouraged, also in order to increase the muscle mass. A reduced stem cell capacity in the elderly is likely associated with a decrease of repair mechanisms of the musculoskeletal system. New treatment strategies, for example with mesenchymal stem cells (MSC) are investigated, despite clear evidence for their efficacy is lacking."


AKH, Physical Activity, and Calorie Restriction Benefits

We know that autophagy seems to be required for calorie restriction to provide benefits to health and and longevity, and here researchers argue that exercise is also required: "Fruit flies on dietary restriction (DR) need to be physically active in order to get the lifespan extending benefits that come from their Spartan diet. ... flies on DR shift their metabolism toward increasing fatty acid synthesis and breakdown, specifically in muscle tissue. ... Dietary restriction is known to enhance spontaneous movement in a variety of species including primates, however this is the first examination of whether enhanced physical activity is necessary for its beneficial effects. This study establishes a link between DR-mediated metabolic activity in muscle, increased movement and the benefits derived from restricting nutrients. ... flies on DR who could not move or had inhibited fat metabolism in their muscle did not exhibit an extended lifespan. ... Our work argues that simply restricting nutrients without physical activity may not be beneficial in humans. ... The research also points to a potential target that could yield a drug that mimics the beneficial effects of DR. ... flies genetically engineered to overexpress the circulating peptide AKH (the fly equivalent of glucagon in mammals) showed increased fat metabolism, spontaneous activity and extended lifespan even though their diet was unrestricted. AKH plays a critical role in glucose and lipid metabolism. ... Our data suggests that DR may induce changes in muscle similar to those observed under endurance exercise and that molecules like AKH could serve as potential mimetics for DR that enhance activity and healthspan."


In Mice, Rapamycin Improves Cognition and DNA Methyltransferase Improves Memory

A pair of recent research results reinforce the idea that - with suitable engineering - the mental decline that occurs with aging can be can be greatly slowed or evaded. This is not repair, but it is a large improvement over the baseline. The work is in mice, which usually means the effects are more dramatic than when translated into human clinical therapies.

Easter Island Drug Raises Cognition Throughout Life Span in Mice

The researchers, appointed in the School of Medicine at The University of Texas Health Science Center San Antonio, added rapamycin to the diet of healthy mice throughout the rodents' life span. Rapamycin, a bacterial product first isolated from soil on Easter Island, enhanced learning and memory in young mice and improved these faculties in old mice, the study showed.

"We made the young ones learn, and remember what they learned, better than what is normal," said Veronica Galvan, Ph.D., assistant professor of physiology at the Barshop Institute for Longevity and Aging Studies, part of the UT Health Science Center. "Among the older mice, the ones fed with a diet including rapamycin actually showed an improvement, negating the normal decline that you see in these functions with age."

Given that rapamcyin was shown in that study to boost levels of neurotransmitters associated with neural plasticity, the first inclination would be to link the improved capabilities of the mice to increased growth and adaptability in neurons across the course of life. Further research will no doubt show whether that is a reasonable hypothesis.

Scientists Successfully Restore Memory in Aging Mice with Enzyme Injections

Researchers from the University of Heidelberg had injected a virus that contains extra copies of the gene responsible for creating DNA methyltransferase into the hippocampus, area of the brain responsible for memory, of elderly mice that were showing signs of diminished memory. Afterwards, the team gave the mice a series of memory tests such as showing the mice a new object to investigate for a period of time, taking it away and presenting them with the same object the next day along with another new object.

Past studies showed that younger more able-minded mice will immediately begin investigating the newer object, while older mice will spend equal amounts of time investigating both objects, having seemingly forgotten that they'd already seen the object the day before.

The research team found that once the older mice were injected with the virus, the elderly mice had spent most of their time, 70 percent of the time, investigating the new object, suggesting that an increase of the enzyme restored their faulty memories to its original capacity. However, when researchers halved the amount of DNA methyltransferase produced by younger mice, the memory abilities deteriorated to that of non-treated older mice.

This second study gives a clear set of targets for the development of therapies that might benefit we humans - though bear in mind that in the present regulatory environment it takes a decade or two to move from a research result like this to clinical therapies, if the development process even manages to proceed that far. The costs imposed by the FDA and similar regulatory bodies make the establishment of a diverse development portfolio of possible therapies too expensive by far. Thus only the most likely and most broadly useful lines of research move deep into development - comparatively little of what may prove to be useful medicine is in fact taken far enough to be certain in this day and age.

A Different Argument for the Age-Dependence of Cancer

The general view of cancer is that it occurs in the old because it depends on nuclear DNA mutations that accumulate over time - the more mutations, the greater the chance of one of them being suitable to trigger a cancer. Here a researcher argues that it has less to do with the number of mutations and more to do with the changing (and more damaged) state of tissue and systems in the body, which increases the ability of mutated cells to survive and prosper: "For evidence, DeGregori points first to the fact that by the time we stop growing in our late teens, we've already accumulated a large fraction of the mutations we will have in our lifetimes. 'There's a mismatch between the mutation curve and the cancer curve,' DeGregori says, meaning that if cancer were due to reaching a tipping point of, say, five or six mutations, we should see higher cancer rates in 20-year-olds, as this is when mutation rate is highest. Second, DeGregori points out that even healthy tissues are full of oncogenic mutations. 'These mutations are many times more common than the cancers associated with them,' DeGregori says. Simply, more mutations doesn't equal more cancer - not across the aging population and not even in specific tissues. DeGregori's final two points come from evolution. As we've evolved from one-celled, short-lived life forms into multicellular, long-lived humans, we've had to develop complicated machinery to maintain our tissues and avoid disease. 'But we're no better at preventing mutations than our yeast or bacteria cousins. You'd think if avoiding mutations was key to avoiding cancer, we'd be better at it than we are.' And finally, if these oncogenes were the evil super-villains they've been made out to be, capable of taking over surrounding tissue, then introducing oncogenes into mice stem cells should help rather than hurt these cells' survival. 'Rather, stem cells harboring the oncogenes tend to get weeded out,' says DeGregori. Instead of gathering mutations until they give us cancer, DeGregori says that as we age, the mechanisms that younger adults use to fight cancer, deteriorate. ... Our healthy cells are optimized for the conditions of our healthy, younger tissue. Change this balance, as does an oncogenic mutation, and they're no longer a perfect fit for the surroundings - healthy cells in young bodies quickly outcompete cells with cancerous mutations. But, 'when tissue is old, healthy cells are no longer a perfect fit, and mutations might help a cancer cell adapt in ways a healthy cell can't,' DeGregori says."


Another Approach to Creating Blood Vessels in Engineered Tissue

Many research groups are working on ways to overcome the challenge of generating suitable blood vessel networks for engineered tissue, as this is one of the major blocking issues in generating large tissue masses from scratch: "Researchers are hopeful that new advances in tissue engineering and regenerative medicine could one day make a replacement liver from a patient's own cells, or animal muscle tissue that could be cut into steaks without ever being inside a cow. Bioengineers can already make 2D structures out of many kinds of tissue, but one of the major roadblocks to making the jump to 3D is keeping the cells within large structures from suffocating; organs have complicated 3D blood vessel networks that are still impossible to recreate in the laboratory. Now [researchers] have developed an innovative solution to this perfusion problem: [rather] than trying to print a large volume of tissue and leave hollow channels for vasculature in a layer-by-layer approach, [they] focused on the vasculature first and designed free-standing 3D filament networks in the shape of a vascular system that sat inside a mold. As in lost-wax casting, a technique that has been used to make sculptures for thousands of years, the team's approach allowed for the mold and vascular template to be removed once the cells were added and formed a solid tissue enveloping the filaments. ... The researchers showed that human blood vessel cells injected throughout the vascular networks spontaneously generated new capillary sprouts to increase the network's reach, much in the way blood vessels in the body naturally grow. The team then created gels containing primary liver cells to test whether their technique could improve their function. ... Though these engineered tissues were not equivalent to a fully functioning liver, the researchers used cell densities that approached clinical relevance, suggesting that their printed vascular system could eventually be used to further research in lab-grown organs and organoids."