Fight Aging!

Sometimes I point out research not because it is relevant to the immediate cause of building therapies to control aging, but because it is interesting. That is definitely the case here: I doubt you can find a practical use for a paper on the modeling of aging and longevity in tyrannosaurs. That doesn't stop it from being a fascinating topic, of course.

Researchers follow their interests, and that is worth celebrating. If no-one was interested in deciphering and more importantly treating aging, we would still be in exactly the same position as all of our ancestors: doomed to short lives terminated by a period of pain, suffering, and debility. As things stand we are only maybe doomed, with the odds strongly depending on date of birth and progress in raising funding for research, but even that is an enormous improvement. Whether or not you and I personally make it into the age of radical life extension, by bootstrapping the use of one therapy at a time to incrementally repair our biochemistry and extend healthy life, it remains the case that by supporting this cause we help to create the means to save countless lives in the near future.

Aging is near universal trait among species, and has been for a very long time, all the way back to the murky origins of cellular life. You might look on the universality of aging as the result of an evolutionary race to the bottom, similar in a way to the human relationship with organized violence. War hurts the individual and diverts efforts from productive use, but the only way to survive as a collective when your competitors are proficient at violence is to follow the same path - and so everyone diverts resources into mutual destruction rather than growth. Aging may be such an effective evolutionary strategy because it enables better survival of a species in the face of environmental change. We age because the world changes, and ancestral species with aging replaced near all species without aging, right from the outset. Only in a few scattered niches do we find a tiny number of species where evolution has led to a move away from aging as a strategy. Thus when we look into the deep past and model the lives of species such as dinosaurs, those for which enough bones exist for decent models of life span, we should not be at all surprised to find the same patterns of aging as we see today.

Tyrannosaurs as long-lived species

Tyrannosaurs including Tyrannosaurus rex (shortly T. rex meaning tyrant lizard king) are very popular to the public as well as among paleontologists although they became extinct 66 million years ago. Many mysteries about population ecology and actual behavior of tyrannosaurs have been resolved thanks to modern technologies and collective data in paleobiology. In particular, rigorous anatomic methods have been developed and eventually reliable life tables for tyrannosaurs were estimated. Using their demographic data, tyrannosaur aging dynamics was carefully interpreted. Gompertz function or Weibull function was utilized to quantify tyrannosaur survival curves, but both might be insufficient to appropriately describe complicated biological survival curves. Suitable mathematical descriptions and statistical methods are still required to quantify survival and mortality curves of tyrannosaurs.

Here we address a methodology that enables us to appropriately quantify tyrannosaur survival and mortality curves by utilizing modified stretched exponential survival functions, which we have developed to precisely quantify human demographics. We find a demographic analogy between tyrannosaurs and 18th-century humans despite scale and ecological differences. Interestingly, mortality patterns for tyrannosaurs resemble those for 18th-century humans: probably tyrannosaurs would be able to live so long to undergo aging before maximum lifespans, while their longevity strategy would be more alike to big birds rather than 18th-century humans. We attribute longevity of tyrannosaurs to late sexual maturity, large body size, and rapid growth rate, which would be favorable for longevity.

Analyzing the stretched exponents helps evaluation of longevity strategy across species. Although survival and mortality curves look very similar between tyrannosaurs and 18th-century humans, their stretched exponent patterns are significantly different. The stretched exponents with respect to the normalized age show a clear difference in longevity strategy between 18th-century humans and tyrannosaurs. For 18th-century humans, the curves are similar to those of apes or crocodilians, whereas those of Albertosaurus sarcophagus show similar patterns with deer, cassoway, or raptors. This analysis suggests that tyrannosaurs would live longer than other species in terms of the normalized age. Tyrannosaurs would exhibit late sexual maturity, large body size, and rapid growth rate, which would be favorable for longevity. There would be benefits from predation relief by rapid growth for longevity of tyrannosaurs. Probably becoming giants through rapid growth or becoming apex predators would be favorable to acquire exceptional benefits for releases from predation in early life, which would be good for longevity, regardless of uncertainty on whether they were primarily predators or scavengers.

Peripheral artery disease is a narrowing of blood vessels in the limbs, usually caused by the progression of atherosclerosis, and consequent failure to deliver enough oxygen to cells. Tissues fail to heal and grow, and ultimately die, causing serious medical conditions along the way. Here researchers are trying a more sophisticated form of patch therapy, not addressing the root causes, but altering the signals delivered to cells in order to create greater growth and regrowth in blood vessels. This has the potential to partially compensate for the progression of blood vessel narrowing, but like all compensatory approaches it can only buy a little time, not fix the problem:

The study examined the safety and efficacy of gene therapy with a plasmid DNA containing human hepatocyte growth factor (HGF) gene, called VM202, in 52 patients with critical limb ischemia (CLI), a severe form of peripheral artery disease. The HGF gene in VM202 produces two isoforms of HGF proteins that are naturally found in the human body. HGF is a growth factor that induces angiogenesis and acts as a neurotrophic factor. After VM202 is injected into a patient's muscle, it is taken up by a cell and produces the HGF proteins, which are then released from the cell and may induce new blood vessel formation by activating various signaling pathways. In this way, VM202 may provide clinical benefits to CLI patients.

VM202 was found to be safe and well tolerated and showed clinical benefits in CLI patients who had no other treatment options. Both ulcer healing and tissue oxygenation improved significantly in patients who were given four series of VM202 injections (spaced 2 weeks apart) in the muscle of the diseased leg. "We are looking forward to conducting a phase III trial to better understand the potential of this novel approach, especially in treating non-healing ulcers, which is a serious symptom that often leads to amputation because of the lack of medical therapies available."

In the study, patients treated with high-dose (16 mg total) VM202 showed significantly better ulcer healing than did patients who were treated with placebo injections. In fact, 62% of ulcers treated with high-dose VM202 healed completely compared with only 11% of ulcers treated with placebo. Statistically meaningful results were also seen in tissue oxygenation (TcPO2 levels). Of patients treated with high-dose VM202, 71% showed increased TcPO2 levels, whereas only 33% of control patients showed better tissue oxygenation.

Link: http://www.texasheart.org/AboutUs/News/2016-1-18news_VM202_promising_for_CLI.cfm

The root cause of amyotrophic lateral sclerosis (ALS) is unknown in most cases, though there are some genetic associations in a minority of patients that suggest possible lines of investigation. The condition is age-related in the sense that it typically emerges in the 50s and 60s. There is no effective treatment at this time and most patients have a short remaining life span of only a few years following onset. So it is good to see the potential for a treatment, not just for the patients, but also because it should help settle the matter of the cause of the condition, how it can be age-related but also occur in only a small number of people:

Researchers announced today that they have essentially stopped the progression of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, for nearly two years in one type of mouse model used to study the disease - allowing the mice to approach their normal lifespan. The findings, scientists indicate, are some of the most compelling ever produced in the search for a therapy for ALS. "We are shocked at how well this treatment can stop the progression of ALS." In decades of work, no treatment has been discovered for ALS that can do anything but prolong human survival less than a month.

The mouse model used in this study is one that scientists believe may more closely resemble the human reaction to this treatment, which consists of a compound called copper-ATSM. It's not yet known if humans will have the same response, but researchers are moving as quickly as possible toward human clinical trials, testing first for safety and then efficacy of the new approach. ALS was identified as a progressive and fatal neurodegenerative disease in the late 1800s. It's known to be caused by the death and deterioration of motor neurons in the spinal cord, which in turn has been linked to mutations in copper and zinc superoxide dismutases.

Copper-ATSM is a known compound that helps deliver copper specifically to cells with damaged mitochondria, and reaches the spinal cord where it's needed to treat ALS. This compound has low toxicity, easily penetrates the blood-brain barrier, is already used in human medicine at much lower doses for some purposes, and is well tolerated in laboratory animals at far higher levels. Any copper not needed after use of copper-ATSM is quickly flushed out of the body. Experts caution, however, that this approach is not as simple as taking a nutritional supplement of copper, which can be toxic at even moderate doses. Such supplements would be of no value to people with ALS.

Using the new treatment, researchers were able to stop the progression of ALS in one type of transgenic mouse model, which ordinarily would die within two weeks without treatment. Some of these mice have survived for more than 650 days, 500 days longer than any previous research has been able to achieve. In some experiments, the treatment was begun, and then withheld. In this circumstance the mice began to show ALS symptoms within two months after treatment was stopped, and would die within another month. But if treatment was resumed, the mice gained weight, progression of the disease once again was stopped, and the mice lived another 6-12 months. "We have a solid understanding of why the treatment works in the mice, and we predict it should work in both familial and possibly sporadic human patients. But we won't know until we try."

Link: http://oregonstate.edu/ua/ncs/archives/2016/jan/new-therapy-halts-progression-lou-gehrig%E2%80%99s-disease-mice

The Rejuvenation Biotechnology Update is a collaboration between the Methuselah Foundation and SENS Research Foundation, a newsletter delivered to SENS supporters and members of the Methuselah Foundation 300. The latest edition arrived yesterday, and as usual it is a look at a few of the interesting research results from recent months, with accompanying explanations of their relevance in the bigger picture.

The 300 is a group of donors who have supported the Methuselah Foundation for more than a decade now, and the first members stepped up to help get the first initiatives off the ground back when there were only ideas and intents, longevity science was ridiculed, and funding was scarce. Last year a monument was raised to record the names of the 300, the people who have helped bring about a sea change in the aging research community, the philanthropists who funded the M Prize for longevity science, launched the SENS rejuvenation research programs, delivered seed funding to Organovo, and today support the ongoing New Organ Prizes for tissue engineering. If you want to help speed progress towards a world without aging, in which all age-related disease can be prevented and cured, you could do far worse than to become a member of the 300.

2016 Q1 Rejuvenation Biotechnology Update (PDF)

Transthyretin deposition in articular cartilage: a novel mechanism in the pathogenesis of osteoarthritis.

Transthyretin (TTR) is a protein that normally serves to transport thyroid hormones and the vitamin retinol in the blood. Normally, TTR is dissolved in the blood. However, during aging, some individuals accumulate masses of abnormally folded TTR in their body tissues, a form of amyloid which is associated with impaired organ function. Amyloid aggregates of TTR especially interfere with heart function, and amyloidosis can be fatal in this manner. However, in this study, researchers examined the role that TTR amyloidosis may play in osteoarthritis, a cause of joint pain and inflammation that is common in older individuals. The researchers found that in young individuals, no amyloid deposits were present in the knee joints. Strikingly, however, it was present in 100% of the older individuals with osteoarthritis they examined, as well as in 58% of the older individuals without osteoarthritis in their study.

Although there were only a small number of people in this study, the results are interesting, and underscore the importance of the development of therapies for TTR amyloidosis. TTR amyloidosis appears to contribute substantially to increased mortality at advanced ages. TTR amyloidosis of the heart affects a quarter of those who are age 80 and older, and we are only recently learning that it is also present in other parts of the aging body. Some evidence suggests that TTR amyloidosis may be the main cause of death in individuals over the age of 110. Now, with this study, we can see that TTR may contribute to osteoarthritis too, which implies that a significant increase in quality of life could be obtained - along with potentially increased longevity - if treatments for TTR amyloidosis could be developed. Accordingly, SENS Research Foundation has been pursuing and funding a project to develop catalytic antibodies to break down TTR amyloid deposits.

GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration

There have recently been several exciting reports about the apparent positive effects of GDF-11 in aged animals. A recent paper has reported some observations about GDF-11 that are the opposite of prior reports. It is this controversy which we highlight. GDF-11 is similar in structure to several other proteins, including myostatin (also called GDF-8), a circulating protein which is known to inhibit muscle growth. The current paper of interest alleges that the antibodies used to detect GDF-11 in previous studies were not specific to GDF-11 and were cross-reacting with myostatin. This, the authors allege, led previous investigators to misinterpret the actual concentration of GDF-11 in their experiments. In contrast to these earlier studies, the authors observed an increase in both GDF-11 and myostatin with age using their reagents, and wrote that GDF-11's function is likely redundant with that of myostatin and could be targeted for blockade to treat age related decline in skeletal muscle mass.

This seems like a complicated story with many contradicting results from different groups. It highlights a couple of key points: (1) The importance of scientific dialog and discourse to sort out apparently contradicting results like this, (2) The importance of making sure that research reagents such as antibodies and primers used to detect specific proteins are actually specific for what researchers want to measure, and (3) The idea of a U-shaped dose-response curve for biological molecules, which is one of the many difficulties of trying to tweak metabolism to inhibit the aging process instead of repairing the damage directly.

Once the antibody specificity issue is sorted out, we will need to learn about the true effects of GDF-11 at a range of doses. It is possible that apparently contradictory results were obtained due to different doses of GDF-11 being used in the studies. There may be a "U-shaped" curve of GDF-11 where the optimal amount lies in the middle, and much more or much less could have vastly different effects. Or, it may be that we have yet to discover additional, harmful effects of GDF-11, or that its effects are similar to myostatin as some groups have reported. As with many processes in the body, having too much or not enough of something can have profoundly negative effects, and nothing produced by metabolism is without the potential for harm.

More research groups these days are trying to produce treatments for cancer by targeting known commonalities shared by all cancers or at least large classes of different types of cancer. This is good, because the cause of slow progress across the modern history of cancer research is arguably the fact that most efforts focus on approaches that can only work for a tiny fraction of cancer types. When talking about commonalities shared by all cancers, I largely mean lengthening of telomeres via telomerase or the less well understood alternative lengthening of telomeres (ALT) processes. All cancers abuse the mechanisms of telomere lengthening, normally inactive in the somatic cells making up the vast majority of tissues, in order to bypass evolved checks on uncontrolled cellular replication. Telomeres are repeated sequences of DNA at the end of chromosomes that shorten with each cell division, forming a clock of sorts. When they are too short, cells become senescent or self-destruct. If cancer cells are prevented from extending their telomeres, they die. Equally, if cancer cells can be reliably identified through the signature of their abuse of telomere lengthening, then they can be targeted for destruction via any of the selective cell killing mechanisms under development in the cancer research community:

Tumour progression, growth, and metastasis are intimately associated with both increased intratumoural angiogenesis, growth of blood vessels to supply the tumor, and increased cell proliferation. Thus, many therapeutic strategies are focused on targeting either or both of these processes. Angiogenesis, the process by which capillaries sprout from pre-existing blood vessels, is a complex multistep process that is tightly regulated by a large number of angiogenic factors. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) play pivotal roles in tumour angiogenesis.

Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase, which is silent in normal tissues but reactivated in most human cancers. TERT expression is directly correlated with tumour growth and progression and TERT serves as a universal tumour antigen in immunotherapy for cancer. Immunization against TERT may overcome tumour cell immune evasion by boosting the level of cytotoxic T cells specifically targeting the cancer. Thus, TERT is a promising immunotherapeutic candidate that should be considered for combination with anti-angiogenic therapies.

Antigen-presenting cells including dendritic cells (DCs) express mannan receptors (MR) on their surface, which can be exploited in cancer therapy by designing immune-stimulatory viruses coated with mannan-modified capsids that then bind to DCs and initiate a potent immune response. Co-immunization against tumour (TERT) and angiogenesis-specific markers (VEGFR-2) has a stronger inhibitory effect on tumour growth than single agents. Similarly, immunization of mice with a 1:1 mixture of dendritic cells transfected with VEGFR-2 and TERT mRNAs in vitro was shown to have a synergistic anti-tumour effect. Nevertheless, preparation of antigen-specific DC vaccine ex vivo is costly and time-consuming. A vaccine that directly targets DCs in vivo could be used to bypass these high costs and dependency on ex vivo manipulation.

We previously constructed a mannan-modified recombinant TERT adenovirus as a prophylactic vaccine for targeting DCs. This virus stimulated an antigen-specific cytotoxic T cell response against TERT in mice that was correlated with a clear anti-tumour effect. However, in our subsequent study, we found that the therapeutic anti-tumour efficacy of the vaccine was unsatisfactory. Here, we have dramatically improved the efficacy of this approach by creating a "universal" and effective vaccine, which consists of mannan-modified TERT and VEGFR-2 recombinant adenovirus. The vaccine was tested for its ability to induce anti-tumour immunity in a mouse tumour model. We found that it elicited two kinds of anti-tumour response: an immune cell-mediated attack of tumour cells and suppression of intratumoural angiogenesis. The reduced requirement for ex vivo manipulation and the remarkable synergy achieved by targeting both tumour cells and tumour vasculature suggest that this approach is may be suitable for translation to future clinical studies.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471666/

In this day and age, the big advantage provided by conducting studies of aging in short-lived, small species such as nematodes is that it is cost-effective to build increasingly sophisticated processes of automation for such research. Gathering very detailed data on large numbers of individuals becomes possible, and this allows for greater introspection into the mechanisms of aging through statistical methods. The results here are quite interesting, for example, and could not be obtained from mammals given current budgets and constraints on technology:

In order to study life span dynamics at the population level, researchers constructed the Lifespan Machine, a device comprising 50 off-the-shelf flatbed scanners purchased from an office supplies store. Each scanner has been retooled to record 16 petri dishes every hour, totaling 800 dishes and 30,000 nematode worms. The scanners capture images at 3,200 dots per inch, which is a resolution high enough to detect movements of eight micrometers, or about 12 percent of the width of an average worm. The researchers subjected the worms to interventions as diverse as temperature changes, oxidative stress, changes in diet and genetic manipulations that altered, for example, insulin growth factor signaling. The Lifespan Machine recorded how long it took the worms to die under each condition. The researchers then aggregated the data, generated life span distribution curves for each intervention and compared results.

The life span distributions provided considerably more information than just changes in average life span. The research team measured variations arising in ostensibly identical individuals, looking at how many worms died young versus how many made it to old age under each condition. This comprehensive view was important for capturing the dynamics and randomness in the aging process. In one sense, the findings were not surprising: different circumstances produced different life spans. Turning up the heat caused the worms to die quickly, and turning it up higher only increased that rate. Pictured as bell-shaped distributions, certain interventions produced a thinner, high-peaked bell, while others resulted in a more drawn-out and protracted bell.

Despite these obvious differences, the researchers found an unexpected uniformity among the curves. The various interventions seemed to affect the duration of life in the same way across all individuals in the same population, regardless of whether chance or randomness had a short or long life in store for them. No matter which genetic process or environmental factor the researchers targeted, all molecular causes of death seemed to be affected at once and to the same extent. These findings suggest that aging does not have a single discrete molecular cause but is rather a systemic process involving many components within a complex biological network. Perturb any node in the system, and you affect the whole thing.

Link: http://hms.harvard.edu/news/lifespan-machine-probes-cause-aging

The SENS Research Foundation seeks to bring an end to aging and age-related disease, and to speed progress towards this goal carries out both research and advocacy. As a part of the outreach conducted by the staff and volunteers, co-founder Aubrey de Grey travels much of the world to give frequent presentations on the SENS approach to rejuvenation research to audiences of all sorts: life scientists, economists, actuaries, students, venture capitalists, advocacy groups, technology convention attendees, TED audiences, and so on. You can find many of these uploaded to YouTube, but there are just as many more that were not recorded at the time. De Grey has been doing this since the turn of the century, and as the opinions of researchers and those who listen to researchers have swayed towards support for treating the causes of aging to extend healthy life spans, the reception in the media has improved greatly. At some point in the last decade, it went from being possible to ridicule any sort of serious longevity science without repercussion to looking like a fool for doing so.

It is well worth noting that little has changed in the underlying science relating to SENS over that time, other than the ongoing progress towards its realization: the list of cell and tissue damage remains much the same, and a person familiar with the topic should have a similar expectation of ultimate success in the medical control of aging through therapies to repair damage whether in 2006 or 2016. What has changed greatly is opinion. There is probably a lesson there in how little consensus matters in comparison to truth and weight of evidence, and how little truth and weight of evidence matters to most people involved in propagating the consensus position. It is something to bear in mind, and it is always worth critically looking at your own beliefs to make sure that they are more than just the party line, for some party, somewhere. The consensus has a way of creeping in around the edges when you are not paying attention.

Today I ran across a couple of articles in the Florida local media resulting from a recent presentation given by Aubrey de Grey. I thought them noteworthy for treating this as just more medical science, something to be discussed respectfully. The times are changing, and as de Grey points out, the near future evolution of this process is one in which the lowest common denominator celebrities are presenting SENS viewpoints on aging and medicine in their own words on prime time television. Once the initial tipping point of about 10% support is reached in the matter of persuading the world to your view, the majority will come around to that view fairly rapidly thereafter. It is pleasing to see this happening.

Scientist envisions perpetual repair process for the human body

The British biomedical researcher Aubrey de Grey, in his quest to press the boundaries of the human lifespan to a point where they essentially no longer exist, often resorts to some provocative soundbites. Like: "Your chance of dying if you're 60 will be the same as your chance of dying if you're 30. That means that most people will live into four digits. Which sounds a bit scary. But get used to it, because it's going to happen." And: "In a worst-case scenario, we might end up having fewer kids than we would like, to make up for all these tedious people who were born a long time ago and haven't had the good grace to die yet." But he also wanted his multi-generational audience this week to understand that he is primarily interested in keeping people healthy.

He described what he called the "sweet spot" between current geriatric treatments that only postpone the deterioration that comes with time, and the elusive ideal of escaping those pathologies through exercise, diet and preventive medicine. He proposed a third approach, which is to repair at certain intervals all the damage that the human body sustains over time, simply by existing. "The idea is that you keep one step ahead of the problem," he said. At the age of 60 or 70, he added, people "will be rejuvenated so that they won't be biologically 60 again until they're chronologically 90."

De Grey referred to the societal implications of life extension as a "side effect" of these future medical technologies, and said he believes those questions are up to our descendants. If we refuse to pursue the possibilities, he added, "We would be condemning a cohort of descendants to the same sort of painful death that our ancestors experienced." After two decades in the field, de Grey believes that consensus in the scientific world is catching up to his own research. "Five years from now," he predicted, "Oprah Winfrey's going to be giving you what I'm telling you. And then you're going to believe it."

Gerontologist tells USF Sarasota-Manatee crowd 'aging' can be reversed

"Tonight I am going to talk about how we are moving forward with research that will lead, in the foreseeable future, to the development of medicines that can rejuvenate the body completely," de Grey said. "In other words, medicines that can repair the molecular and cellular damage the body does to itself in the course of life." Why aren't drug companies on this? "The reason why drug companies are not yet jumping all over this is the same reason they never jump on really early stage drugs," de Grey said. "Drug companies just don't do any drug development anymore in the early stages. We are going to see drug companies jumping on these coming drugs like you have never seen before. We are not going to see it until organizations like the SENS Research Foundation have progressed far enough, however."

Kathy Black, a gerontologist and a professor at USF Sarasota-Manatee, and Paula Bickford, a professor in the department of neurosurgery and brain repair at USF Tampa, gave de Grey an A-plus for innovation and diaglogue-sparking enthusiasm. They downgraded the doctor on some predictions. "I also study aging, and a lot of the things he said about the causes of aging were right on," Bickford said. "I disagree on a few things. You can't just cure arteriosclerosis and everyone is going to live a thousand years. We would have to target all those key things that are changing with aging and I am not sure we are going to be there as soon as he thinks we are."

Black weighed in: "Throughout history the human lifespan has never exceeded about 120. That is the part that I think traditional gerontologists are struggling with. There's a maximum life span for all species, including humans and that's the part we are waiting to see, and we are not quite sure, but innovative thinking and science can take us to places we don't know. So, I don't want to be entirely pessimistic. But I guess I just want to be more cautious." The first 30 extra years don't bother Black and Bickford as much as the next 30 years later, up to 150, they said. "Throughout history that has never occurred," Black said. "That's the one piece we are stuck on but we are willing to travel this road and see." "He's right as far as the areas that need to be targeted," Bickford said. "I just think you would have to target all seven or nine at the same time and maybe even more for this to be put in practice to actually get that 30 years."

There is a well known association between intelligence and life expectancy, part of a web of related correlations that include wealth, social status, networks of relationships, and education, among others. In the case of intelligence, there is the intriguing possibility that genetics plays a significant role in this statistical relationship with longevity, and effects on life span are not just the results of a greater capability to succeed in obtaining wealth, status, and a consequently better usage of medical technology, for example. This paper points out that some of the same genetic variants influence determinants of both intelligence and mortality:

Cognitive functioning is positively associated with greater longevity and less physical and psychiatric morbidity, and negatively associated with many quantitative disease risk factors and indices. Some specific associations between cognitive functions and health appear to arise because an illness has lowered prior levels of cognitive function. For others, the direction of causation appears to be the reverse: there are many examples of associations between lower cognitive functions in youth, even childhood, and higher risk of later mental and physical illness and earlier death. In some cases, it is not clear whether illness affects cognitive functioning or vice versa, or whether both are influenced by some common factors. Overall, the causes of these cognitive-health associations remain unknown and warrant further investigation. It is also well recognized that lower educational attainment is associated with adverse health outcomes, and educational attainment has been used as a successful proxy for cognitive ability in genetic research.

The associations between cognitive and health and illness variables may, in part, reflect shared genetic influences. Cognitive functions show moderate heritability, and so do many physical and mental illnesses and health-associated measures. Therefore, researchers have begun to examine pleiotropy between scores on tests of cognitive ability and health-related variables. Pleiotropy is the overlap between the genetic architecture of two or more traits, perhaps owing to a variety of shared causal pathways. Originally, the possibility of pleiotropy in cognitive-health associations was tested using family- and twin-based designs. However, now data from single-nucleotide polymorphism (SNP) genotyping can assess pleiotropy, opening the possibility for larger-scale, population-generalizable studies. We aimed to discover whether cognitive functioning is associated with many physical and mental health and health-related measurements, in part, because of their shared genetic aetiology using the recently released UK Biobank genetic data. We curated genome-wide association study meta-analyses for 24 health-related measures, and used them in two complementary methods to test for cognitive-health pleiotropy.

Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.

Link: http://dx.doi.org/10.1038/MP.2015.225

There is a contingent of researchers who see increased levels of telomerase as a viable therapy to slow aging, and shortened telomeres as a contributing cause of aging. Below find linked an open access paper written from that perspective.

It is certainly the case that genetic engineering of mice to produce additional telomerase results in a modest extension of life, though not as much as initially reported. It seems to generally boost regenerative activity, which results in similar outcomes to stem cell therapies. The primary mechanism associated with telomerase is the lengthening of telomeres, the repeated DNA sequences at the end of chromosomes that act as a counter of cell divisions - a little is lost each time a cell divides and replicates its DNA. While some researchers see shortened telomeres as a cause of aging, it seems pretty clear to me, and others, that average telomere length as presently measured is a reflection of processes of aging, not a cause. There has in the past been some discussion of other ways in which telomerase might be acting on life span, such as by affecting the pace of mitochondrial damage, for example.

In this review, we will discuss the role of telomeres in the origin of age-associated diseases and organismal longevity, as well as the potential use of telomerase as a therapeutic target to delay aging and to prevent and treat age-related diseases. Aging is a multifactorial process that results in a progressive functional decline at cellular, tissue, and organismal levels. During recent years, a number of molecular pathways have been identified as main molecular causes of aging, including telomere attrition, cellular senescence, genomic instability, stem cell exhaustion, mitochondrial dysfunction, and epigenetic alterations, among others. Interestingly, telomere attrition is considered a primary cause of aging, as it can trigger all the above-mentioned hallmarks of aging, although the degree to which it is a principal cause of aging is under active investigation. Critical telomere shortening elicits the induction of cellular senescence or the permanent inability of cells to further divide, which in turn has been proposed to be at the origin of different disease states. In addition, telomere attrition in the stem cell compartments results in the exhaustion of their tissue- and self-renewal capacity, thus also leading to age-related pathologies.

A substantial number of companies are now aiming to harness the knowledge that has been generated, unveiling the molecular mechanisms of aging in order to develop a new class of drugs to prevent and treat the major age-related diseases. In this regard, telomerase overexpression studies in mice have been proof of principle that just modifying a single hallmark of aging, i.e. telomere shortening, this was sufficient to delay not one but many different age-associated pathologies in mice, including cognitive decline. Indeed, the use of telomerase activation in delaying aging-associated conditions has spurred the interest of commercial enterprises.

It is likely that the first clinical use of a telomerase reverse transcriptase (TERT)-based therapy, such as the TERT gene therapy approach developed by us, will be for the treatment of the human telomere syndromes, including aplastic anemia and pulmonary fibrosis. However, this requires the development of appropriate preclinical models and the subsequent clinical trials in humans. In this regard, we have recently generated two mouse models which recapitulate the clinical features of aplastic anemia and pulmonary fibrosis. The disease in both models is provoked by short and dysfunctional telomeres and thus these models provide a platform for further testing of TERT-based treatment strategies for the telomere syndromes.

Given that physiological aging is provoked, at least in part, by telomere shortening, a TERT gene therapy may be used not only for the prevention and treatment of telomere syndromes but also for the treatment of multiple age-related diseases. In this regard, short telomeres have been extensively associated with a higher risk for cardiovascular disease. In support of a potential use of TERT activation in the treatment of age-related diseases, we demonstrated that TERT gene therapy can efficiently rescue mouse survival and heart scarring in a preclinical mouse model for heart failure upon induction of acute myocardial infarction. Collectively, experiments in cell and animal models provide proof of concept for the feasibility of telomerase activation approaches to counteract telomere shortening and its consequences. In particular, the successful use of telomerase gene therapy in animal models of aging and short telomere-related diseases paves the way for the development of therapeutic telomerase treatments in human aging and associated disease.

Link: http://dx.doi.org/10.12688/f1000research.7020.1

Cross-links are in essence a type of damage resulting from metabolic waste, a natural side-effect of the normal operation of our cellular biochemistry. Many different types of sugary molecules known as advanced glycation end-products (AGEs) end up in the spaces between cells and can react with and link together the intricate structures of the extracellular matrix. The arrangement and constituents of the matrix are what gives each tissue its particular set of properties: elasticity in skin and blood vessels, the ability to bear load without brittleness in cartilage and bone, and so forth. The presence of cross-links in significant numbers sabotages these properties, such as by preventing long, parallel molecular structures from sliding freely past one another. Further, there is evidence to suggest that AGEs produce raised levels of chronic inflammation by altering cellular behavior through the receptor for AGEs, RAGE. Inflammation contributes to the pathology of all of the common age-related diseases.

Most cross-links formed by AGEs are transient, and perhaps only significant in an abnormal metabolism, such as that produced by obesity or type 2 diabetes. The present consensus is that the real problem - leading to age-related loss of skin elasticity and stiffening of blood vessels, among other issues - is produced by a single type of hardy cross-link formed by one type of AGE called glucosepane. Studies suggest that glucosepane makes up the overwhelming majority of cross-links in old humans, and our natural biochemistry is not equipped with tools that can effectively remove these chains.

This is one compound, and to greatly reduce its contribution to aging all that is needed is one moderately effective drug candidate that can break it down. This drug candidate would have as its target market more than half of the human race - pretty much everyone over the age of 30. Yet the broader research community has shown no interest in this goal, an issue we might blame on the lack of tools for working with glucosepane. Any research group diving into this problem would have to build all of the tools from scratch, and that means that near everyone who did take the time to think about it has chosen, again and again, to work on other, more accessible problems instead. This sort of situation requires philanthropy to break the log jam, and thus the only significant funding for glucosepane research in the past few years has come from the SENS Research Foundation, via philanthropists such as Jason Hope, and of course the charitable support of this community.

Nonetheless, because this is a narrow domain problem, the search for one drug candidate for one target, I believe it is the most likely SENS technology to follow on from senescent cell clearance as next in line for commercial development. A method of senescent cell clearance is currently being developed by Oisin Biotechnology, and whatever happens next after that in the SENS space is probably a race between a viable glucosepane breaker drug and transthyretin amyloid clearance, with mitochondrial DNA repair just a few years behind those. However, my knowledge of the latest activity has been getting out of date, so I recently talked to some of the people involved; Aubrey de Grey of the SENS Research Foundation, David Spiegel who runs a lab at Yale, and William Bains who collaborates with an eclectic range of researchers in numerous fields, including this one. What follows is a rough summary of their thoughts on the matter.

A Way to Make Glucosepane is a Big Step Forward

The Spiegel lab developed a reliable way to make glucosepane last year. This is a big deal because people who could not previously collaborate with this type of research can now set up their own studies and investigations. It also ensures that, at least for the foreseeable future, everyone is working from the same definition of what exactly is meant by glucosepane and its particular molecular structure.

There are Still Doubts Over the Glucosepane Consensus

The consensus on glucosepane as the overwhelming majority of relevant cross-links in the process of aging is not airtight - there are growing doubts. It is perhaps reasonable to think that it should be the primary target based on the evidence to date, and Spiegel is optimistic that useful therapies will emerge, but de Grey is cautious, and Bains somewhat unhappy about the poor quality of some past research on this topic. If there was a way to break glucosepane, then doubts could be rapidly solidified or put to rest, but that still lies in the future. The SENS Research Foundation is presently funding research with Jonathan Clark at the Babraham Institute to attempt to ratify that glucosepane is the target, determine whether or not there are other targets, and establish that the present understanding of the structure of glucosepane is in fact the right thing to aim for. Remember that a molecule made of a given set of constituent parts might have a poorly understood shape when folded, these molecules are large and complicated, and shape determines function.

A Drug Candidate Doesn't Exist Yet

There is no drug candidate to clear glucosepane at this time, and not even a speculative idea of where to look for possibilities in the enormous back catalog of existing and explored pharmacology. This lack of direction is a consequence of the lack of exploration of this type of compound in the field. Finding the drug candidate is the big gap that lies between where things stand today and the point at which someone could launch a startup company to finalize a potential glucosepane breaker therapy. The labor required to verify that such a drug candidate works or does not work is modest in comparison to the work of finding such a candidate; this would involve building fairly standard forms of assay to determine levels of glucosepane before and after treatment. One standard approach to this sort of thing would be to equip the immune system with antibodies that react to glucosepane, and then measure the response.

A Drug Candidate Will Most Likely Emerge from Mining the Bacterial World

The Spiegel lab is following the same approach as the LysoSENS research program did over the past decade, which is to search for enzymes in bacteria capable of efficiently breaking down glucosepane. We know they exist because graveyards are not sticky sumps of metabolized sugar. This might actually be discouraging to hear at first, as LysoSENS ran for a decade before transferring the first drug candidates for commercial development by Human Rejuvenation Technologies. However, an enormous advance in the ability to culture bacterial species has taken place in just the past couple of years, an advance not available to the LysoSENS researchers. One of the open secrets of the life sciences used to be that 99% of all bacterial species couldn't be cultured in the lab - but all of a sudden and with a comparatively simple technological advance, that has changed. Everything that bacterial researchers achieved in the past was accomplished with the 1% of bacterial species that were suitable to work with, but now that all bacterial species are fair game, the search space for new molecules has multiplied a hundredfold.

The researchers at the Spiegel lab have already isolated and cultured bacterial species that they are reasonably confident are consuming glucosepane. David Spiegel believes that it might plausibly take two years at the present level of funding to characterize how the bacteria are doing this and whether it involves a simple, single enzyme or something more complicated. If it is a single enzyme, then that can move fairly rapidly to becoming a drug candidate. If not, well, it is probably faster just to look for more bacteria with better candidates. This is a research project that could move faster with more money, as the activities can be carried out in parallel were there more researchers on the staff - but of course raising funds for research in this field is ever a challenge.

Note that I'm glossing over the challenges inherent in picking out enzymes from bacteria and turning them into drugs. There are often unwanted effects, such as triggering of the immune system, that have to be designed out. Many of the options for working around this problem, such as encapsulating drug molecules in a protective sheath, are not practical for something that is intended to get into the tiny spaces of the extracellular matrix. And so on. But these are all challenges that can be addressed, extra work requiring technologies and approaches from elsewhere in the research community to be pulled in.

Two Models for Future Commercial Development

There are two models for commercial development from this point. The first is for an investor with two years of patience, $2 million, and an appetite for risk and uncertainty to come in and fund a company to finish the work started by David Spiegel, William Bains, and Jonathan Clark and their research teams. This sort of thing does happen in many industries, but it is very hard to arrange without deep pockets and good connections. That is why you see this sort of arrangement more often taking the form of a partnership with a pharmaceutical company, as happened for the development of the transthyretin amyloid clearance therapy based on CPHPC.

The other model is to cheer on the researchers, and support them as we can with our donations, for the perhaps few years needed to iron out the doubts about glucosepane, and find a candidate bacterial enzyme. Once they are within striking distance of a proof of concept in mice or rats, then a seed-funded startup could be founded and work proceed from that point. That is much easier to swing for this community - if Oisin managed to obtain seed funding from SENS supporters, then a glucosepane-breaker company could certainly do so to the same level a few years from now.

The Palo Alto Longevity Prize launched back in 2014, one of a number of research prizes created over the past decade aimed at encouraging greater progress in the application of aging research. This popular press article takes a look at one of the competitors, but note it is garbling the science in a few places. In particular the line on quadrupling mouse life span is probably a reference to a study on a mouse model of multiple sclerosis or similar work on short-lived lineages where any intervention will greatly extend remaining life span by partially fixing the problem that is killing the mice at a young age. Certainly no-one has yet quadrupled remaining life span in normal aged mice - that would be an event echoed around the world.

Researchers say a drug that blocks a protein produced by aging cells in your body could control how fast you grow older. They were contacted by the Palo Alto Longevity Prize to compete against teams from all over the world for $1 million. The protein, known as plasminogen activator inhibitor-1, or PAI-1, normally helps control the body's clot-dissolving system. The scientists believe controlling the protein is a way to prolong life. "The biology of aging is becoming more evident every day that goes by. We're understanding that there are specific changes about cells and tissues as they age, and that there are markers that aging cells make and it's possible to identify those molecules and theoretically slow down the aging process."

The interest surrounding longevity research has grown in recent years, especially after Google announced Calico, a longevity research and development company, in 2013. AbbVie, a pharmaceutical and research company, teamed up with Calico in 2014 to understand the biology that controls life span and ultimately accelerate the availability of new therapies for age-related diseases. In the Palo Alto competition, teams can enter one or both of two categories. The $500,000 Homeostatic Capacity Prize is given to the team that can turn back the clock in a mammal. The second is the $500,000 Longevity Demonstration Prize, which is given to the team that can extend the life span of a mammal by 50 percent. Although the deadline for registration was Dec. 31, the competition will not end until 2019 because different therapies have to be tested. Nearly 30 teams are competing with various approaches like hormone therapy and gene modification.

"I think this competition puts a spotlight on aging, and the fact that this science is advancing very rapidly. We're excited to participate because we think we can make a contribution to the understanding of the aging process in mammals. Almost any disease you can think of is highly dependent upon age." Aging more slowly is especially beneficial to people who have chronic diseases that make their cardiovascular health older than it should be. "Aging is the most important risk factor of heart disease, cancer and neurodegenerative diseases. We all want to have a longer, healthier life span. I don't think people want to live a long time and be infirm, but if you can maintain your vitality and function, I think that's a pretty desirable goal."

Link: http://www.chicagotribune.com/business/ct-longevity-research-prize-northwestern-1126-biz-20160125-story.html

A panel session titled "What If You Are Still Alive in 2100?" was held at the World Economic Forum's 2016 meeting last week. I point this out as an indicator of the degree to which the idea of treating aging to greatly extend healthy life spans is percolating into the broader mainstream, with ever more people recognizing both the great opportunity for individuals, as well as the fact that existing institutions of entitlement and wealth transfer fall apart when people live in good health for decades longer than is presently the case. In effect those systems have already failed, are already terrible, fragile, and unethical, and already represent considerable economic risk, but those involved have few incentives to take anything but the most damaging path of ignoring the problem:

Chances are, most of us haven't asked ourselves the question: What if I live until 2100? Most people would probably pin the average human lifespan at somewhere around 70 to 80 years old. But within academia there are some serious discussions being had about what the world will look like when the average person lives past 100. But those discussions are only just beginning to permeate governments and the business world. "What's clear is the major restructuring of life that we think is going to happen with regards to longevity - corporations are not prepared for this. Governments are not prepared for this. It will rest with the individual both working on their own and collectively who will be the agents of change. I expect to see and we are certainly monitoring some amazing experiments occurring over the next decade as people come to terms with what it really means to live 100 years."

It's clear the idea of pushing people out of work at 60 is already behind the times. If we're working longer, we're going to need to keep on learning. So economists think there'll be a shift among people at an older age from a notion of leisure to a notion of recreation. In an elongated life, there will be new life stages. The idea of leisure, work, and retirement will be turned on its head. Individuals will take their own individual paths and have the capacity to transform themselves. The UK government predicts that a child born today will live to 85. That's "obviously ridiculous" but there's a clear reason why governments are sticking to these kinds of estimates, rather than extending life expectancy forecasts to nearer 100. "The reason why they are doing that is that all our pension schemes would go under water and would look more and more like a Ponzi scheme." Corporations and individuals need to realize employees need to work into their 70s and mid-70s - and they'll have to save.

Link: http://www.businessinsider.com/davos-what-if-i-live-to-2100-2016-1

The Global Healthspan Policy Institute is a new group that will focus on lobbying for longevity science, primarily in the US, but some of the participating members bring experience from similar efforts in Europe. This initiative is organized by a mix of new faces and folk you might be familiar with from the International Longevity Alliance and other advocacy organizations in the community. For the past few months the GHPI members have been making connections and setting out an agenda in order to take a swing at the same targets as the Longevity Dividend initiative, which is to say (a) recognition of the value of treating aging among the politicians and bureaucrats who set and allocate public funding for research, and (b) greater funding for those lines of research most likely to produce results. At present, that second point largely boils down to more funding for the National Institute on Aging (NIA), though I imagine that once a debate is opened in earnest many more options than that are on the table.

On that second count, I should say that the initiatives to date, such as the Longevity Dividend, fall down badly to my eyes, as open and public support for SENS rejuvenation research has been pretty thin on the ground among those involved in lobbying. This is, of course, setting aside my views on involving government at all in these matters - the net outcome of the package deal of government funding (National Institutes of Health) plus government regulation (FDA) is a negative to my eyes. Public funding for medical research represents perhaps a third of the overall total, but the FDA certainly represents more than a third of the cost of bringing medicine to market, and that isn't even to start in on the way in which regulatory costs remove many lines of development from economic viability, ensuring that countless new therapies are never built.

I'm in a minority with that position, needless to say. The overwhelming majority of the research community support the existing system, even broken as it is, and would rather work to change it slowly through lobbying than bypass it via philanthropy and medical tourism, as would be my preference. Even outside the research world, the sheer size of public budgets has a mesmerizing effect, I think, causing people to forget that tapping them is a corrupting, difficult process that rarely produces the desired outcome. Just ask the molecular nanotechnologists who tried more than a decade ago to obtain US government support for their work as publicity swelled: they were outmaneuvered by existing factions, and their visions derided and spokespeople attacked where that helped said existing factions. Where funds were deployed in alleged support of nanotechnology development, they went to those organizations already well-equipped with lobbyists, and to existing projects that had nothing to do with nanotechnology as defined in the original vision. It was very much a cautionary tale made real.

In any case, it seems clear that we're reaching the point at which a critical mass of people are enthused by the potential for the medical control of aging, and are now ramping up new organizations to engage the political class and sway present streams of funding. The Global Healthspan Policy Institute have allied with the Longevity Dividend researchers, among others, and are readying for their first efforts to obtain more support for aging research in the US political system. Unlike the Longevity Dividend folk, the Global Healthspan Policy Institute principals are at least somewhat more inclined to support SENS rejuvenation research as a strategy based on what I know of them.

Global Healthspan Policy Institute

For the first time in the history of humanity, we're faced with the prospect of a planet where the elderly outnumber the young. As the broken budgets of already strained healthcare systems struggle to cope with this revolutionary shift and the associated burden of degenerative disease, new science tells us we are within reach of healthier, longer lives - while our public policies remain decades out-of-step.

We're leading the charge in bold new policy initiatives on Capitol Hill and around the world, ensuring that policy makers have the tools and resources they need to make the right decision for the people they represent. We invite you to learn more about our mission, principles, and priorities as we take the steps necessary to bring our timely and powerful message to the world.

We are a patient-centered, consumer-oriented public policy coalition and 501c3 nonprofit thinktank working directly with members of the healthspan research industry and scientific community worldwide in support of the large-scale research and development of new treatments to address the underlying causes of aging-related disease. Our direct role is to facilitate the inclusion of all relevant stakeholders in a think tank setting in order to create broader consumer and regulatory acceptance for new treatments relevant to our core purpose of advancing the development of immediate interventions for aging-related disease.

New Thinktank to Promote Research, Innovation for Treatment of Underlying Causes of Aging-Related Disease

A new think tank to support the research and development of innovative treatments for the underlying causes of aging-related disease has been founded in Washington, D.C. The Global Healthspan Policy Institute represents a member network of over 50,000 international supporters. GHPI's present focus is in educating Congress and members of the Administration on the current impact of aging-related disease on public health, well-being, and the economy: (1) Nearly 75% of all U.S. deaths are linked to 9 aging-related diseases. (2) By 2030, the number of U.S. adults aged 65 years or older will more than double, to about 71 million, and Medicare spending will increase by 25% ($9 billion). (3) One-third of all Medicare spending ($15,000 per person) is tied to aging disease. (4) The economic value of treating the underlying causes of aging-related disease in the U.S. - instead of just one disease at a time - is projected at $7.1 trillion for the next 50 years.

"Medicare and the healthcare systems have spent untold trillions on the 'one disease, one cure, one treatment' model. However, if we address the aging processes that are happening in our bodies right now - and that will lead to a host of new and existing diseases in the future - we can stop these problems before they ever begin, and halt the economic crisis that's bankrupting America. Extending the healthspan, and dramatically reducing the period of compromised living, is now clearly in sight. Longer, healthier living is no longer a hope for the future. It is a reality for the present if we will embrace and invest in the current options that are available to us."

The authors of this paper propose that suitably tailored periodic destruction of cells combined with cell therapies to replace lost cells could have an impact on many of the forms of cell and tissue damage that cause aging. This is not something that can be achieved today with suitable control over the results at the detail level, but that level of control is a plausible target to aim for in the decades ahead. While looking this over, it might be worth recalling a study published last year in which researchers caused low-quality cells to be continuously destroyed in flies. There is an existing mechanism by which cells compare quality, connected to the triggering of programmed cell death, and the operation of these processes can be adjusted, as was the case in that study. The result was flies that lived 50% longer, an interesting result in this context.

In both biomedicine in general and biomedical gerontology in particular, cell replacement therapy is traditionally proposed as an intervention for cell loss. This paper presents a proposed intervention - Whole-body Induced Cell Turnover (WICT) - for use in biomedical gerontology that combines cell replacement therapy with a second therapeutic component so as to broaden the therapeutic utility of cell therapies and increase the categories of age-related damage that are amenable to cell-based interventions. In particular, WICT may allow cell therapies to serve as an intervention for accumulated cellular and intracellular damage, such as telomere depletion, gDNA and mtDNA damage and mutations, replicative senescence, functionally-deleterious age-related changes in gene expression, accumulated cellular and intracellular aggregates and functionally-deleterious post-translationally modified gene products.

WICT consists of the gradual ablation and subsequent replacement of a patient's entire set of constituent cells gradually over the course of their adult lifespan via the quantitative and qualitative coordination of targeted cell ablation with exogenous cell administration. The aim is to remove age-associated cellular and intracellular damage present in the patient's endogenous cells. Here we outline the underlying techniques and technologies by which WICT can be mediated, describe the mechanisms by which it can serve to negate or prevent age-related cellular and intracellular damage, explicate the unique therapeutic components and utilities that distinguish it as a distinct type of cell-based intervention for use in biomedical gerontology and address potential complications associated with the therapy.

Link: http://dx.doi.org/10.1089/rej.2015.1763

A small number of species show few or no apparent signs of age-related degeneration across near all of a life span, such as lobsters, naked mole rats, urchins, and so forth. This phenomenon is known as negligible senescence and is of considerable interest to the life science community. Here, researchers provide evidence for an ant species to be negligibly senescent:

Once quick and strong, both body and mind eventually break down as aging takes its toll. Except, it seems, for at least one species of ant. Pheidole dentata, a native of the southeastern U.S., isn't immortal. But scientists have found that it doesn't seem to show any signs of aging. Old worker ants can take care of infants, forage and attack prey just as well as the youngsters, and their brains appear just as sharp. "We really get a picture that these ants - throughout much of the lifespan that we measured, which is probably longer than the lifespan under natural conditions - really don't decline." Such age-defying feats are rare in the animal kingdom. Naked mole rats can live for almost 30 years and stay spry for nearly their entire lives. They can still reproduce even when old, and they never get cancer. But the vast majority of animals deteriorate with age just like people do.

In the lab, P. dentata worker ants typically live for around 140 days. Researchers focused on ants at four age ranges: 20 to 22 days, 45 to 47 days, 95 to 97 days and 120 to 122 days. Unlike previous studies, which only estimated how old the ants were, this work tracked the ants from the time the pupae became adults, so researchers knew their exact ages when putting them through a gamut of tests. The researchers expected the older ants to perform poorly in all these tasks. But the elderly insects were all good caretakers and trail-followers - the 95-day-old ants could track the scent even longer than their younger counterparts. They all responded to light well, and the older ants were more active. Ants of all ages attacked fruit flies with the same level of aggressiveness, flaring their mandibles or pulling at the fly's legs.

Then the researchers compared the brains of 20-day-old and 95-day-old ants, identifying any cells that were on the verge of dying. They saw no major differences with age, nor was there any difference in the location of the dying cells, showing that age didn't seem to affect specific brain functions. Ants and other insects have structures in their brains called mushroom bodies, which are important for processing information, learning and memory. The researchers also wanted to see if aging affects the density of synaptic complexes within these structures - regions where neurons come together. Again, the answer was no. The old ants didn't experience any drop in serotonin or dopamine levels either, two brain chemicals whose decline often coincides with aging.

Link: http://www.smithsonianmag.com/science-nature/these-unusual-american-ants-never-get-old-180957887/

Death, aging, and politics: insofar as I have views on these things, I'm against them all. There are deep mysteries in this universe of ours, the Fermi Paradox central to them all, and you can't make progress in these things if you are dead, dying, or drowned in the yammering of those who seek to divide a present stasis rather than build a dynamic, better future. The only thing that matters in the long term is technology, and of that technology the most important facets at present are those involved in the development of rejuvenation therapies that will enable either us or our immediate descendants to remain here, in this world, to see the long term up close and in person. That isn't exactly philosophy, but it does the job for me.

I don't think it is any big secret that the history of philosophy is replete with people giving serious consideration to death and the principle modes of getting to that state, such as aging, and from there what to do about it. In ancient times, the development of strategies for coping with the inevitability of suffering and death was a fine art. The best of these, such as the varieties of stoicism, are so good that they have survived for more than two thousand years in much the same form. We still have access to copies of the original advice as it was written in many cases, and that is only the case because forty generations of humanity have found worth in these thoughts. A great change is underway at present, however, a discontinuity in the making that within our lifetimes will separate both us and our descendants from thousands of years of civilized rumination on the human condition. We are building technology that will radically change what it is to be human in many ways - and of course the part of this great transition that I am most interested in is the end of aging and involuntary death. Ultimately there will be an end to suffering too, and any need for stoicism will be buried by the paradise engineering of the more distant future, but we have to start at the top of the list.

Over at The Meaning of Life, you'll find a recently posted collection of interesting references to various positions on death, suffering, and aging. It is worth perusing. After all, we should be able to deploy a good answer to anyone who earnestly asks why we do this, why we care, why we seek to bring an end to aging and age-related disease. The first place to look for good answers is in the works of those who have spend a good deal more time than you and I thinking on the topic. A part of that reading is a matter of understanding the mistaken paths, as sadly many of these people arrived at positions on death and suffering that supporters of radical life extension would reject out of hand. The world is full of those who embrace the march towards death, or even the extinction of all life, and who believe that longer healthy lives would somehow be a loss rather than a gain. This contingent of humanity has its philosophers, just as do those who, instead of accepting what is, reach to make something greater and better of the human condition.

Summary of Nick Bostrom's, "The Fable of the Dragon-Tyrant"

Bostrom's article, "The Fable of the Dragon-Tyrant," tells the story of a planet ravaged by a dragon (death) that demands a tribute which is satisfied only by consuming thousands of people each day. Given the ceaselessness of the dragon's consumption, most people did not fight it and accepted the inevitable. Finally, a group of iconoclastic scientists figured out that a projectile could be built to pierce the dragon's scales.

Summary - We should try to overcome the tyranny of death with technology.

Summary of James Lenman's Immortality: A Letter"

Lenman's article, "Immortality: A Letter," (1995) concerns a letter from a fictional philosopher to her fictitious biological friend in which she presents arguments against taking his immortality drug. She worries that if only some people get the drug, those who don't will regret it; while if everyone gets the drug, overpopulation will ensue unless people stop having children. But this will lead to more unhappiness, as people want to have children. Most importantly immortality would undermine our humanity by transforming us into different kinds of beings. In addition an immortal life might become boring. And finally the value of life derives in large part from its fragility, which would be undermined by immortality.

Summary - More value will be lost than gained if we become immortal.

John Leslie's, "Why Not Let Life Become Extinct?"

In the end, we cannot show conclusively that we should not let life become extinct because we can never go from saying that something is - even happiness or pleasure - to saying that something should be. And it is also not clear that maximizing happiness is the proper moral goal. Perhaps instead we should try to prevent misery - which may entail allowing life to go extinct. Philosophers do not generally advocate such a position, but their reluctance to do so suggests that they are willing to tolerate the suffering of some for the happiness of others.

Summary - There are strong arguments for letting life go extinct, although Leslie suggests we generally reject them because life has intrinsic goodness.

Summary of David Benatar's, Better Never to Have Been

It is commonly assumed that we do nothing wrong bringing future people into existence if their lives will, on balance, be good. This assumes that being brought into existence is generally beneficial. In contrast Benatar argues that: "Being brought into existence is not a benefit but always a harm." While most maintain that living is beneficial as long as the benefits of life outweigh the evil, Benatar argues that this conclusion does not follow. Benatar concludes by saying: "One implication of my view is that it would be preferable for our species to die out."[ii] He claims that it would be heroic if people quit having children so that no one would suffer in the future. You may think it tragic to allow the human race to die out, but it would be hard to explain this by appealing to the interests of potential people.

Summary - It is better never to come into existence as being born is always a harm.

Summary of Steven Luper's, "Annihilation"

In his essay "Annihilation," Luper argues that death is a terrible thing and that Epicurus' indifference to death is badly mistaken. Death is a misfortune for us primarily because it thwarts our desires. If we have a desire we want fulfilled, then death may prevent its fulfillment; if we enjoy living, then dying prevents us from continuing to do so; if we have hopes and aspirations; then they will be frustrated by our deaths; if we have reasons to live, then we have reasons not to want to die. For all these reasons death is a grave misfortune.

Summary - Death is a misfortune because it thwarts our desires.

Summary of George Pitcher's, "The Misfortunes of the Dead"

By definition harms are events or states of affairs contrary to your desires or interests. Of course we cannot be killed or experience pain after death - the post mortem person can't be harmed - but we can have desires thwarted after death - the ante mortem person can be harmed. If I desire to be remembered after I die with a statue on campus and you destroy the statue, then you have defeated my desire and harmed the ante-mortem person I was. Pitcher doesn't think he needs to invoke backward causation to make his argument work. All he needs to show is that being harmed does not entail knowing about the harm.

Summary - We are harmed by death because while alive the knowledge of death harmed us.

Oswald Hanfling on Death and Meaning

Hanfling accepts as obvious the claim that meaning is affected by our knowledge of death, and agrees that "death casts a negative shadow over our lives." Moreover, while the naturalness of death may provide some consolation from our anxiety, it does not show that our apprehension about death is misplaced. But are there any overriding reasons to regard death as mostly evil? Hanfling does not think such reasons are convincing. For while I may wish to fulfill some goal and regret that I cannot, I will not be harmed after my death by the fact that I didn't fulfill that goal. Or though one might argue that death is bad because life is good, it is unclear whether life in general is good.

Summary - The thought of death is unpleasant, but we cannot determine the implications of death for meaning.

Summary of Stephen Rosenbaum's "How to Be Dead and Not Care: A Defense of Epicurus"

In his 1986 piece, "How to Be Dead and Not Care: A Defense of Epicurus," he rejects the view that death is bad for the person that dies, undertaking a systematic defense of the Epicurean position. As we have seen, while we ordinarily think that death is bad for the person that dies, Epicurus argued that this is mistaken. And, since fear of something that is not bad is groundless, it is irrational to fear death.

Summary - The Epicurean argument that death is not bad and nothing to fear is sound. Being dead is not bad for the dead person.

Summary of Vincent Barry's Philosophical Thinking about Death and Dying

One of Barry's main concerns is whether death is or is not bad for us. As he notes, the argument that death is not bad derives from Epicurus' aphorism: "When I am, death is not; and when death is, I am not." Epicurus taught that fear in general, and fear of the gods and death in particular, was evil. Consequently, using reason to rid ourselves of these fears was a primary goal of his speculative thinking. A basic assumptions of his thought was a materialistic psychology in which mind was composed of atoms, and death the dispersal of those atoms. Thus death is not then bad for us since something can be bad only if we are affected by it; but we have no sensation after death and thus being dead cannot be bad for us.

Epicurus' argument relies on two separate assumptions - the experience requirement and the existence requirement. Counter arguments attack one of the two requirements. Either they try to show that someone can be harmed without experiencing the harm, or that someone who is dead can still be harmed. While there are many arguments that death makes life meaningless, there are also many philosophical arguments, in addition to religious ones, that death makes life meaningful. These latter arguments all coalesce around the idea that death is necessary for a life to be truly human. In opposition to all those who think death does or does not give meaning to life are those who argue that life has or lacks meaning independent of death. In other words, they argue that life gives or does not give meaning to death, thereby turning all our previous considerations upside down. But how does a life give or not give death a meaning?

Summary - It is uncertain if death is a good or bad thing. The connection between death and meaning is that thinking about death can make a life subjectively meaningful.

Summary of Tolstoy's, The Death of Ivan Ilyich

Leo Tolstoy's short novel,The Death of Ivan Ilyich, provides a great introduction to connection between death and meaning. It tells the story of a forty-five year old lawyer who is self-interested, opportunistic, and busy with mundane affairs. He has never considered his own death until disease strikes. Now, as he confronts his mortality, he wonders what his life has meant, whether he has made the right choices, and what will become of him. Tolstoy's story forces us to consider how painful it is to reflect on a life lived without meaning, and how the finality of death seals any possibility of future meaning. If, when we approach the end of our lives, we find that they were not meaningful - there will be nothing we can do to rectify the situation.

Summary - Confronting the reality of death forces us to reflect on the meaning of life.

Aging is caused by a number of processes, each of which contributes its own form of cell and tissue damage to the bigger picture of breakage and decline. When shaping research strategy, it seems sensible to ask which of these processes is the most important cause of aging: there are limited funds for scientific and clinical development, and we'd like the research community to start at the top of the list. Is this a question that has a simple answer, however? The author of this open access paper would say no, pointing out that the processes and damage of aging interact with one another, and even in very simple models of interacting systems you cannot talk about significance of a single process in isolation, as interacting processes have synergies.

The background for this discussion is another question: can we obtain meaningful benefits to longevity by fixing just one of the forms of damage that cause aging? Insofar as there is a consensus at the moment, that consensus is "no." Even a perfect repair of one cause of aging will still leave medical conditions largely or completely caused by the others, conditions that will kill people on the same schedule as the smaller set of age-related diseases that are prevented or diminished by this narrow scope repair. Taking the other side, the author here proposes that the existence of interactions between forms of damage means that repair of one form of damage may indeed produce a large benefit - but whether this happens in reality is strongly dependent on details that we'll only learn in the near future by building and using rejuvenation therapies capable of this repair:

It becomes clearer and clearer that aging is a result of a significant number of causes and it would seem that counteracting one or several of them should not make a significant difference. Taken at face value, this suggests, for example, that free radicals and reactive oxygen species (ROS) do not play a significant role in aging and that the lifespan of organisms cannot be significantly extended. In this review, I point to the fact that the causes of aging synergize with each other and discuss the implications involved. One implication is that when two or more synergizing causes increase over time, the result of their action increases dramatically.

Here is a summary of what we have learned so far as a result of the analysis of aging and its mechanisms in yeast: during the replicative lifespan of yeasts some damage, such as protein aggregates and some mutations, accumulates and this potentially may lead to further damage. The damage accumulated during the replicative lifespan, but not due to mutations, is sufficient to eliminate the ability of the cells to reproduce but does not kill them in the literal sense of the word. In the subsequent period, as a result of further damage, aging accelerates, likely because the causes of aging, whose levels increase, synergize with each other and this finally leads to death. The synergizing causes likely include genomic changes and aggregates formation, as well as other forms of damage such as oxidative stress.

Due to the existence of synergistic interactions between the causes of aging, our perception of which causes are most important is influenced by a relativistic effect. Thus, to the observers investigating the toxicity of free radicals and/or their role in aging, they appear as the main cause, while the other causes appear insignificant, but the opposite appears to be the case for those that study other causes. Both are correct but also incorrect, specifically since the "other causes" are not insignificant! In reality, the processes are interdependent and it cannot be said that a given cause is responsible for 3% of aging, while another one for 33.3%. This undermines the arguments of those who suggest that the free radical theory of aging is dead or about to die, while certainly the free radicals and ROS are not the only important causes of aging. The same could be said for other theories, so such theories are still alive, at least for now. Since the causes of aging are synergizing, it is also concluded that none of them is the major one but many including free radicals, etc, play significant roles. It follows that health/lifespan might be significantly extended if we eliminate or even attenuate the increase of a few or even just one of the causes of aging.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712935/

Hypertension, chronic high blood pressure, is largely a consequence of arterial stiffening, which in turn is caused by processes such as low-level accumulation of cross-links in the extracellular matrix, a form of metabolic waste that our biochemistry cannot effectively remove. One of the many harms done by hypertension is to cause a slow remodeling of portions of the heart, making it larger, weaker, and more prone to failure. The ideal solution to this problem is to remove the root cause - break the cross-links and repair the other forms of cell and tissue damage that degrade the elasticity of blood vessel walls. The medical research community is, as a rule, much more focused on proximate causes and their manipulation, however. So here, researchers identify genes and proteins necessary for the untoward growth and weakening of the heart in response to hypertension - the first step to a treatment that fails to address hypertension, but would diminish one of its consequences. This is the sort of outcome that tends to emerge from restricting the view to proximate causes; just as much time and effort goes into producing a therapy, but the therapy is limited in its scope, and the underlying problem continues on to cause numerous other issues:

Researchers have identified how two proteins, p38 gamma and p38 delta, control the growth of the heart and its adaptation to high blood pressure. The results not only increase our understanding of the mechanisms used by cardiac cells to grow and adapt, but could also help in the design of new strategies to treat heart failure caused by excessive growth of the heart. The heart adapts to the changing needs of each stage of life by adjusting its size. In this way the heart grows in line with the rest of our body, including during pregnancy, in a process called cardiac hypertrophy. However, excessive physical exercise, hypertension, and obesity can trigger excessive heart growth (pathological hypertrophy), a situation that can lead to a heart attack. Understanding the molecular processes that regulate heart function and growth is therefore of immense importance.

The researchers found that p38 gamma and p38 delta regulate the growth of the left ventricle, the largest and strongest heart chamber, responsible for pumping oxygenated blood to the body. The research team showed that the hearts of mice lacking these proteins are smaller than normal. These hearts, although they function normally, are incapable of responding to external stimuli, such as high blood pressure. The discovery advances understanding of the mechanisms through which heart cells grow and adapt. Moreover, "this new information could help in the design of new strategies to combat heart conditions caused by anomalous growth of heart muscle."

Link: http://www.eurekalert.org/pub_releases/2016-01/cndi-tpc011916.php

The recent increase in size of the centenarian population, happening as it did over a comparatively short period of time, is one measure of the steady increase in human life expectancy at older ages, achieved through progress in medical science and a growing wealth that grants access to the resulting treatments. The size of the very aged population is also subject to variations in the size of birth cohorts, however. It is far from true that the same number of people were born in every year over the past century, or even that the historical numbers are a smooth increase that matches the growth in overall population. The 1940s to 1960s saw a large rate of births in the US in comparison to later decades, for example. From the data for the first decades of the 20th century, a time of declining births in the US, we might expect the present centenarian population to fall over the next few decades if birth cohort size year after year were the only determinant. It isn't, of course.

In extreme old age, the greatest determinants of continued survival are at present some combination of genetics and use of medical technology. The latter will outstrip the former in its degree of influence over life span and health in old age, but over the course of recent decades gains in remaining life expectancy in old age have been very slow in coming. This is a trend of perhaps one year gained for every decade of progress when considering life expectancy at 60, for example. Such slow improvement is the result of a medical and research community that has focused on treating end stages of age-related disease without aiming for prevention in any significant way and without aiming to treat the true root causes, which is to say the processes of aging that produce accumulating cell and tissue damage. Patching over the problem of an age-related disease is expensive and produces marginal results: patches don't last when the damage, the underlying cause of the problem, continues to grow unaddressed.

This will change dramatically in the years ahead as rejuvenation technologies after the SENS model emerge from the laboratories. The difference between not treating the causes and treating the causes will be night and day in terms of the effects on age-related disease and mortality rates. A great upward discontinuity in life expectancy lies ahead, ultimately making the genetics of survival in old age irrelevant. After the advent of a complete toolkit of rejuvenation treatments capable of repairing the damage that causes aging, no-one will have to suffer in the state of being heavily damaged and on the brink of organ failure for years on end. In the average adult individual who bears little of that damage, currently only people not yet in their 40s, genetic variation has next to no effect on mortality rates.

More Americans Living Past 100, Thanks to Modern Medicine

More Americans than ever before are living past the age of 100, according to a new report (PDF) from the U.S. Centers for Disease Control and Prevention (CDC). The agency finds the number of the centenarians increased by 43.6 percent between 2000 and 2014 - from 50,281 to 72,197. Currently, there are some 317,000 centenarians worldwide, and that number is projected to rise to about 18 million by the end of this century, according to one report published in 2014.

In 2014, the top five causes of death among the oldest of the old were heart disease, Alzheimer's disease, stroke, cancer, influenza and pneumonia. Unfortunately, the number of super seniors dying from Alzheimer's disease continues to rise. Between 2000 and 2014, the rates of Alzheimer's disease-related deaths increased by 119 percent. Rates of deaths from other causes also spiked within the same time period, including hypertension (88 percent), chronic lower respiratory disease (34 percent) and unintentional injuries (33 percent). However fewer centenarians are dying from other causes. Between 2000 and 2014 the rate declined by 48 percent for influenza and pneumonia, 31 percent for stroke and 24 percent for heart disease.

Mortality Among Centenarians in the United States, 2000-2014 (PDF)

National Vital Statistics System mortality data for years 2000 through 2014 were analyzed to determine the number of deaths, age-specific death rates by race and ethnicity, and sex-specific leading causes of death among centenarians. As the population in the United States has aged, the number of deaths among centenarians continues to increase. Death rates increased for both male and female centenarians from 2000 through 2008 and decreased from 2008 through 2014. Deaths for females accounted for more than 82% of total deaths each year, and females accounted for 80%-84% of the total centenarian population from 2000 through 2014. Heart disease remained the leading cause of death in 2014 as in 2000 for both male and female centenarians.

Researchers here demonstrate the ability to grow neural networks, consisting of neurons linked by long axons, in the laboratory and transplant them into rats, where they integrate with brain tissue. This is a strategy that might in the future be employed to augment the natural plasticity of brain tissue, or repair damage in the central nervous system, as long axons don't to tend to regrow on their own:

Complex brain function derives from the activity of populations of neurons - discrete processing centers - connected by long fibrous projections known as axons. When these connections are damaged, by injury or diseases such as Parkinson's or Alzheimer's disease, they, unlike many other cells in the body, have very limited capacity to regenerate. Researchers have shown that lab-grown neural networks have the ability to replace lost axonal tracks in the brains of patients with severe head injuries, strokes or neurodegenerative diseases and can be safely delivered with minimal disruption to brain tissue.

Researchers have been working to grow replacement connections, referred to as micro-tissue engineered neural networks (micro-TENNS), in the lab and test their ability to "wire-in" to replace broken axon pathways when implanted in the brain. They have advanced the micro-TENNs to consist of discrete populations of mature cerebral cortical neurons spanned by long axonal projections within miniature hair-like structures. Preformed micro-TENNS can be delivered into the brains of rats to form new brain architecture that simultaneously replace neurons as well as long axonal projections. "The micro-TENNS formed synaptic connections to existing neural networks in the cerebral cortex and the thalamus - involved in sensory and motor processing - and maintained their axonal architecture for several weeks to structurally emulate long-distance axon connections."

In the latest paper, the research team report on a new, less invasive delivery method enabled by applying an ultra-thin coating to the micro-TENNs using a gel commonly found in food and biomedical products. This new biomaterial strategy allows the encapsulation of fully formed engineered neural networks for insertion into the brain without the use of a needle. "We searched for materials that could form a hard shell that would soften immediately following insertion to better match the mechanical properties of the native brain tissue." This, the team hypothesized, would minimize the body's reaction and improve the survival and integration of the neural networks. The additional coating was not detrimental to the number of surviving neurons, and the needleless method substantially reduces the implant footprint, suggesting that it would cause less damage and thus provide a more hospitable environment for implanted neurons to integrate with the brain's existing nervous system.

Link: http://www.uphs.upenn.edu/news/News_Releases/2016/01/cullen/

Many research groups are looking for protein levels and mechanisms that act as regulators or proximate causes of age-related reductions in stem cell activity. Here is one example, focused on tendon tissue:

Aged or degenerated tendons respond poorly to classical medicinal treatments, which often leads to rupture reoccurrence. Until now, several major factors contributing, directly, or indirectly, to tendon aging and degeneration were identified: disturbance of extracellular matrix turnover; decreasing cell numbers and metabolic activity; tenocyte dedifferentiation; and depletion or senescence of the local stem/progenitor cell pool. Tendon stem/progenitor cells (TSPCs) were first reported in 2007 as as plastic adherent cells that express classical stem cell markers while maintaining the expression of typical tendon-lineage genes. It was proposed that tendon healing is carried out mainly by such local tendon progenitor cells, which actively migrate to the wound site and engage in cell proliferation. However, TSPC features alter during tendon aging and degeneration. Aged TSPC display a profound self-renewal deficit accompanied with premature entry into senescence and substantial changes in their transcriptome. Furthermore these cells exhibit severely dysregulated cell-matrix interactions, motility and actin dynamics.

In the current study, we report for the first time that aged TSCP have dysregulated cell-cell interactions mediated by the ephrin family. By comparing young to aged TPSC we found that the expression of several ephrin members is significantly changed. Next, by carefully examining the role of two main candidates, namely the receptors EphA4 and EphB2, we could demonstrate that by activating their reverse signaling we can normalize several of the aged TSCP deficits, the migratory ability and actin turnover. However, only EphA4 stimulation improved aged TSPC cell proliferation to levels comparable to young TSPC. We propose that dysregulation in EphA4-triggered bi-directional signaling may contribute to the inferior and delayed tendon healing common for aged individuals, which will be the focus for upcoming investigation.

Link: http://dx.doi.org/10.3389/fnagi.2015.00246

Here is an interesting question for today's discussion: do present stem cell therapies produce results that we might in any way classify as rejuvenation? The therapies presently available in numerous clinics around the world vary in the type and quality of cells used, and whether they are derived from the patient's tissues. Simple approaches extract cells from fat tissue or cord blood or similar sources and use limited purification to enrich the proportion of stem cells and progenitor cells of various types. More sophisticated approaches standardize to proven, narrow methodologies for a single cell type at high purity levels, such as the widely used mesenchymal stem cells. Further variants involve the addition of scaffolds, nutrient gels, or adjuvant treatments to try to keep the transplanted cells alive and doing their thing for longer. The evidence gathered to date strongly suggests that near all of the stem cell transplant therapies deployed over the past fifteen years produce benefits through signaling: the transplanted cells don't as a rule hang around for long, but they alter the behavior of native cells, such as stem cells and immune cells.

This is a far cry from the class of stem cell treatment envisaged for the future of rejuvenation treatments after the SENS model. That would include the delivery of populations of engineered stem cells, derived from the patient, but with their age-related molecular damage removed. The intention would be for these cells to take up residence, possibly at the same time as the existing damaged stem cell populations are cleared out. It may involve repair of the stem cell niche as well, a more complex and daunting prospect given the complexities of the niches that are well understood. Many more are not, and even if simply delivering new stem cells for the long term, something that is presently beyond the state of the art, there are scores of such cell types. Each will require their own special handling, if the challenges seen so far in regenerative medicine continue to hold true. The reason that only a few cell types are widely used in today's stem cell treatments is that each cell type requires a very different recipe and methodology. It has taken a great deal of time and effort to arrive at the recipes presently in circulation. This SENS approach to stem cell replacement is clearly rejuvenation, however. The old is cast out and the youthful ushered back in.

The closest thing to a SENS-style stem cell therapy that has taken place are the immune system reboot treatments for type 1 diabetes and multiple sclerosis. Chemotherapy is used to kill off the old immune cells and stem cell therapy delivers a new set of cells, albeit not a set of cells with any age-related damage removed. Chemotherapy is an unpleasant thing to go through, but it actually worked. This is quite an old approach in comparison to much of what is discussed here; if you go digging you'll see that it was even attempted with mixed results for rheumatoid arthritis long enough ago to predate the advent of the modern standard treatment of biologics for immune suppression. The need for aggressive chemotherapy seems to have discouraged adoption of this approach, at least until targeted cell killing is a safer, less unpleasant undertaking.

Is this rejuvenation, however? Neither type 1 diabetes nor multiple sclerosis are age-related diseases; they are not a part of aging, though like all non-age-related disease they interact with aspects of aging in ways that are never good for the patient. I think we can all agree that fixing a broken leg isn't rejuvenation, and for the same reasons neither is fixing an immune system that breaks because of inherited genetic mutation, inflammatory injury, or simple bad luck. How about the rest of the modern panoply of stem cell therapies, the much more common and straightforward transplantation to enhance regeneration? These treatments produce benefits by providing a temporary period of (a) increased healing, sometimes regeneration that would never normally happen, such as in heart tissue, in other cases a matter of restoring more youthful levels of healing, (b) reductions in chronic inflammation via interaction with immune cells, and (c) other, less well cataloged changes such as lowered oxidative stress in tissues.

Perhaps the most common form of present day stem cell therapy are those intended to partially address joint wear in the old, such as early osteoarthritis, and the less dramatic but still potentially debilitating cases of middle-aged muscle and tendon damage. There is a high expectation of attaining modest benefits in terms of reduced pain and increased capacity for use, the risks are minimal, and the costs are reasonable - as little as a few thousand dollars with some footwork, even in the broken US medical system. You probably know someone who has investigated the treatment, and if not today then you will a few years from now. If an age-worn joint is marginally improved, but via the actions of your old cells, shoring up old tissues with more age-damaged cells, is that rejuvenation? You are better off, but the joint is no younger in any biochemical measure of aging. I can see the way to argue either side of that question with little difficulty, but on the whole I'm inclined to say that if there is room for debate then the results are not rejuvenation - and thus we're not close enough to the point in the road ahead where we can relax.

Methods of preserving the brain for the long term immediately following death include cryonics, currently a long-standing but small industry, and plastination, a form of chemical fixation that has not yet progressed to the point of commercial availability for this purpose. Why preserve the brain? Because it is a favorable alternative the the oblivion of the grave, one that offers the possibility of a return to active life in a future in which advanced molecular nanotechnology and cellular medicine can be used to restore a preserved individual. In this age of rapid progress in molecular biochemistry more consideration is being given to proving that ideal preservation techniques do in fact preserve the structures thought to encode memory, as if that is not the case then the whole business is moot. Fortunately memory does appear to be preserved based on evidence to date, but the careful consideration continues:

Although most people usually focus on the brain cells when discussing brain preservation techniques, extracellular space is also worthy of consideration. In vivo, extracellular space makes up around 1/5th of overall brain volume, although this varies based on brain region, developmental stage, and surely many other factors. Over the past few months, researchers published two articles relevant to the preservation and importance of the extracellular space. As a very brief summary, one of the things that the authors show is that extracellular space is dramatically lower (less than 1%) following perfusion fixation than it is following their optimized chemical tissue fixation protocol, which involves varying the osmolarity of the buffer. And among other things, they show that cryofixation of tissue slices better preserves extracellular space as it occurs in vivo in comparison to conventional fixation procedures.

The mechanism for these findings is simple: fixation, as well as the ischemia that typically precedes it, causes a dramatic decrease in the number of extracellular ions, which causes water to enter cells and for them to expand. In particular, it appears that astrocytes expand preferentially during this process. One reason that this matters for people interested in brain preservation is that any information contained within or dependent upon the extracellular space is especially likely to be affected by most extant brain preservation procedures. For example, one extracellular structure proposed to play a role in memory is the perineuronal net. So it's worth asking the question: do perineuronal nets survive fixation? And evidence suggests that they do - indeed, some researchers thought that they were a fixation artifact!

Since water fluctuations are common in vivo, and animals often retain memories following ischemic events that presumably lead to dramatic local osmotic shifts of water, it is likely that most key elements of memory are encoded - or at least, encoded redundantly - by more stable structures than those which would be affected by extracellular water fluctuations. That said, it would be quite worthwhile to consider systematically what structures appear to hold information in the extracellular space, and evaluate whether they are preserved by any brain preservation procedure that purports to retain key elements of personal identity, such as memory.

Link: http://www.brainpreservation.org/the-preservation-of-extracellular-space-in-the-brain/

Cellular quality control mechanisms such as autophagy are though to be an important part of the metabolic response to calorie restriction (CR), contributing to its ability to slow aging and lengthen life in most species and lineages tested. Here researchers dig into the biochemical details of the calorie restriction response in muscle tissue, and in this context it is interesting to note that calorie restriction has been shown to slow age-related loss of muscle mass and strength in mice:

It has been hypothesized that CR exerts its beneficial effects via a hormetic response that results in activation of protein chaperones, e.g. heat shock proteins (HSF), and autophagy, as well as in the inhibition of inflammation in rodents. However, the hormonal and molecular effects of long-term CR with adequate nutrition on stress-related factors have not been carefully evaluated in humans on long-term severe CR. In this study, we found that serum cortisol concentration, a major stress hormone, was significantly higher in the CR group than in sedentary or exercising subjects eating a Western diet and was notably inversely correlated with serum TNF-α levels. We also found that key stress-induced cytosolic chaperones and autophagic transcript and protein levels were significantly higher and inflammatory factors were lower in the skeletal muscle of CR individuals than in age-matched controls, providing evidence for a CR-induced enhancement of protein quality control and of the ability of cells to eliminate damaged proteins and organelles.

Chronic CR has consistently been shown to cause a dose-dependent moderate elevation (i.e., 30%-50% above baseline) of circulating corticosterone levels in both rats and mice. Data from a recent randomized clinical trial of 2-year mild CR in nonobese humans has shown a small, 7% transient increase of serum cortisol levels. Here, we show that serum cortisol concentration is ∼30% higher in humans practicing long-term severe CR than in age-matched control subjects. Our data suggest that the mechanism responsible for the sustained increase in serum cortisol concentrations induced by CR is likely related to CR itself, rather than changes in body composition, because the equally low body fat and leptin levels of the exercisers were not associated with high cortisol in the exercisers. Elevation of glucocorticoid levels is an essential adaptation required to cope with a variety of stressors, and in CR animals, high corticosterone level has been shown to play a role in inhibiting inflammation and cancer progression.

Whether the increased level of cortisol plays a direct role in upregulating HSPs is unclear. However, it is well known that CR increases HSF1 and HSP70 levels in rodents. Here, we show that long-term CR significantly upregulates transcripts along the HSF/HSP70 pathway and increases HSP70 and GRP78 protein levels in the human skeletal muscle. Because aging is associated with reduced protein folding capacity and ability to maintain homeostasis in response to stress, these data suggest that CR in humans prevents this decrease and may be involved in the slowing of age-dependent accumulation of damaged and dysfunctional proteins. We also found that chronic CR in humans is associated with lower inflammation.

Link: http://dx.doi.org/10.1016/j.celrep.2015.12.042

Today I'll point you to an interesting paper in which the authors investigate one of the contributing factors that cause ever greater levels of chronic inflammation to accompany aging, in this case the factor being detrimental changes in the behavior of monocyte immune cells in older individuals. The researchers demonstrate that monocytes are influenced by rising levels of the inflammatory cytokine TNF, and either removing TNF or the problem monocytes improves the impaired immune response in aged mice.

The immune system is enormously complex, one of the many aspects of our biology in which the high level sketch - information that fills books in and of itself - must still be painted in at the detail level. One measure of what is left to learn is the present lack of understand of the root causes of many autoimmune diseases, intricate failure modes in the regulation of immune activities in which immune cells attack healthy tissue. If the research community understood the immune system completely, the scientists involved would also understand autoimmunity well enough to prevent it and reverse it. As it is, there are only hints and connections made in a growing, ceaseless river of data, while cures are yet to be found. The situation for the aging of the immune system is much the same. A variety of theories backed by differing levels of evidence explain why the immune system in aged individuals becomes both progressively less effective and progressively more active at the same time, chasing its tail to no good end. Greater activity means more inflammation, and sustained inflammation is a source of tissue damage and cellular dysfunction, a potent contribution to the pathology of many age-related diseases. Researchers have given the name "inflammaging" to this unfortunate end stage of the immune system and its detrimental effects on health.

Today we are at a point at which the research community can present a convincing story of immune aging based upon processes such as the atrophied thymus reducing the supply of new immune cells, the limited number of immune cells increasingly consisting of those uselessly devoted to a few persistent pathogens rather than capable of dealing with new threats, and so on and so forth. The relevance and importance of these processes can still be argued, however. Given the pace of progress in biotechnology, I believe that the proof of theories on immune aging will be provided by therapies capable of addressing the causes of immune decline, and this will happen long before proof can be provided via a full mapping of the biochemistry and processes of the immune system. Therapies that work will point the way, and the cost of testing any given hypothesis in mice continues to fall year after year.

Studying 'inflammaging': Monocytes, cytokines, and susceptibility to pneumonia

Researchers are interested in how the immune system ages. In this study, they focus on monocytes, immune cells that are central to the process of inflammation. Monocytes multiply and mature in the bone marrow and circulate in the blood stream. They are recruited to sites of injury or infection and there turn into macrophages that ingest pathogens, infected cells, or cellular debris. Monocytes are also potent producers of pro-inflammatory cytokines, small molecules that promote an inflammatory immune response.

Comparing younger and older mice, the researchers found that the latter have higher numbers of monocytes both in the bone marrow and in the blood. They also saw higher levels of TNF and IL-6, two pro-inflammatory cytokines, in blood from older mice and blood from older human donors. Studying mouse monocytes in more detail, the researchers found that the increase in TNF levels that occurs with age causes premature release of immature monocytes from the bone marrow into the blood stream. When stimulated with bacterial products, these immature monocytes themselves produce more inflammatory cytokines, thus further increasing levels in the blood.

The researchers then infected younger and older mice with the bacteria Streptococcus pneumoniae, which causes so-called pneumococcal pneumonia. They found that, although the older mice had higher numbers of monocytes in the blood and at the sites of infection, their monocytes were not able to clear the bacteria and successfully fight the infection. However, when the researchers used drugs or mouse mutations that reduced the number of monocytes or removed TNF, they were able to restore antibacterial immunity in aged mice. The researchers conclude that "monocytes both contribute to age-associated inflammation and are impaired by chronic exposure to the inflammatory cytokine TNF, which ultimately impairs their anti-pneumococcal function." They go on to suggest that "lowering levels of TNF may be an effective strategy in improving host defense against S. pneumoniae in older adults."

TNF Drives Monocyte Dysfunction with Age and Results in Impaired Anti-pneumococcal Immunity

As we age, levels of inflammatory cytokines in the blood and tissues increase. Although this appears to be an inevitable part of aging, it ultimately contributes to declining health. Epidemiological studies indicate that older adults with higher than age-average levels of inflammatory cytokines are at increased risk of acquiring, becoming hospitalized with and dying of pneumonia but how age-associated inflammation increased susceptibility to was not entirely clear. We demonstrate that the increase in the inflammatory cytokine TNF that occurs with age cause monocytes to leave the bone marrow prematurely and these immature monocytes produce more inflammatory cytokines when stimulated with bacterial products, thus further increasing levels of inflammatory cytokines in the blood. Furthermore, although old mice have higher levels of these inflammatory monocytes arriving at the site of S. pneumoniae, they are not able to clear the bacteria. By pharmacologically or genetically removing the inflammatory cytokine TNF or reducing the number of inflammatory monocytes we were able to restore antibacterial immunity in aged mice.

Aubrey de Grey of the SENS Research Foundation recently spoke on the future of rejuvenation biotechnology at a technology conference in Beijing. The Chinese language press have the text of his presentation - you'll need to use a tool such as Google Translate, though note that Chinese is one of those languages with a way to go yet in the quality of the automated translation.

This is the second time I came to Beijing, the first time I came to Beijing a decade ago, and I want to tell you the last time I came here, I was very disappointed, because few people heard my message. For I represent academia, and as a scholar I want to let many people know what I am talking about. Today we are here at the future forums, and earlier we have heard a lot of wonderful speech. Venture capitalists talked about a lot of big companies and big capital. Now we are in a good position to talk about control of aging, which is what we mean by rejuvenation biotechnology. Our technology in constant development and innovation in rejuvenation can help us achieve this vision, so that maybe in the future we can develop the ability to control the emergence of age-related human diseases, and and as a consequence improve the people's quality of life and well-being. As all human beings suffer the problems of aging, the problem may be the most serious in China, in the world, too, and so I believe that the issue of aging is a very difficult problem, is a very important issue, and is the human face put on a very grim reality. So today I want to discuss a topic of rejuvenation biotechnology, using biotechnology to achieve rejuvenation.

I do believe it will happen soon, and I will give you two reasons to make you believe as well. First and foremost we have to accept that the scientific community has accepted our view on rejuvenation biotechnology: we have published scientific papers and articles in top journals, and thus scientists have accepted that these researchers are leading scientists. Many researchers in different scientific fields have collaborated on this project. I can also point to our leading scientific advisers, who provide us with support and endorsement. Another way to make everyone believe that this is the fact, that I am not blindly optimistic, is that I can show you the work in progress. This image under the microscope is the number one killer in the world, the foam cells and damaged lipids that gather to block our blood vessels. With the continuous accumulation of damage and waste in blood vessels, macrophages continue to arrive and turn into more foam cells to make the problem worse. We have found a way to prevent this from happening, using bacterial enzymes that naturally consume these waste compounds, we modify them so that they can be effective in therapy. We have shown that using these bacteria, through genetic modification, it is possible to reduce the body's sterol content, which will improve healthy longevity.

We do not know how rapidly any of the advanced science needed will arrive, but it is likely that we can achieve the goals of rejuvenation biotechnology in 20-25 years to achieve, which would give us enough time to benefit. With time left in my last moment, I would like to talk entrepreneurial spirit: I have created this organization, the SENS Research Foundation, and I now have ten to twelve years of history working towards these goals in non-profits rather than the private sector so as to obtain the support of the scientific community. The science has made great progress, and now investors are interested - so you can get involved in this, and make a lot of profit. I think it is not the case that therapies will appear in twenty years, but rather that the first medical technology will be implemented in the next few years. People will realize that we can end aging as the technology appears, and will get involved. As things stand now worldwide, especially in China, the world's worst aging problem at the moment is that people have not yet begun to be involved.

Link: http://tech.sina.com.cn/d/f/2016-01-17/doc-ifxnqriz9765311.shtml

Near all studies on the matter show that regular moderate exercise improves health and extends healthy life span, though the effects on overall life span are mixed, unlike the data for calorie restriction. With the advent of small, cheap accelerometers, the research community is now making headway into determining the dose-response curve for exercise, the degree to which more is better:

The majority of citizens in developed countries should not be concerned by potential harm from exercise but rather by the lack of exercise in their lives. Small amounts of physical activity, including standing, are associated with a lower risk of cardiovascular disease, but more exercise leads to even greater reduction in risk of death from cardiovascular disease. "The evidence with regard to exercise continues to unfold and educate the cardiovascular clinical community. The greatest benefit is to simply exercise, regardless of the intensity, while the danger is two-fold: to not exercise at all or to exercise intensely, without due preparation." Studies have shown that regular physical activity reduces a person's risk of death from cardiovascular disease; however, only half of U.S. adults meet the federally recommended guidelines of 150 minutes per week of moderate intensity exercise or 75 minutes per week of vigorous intensity exercise.

Scientists examined recent research on the volume and intensity of aerobic exercise required for favorable cardiovascular health. With the rise in participation in endurance races over the past three decades, they also address the question of whether or not there is an amount of exercise that increases cardiovascular disease risk. They found that moderate and vigorous intensity exercise in amounts lower than the 2008 Physical Activity Guideline recommendations still significantly lower mortality risk in different populations around the globe. Increasing the amount of moderate intensity exercise a person engages in results in increased reductions in cardiovascular disease mortality; however, the reductions in cardiovascular mortality benefits from vigorous intensity exercise do level out at a certain point.

There is no evidence for an upper limit to exercise-induced health benefits and all amounts of both moderate and vigorous intensity exercise result in a reduction of both all-cause and cardiovascular disease mortality compared to physical inactivity. While controversial, a few limited studies have raised the concern that high volumes of aerobic exercise may be as bad for cardiovascular outcomes as no exercise at all. Researchers suggest that the possibility that too much exercise training could be harmful is worthy of investigation, but research results show that even for the very active, life-long endurance athletes, the benefits of exercise training outweigh the risks.

Link: http://www.eurekalert.org/pub_releases/2016-01/acoc-rec011416.php

In the open access paper I'll point out today, researchers demonstrate a comparatively straightforward way to enhance the diminished functions of the thymus in old mice, and thus partially reverse the dysfunction in immune response that accompanies aging. The thymus might be thought of as an incubator for the varied types of cell belonging to the active immune system that are collectively known as T cells. In childhood the thymus is very active, producing a flood of new cells. Unusually among mammalian organs, however, the thymus atrophies very early in adulthood in a process known as thymic involution, reducing the supply of new T cells to a trickle. This in effect limits the size of the immune system, and that limit becomes an increasing problem as the years pass. Ever more T cells are focused on specific pathogens and ever fewer remain capable of tackling new threats, for example.

Any and all methods that might prove effective in breaking the natural limits on T cells are of interest, given the importance of immune dysfunction in the progression of age-related frailty. The immune system doesn't just fight off invaders: it is also involved in wound healing, destruction of potentially cancerous and senescent cells, and a variety of other necessary tasks. As the effectiveness of the immune system winds down, many contributions to aging and age-related disease accelerate as a result.

How to restore the legions of competent, useful immune cells, however? Destroying the many duplicate cells that are uselessly focused on specific pathogens, and as a consequence take up space to no good end, seems to work based on animal studies carried out to date. That destruction provokes their replacement with competent new cells, albeit at a slow pace, and - fortunately - targeted cell destruction is a going concern these days thanks to the work taking place in the cancer research community. Another possibility is to use the techniques of stem cell medicine to culture large numbers of patient-matched immune cells and infuse them on a regular basis. This is technically well within the grasp of the clinical community, but not yet adopted. Other approaches focus on restoration of the thymus to its childhood state of activity, such as via tissue engineering and transplantation, or reprogramming of thymic cell state with gene therapy.

That brings us to this simpler approach to alter the behavior of the cells making up the thymus, as well as those involved in the many complicated stages that make up the production of T cells. A T cell doesn't just spring into being, but is rather the result of numerous steps of cellular migration and differentiation that starts with thymocytes, a type of progenitor cell in the thymus, before eventually giving rise to forms of T cell. Here, researchers are using a very blunt tool to achieve their results, simply injecting the mice in their study with the cytokine interleukin-21 (IL-21). Eyeing the data, the results look like a temporary doubling or more of relevant counts of cells, but that isn't enough to pull things back to where they were in youth. Still, the outcome is good given that it is such a simple approach:

Interleukin-21 administration to aged mice rejuvenates their peripheral T-cell pool by triggering de novo thymopoiesis

The vaccination efficacy in the elderly is significantly reduced compared to younger populations due to thymic involution and age-related intrinsic changes affecting their naïve T-cell compartment. Interleukin (IL)-21 was recently shown to display thymostimulatory properties. Therefore, we hypothesized that its administration to ageing hosts may improve T-cell output and thus restore a competent peripheral T-cell compartment. We show in this report that administration of recombinant IL-21 (rIL-21) enhances thymopoiesis in aged mice through expansion of both the stromal and responsive thymocytes compartments without the induction of any apparent pathology in peripheral organs.

Enhanced production of naïve T cells improved the T-cell receptor (TCR) repertoire diversity and re-established a pool of naïve CD4+ and CD8+ T cells displaying potent effector functions in response to TCR stimulation. This increase in the availability and potency of naïve T cells augmented the responsiveness of aged mice to vaccination and tumor challenge.

Besides physiological ageing, contraction of the TCR repertoire is commonly observed in patients suffering from infections, cancers, or following bone marrow transplantation. There are currently no effective therapies capable of exerting a positive impact on broadening the spectrum of TCR. Studies involving IL-21R−/− mice clearly showed that IL-21 is dispensable for immune cell development as normal proportions of lymphocytes, monocytes, and granulocytes have been reported. Our data nevertheless suggest that rIL-21 administration to ageing hosts could have potent clinical uses related to its ability to promote the expansion of thymic progenitor cells, which can be further enhanced if combined with other thymostimulatory compounds.

A group of clinicians involved in delivering stem cell transplants to patients to treat various age-related conditions have observed temporary reversal of hair graying following treatment. Their open access paper is offered in the spirit of "look at this interesting thing that happened," and there is no deep analysis of underlying mechanisms - though it isn't hard to speculate based on what is known. The approach used mesenchymal stem cells (MSCs), which in the current standard treatment models are thought to produce benefits through signaling that alters the behavior of native cells. The transplanted cells don't live for very long and don't themselves work to maintain tissues. MSC transplantation is known to temporarily reduce chronic inflammation and measures of oxidative stress in tissues, as well as spurring native stem cells to restored activity.

Hair graying is generally considered to be some mix of (a) damage and decline of the melanocyte cells responsible for coloring hair, present in the hair follicles, and (b) dysfunction in the activity of melanocytes and related cell populations caused by the higher levels of oxidative stress that accompany aging. These cells are more sensitive to that increase than most, and so this is one of the first signs of aging. Hair greying can be reversed by treatments that suppress oxidative stress, as has been demonstrated in recent years. So joining all the dots, it isn't unreasonable to propose that stem cell transplantation is temporarily reducing oxidative stress to levels low enough to put melanocytes back to work - but that would have to be confirmed with more careful studies.

Adipose derived autologous mesenchymal stem cells have been transplanted and tested for their ability to regenerate tissues for several indications. We treated a total number of 14 patients between the age group 38-75 years, out of them 4 subjects had completely grey hair. Three subjects were males and one female. While treating these patients for their various age related neurodegenerative disorders with autologous mesenchymal stem cells for their regenerative and rejuvenating properties, we accidentally observed a transition of hair colorations from mostly grey to black in all the 4 elderly patients. Each patient received more than one session within a time frame of 2-3 weeks. Each time the MSCs were administered by spinal intrathecal route (20 million) and intravenously (20 million) after over a period of 20 minutes. There were no notable complications post transplantations. We observed remarkable improvement in the neurological status (being reported separately) and the only adverse effect was transient headache.

In observed patients about 50% of the hairs were seen turning black after duration of 3-6 weeks. This was observed on the scalp and on the beard as well. However, the effect was not permanent; as the age progressed the greying process continued. The longest period of follow up was 20 months for all the 4 patients. All the subjects continue to have some black hairs but were now lesser in density and number. This may be through positive activation and regeneration of melanocyte stem cells in the hair follicular niche. In this paper we intend to report this unique observation which may lead to further research. We do not view MSCs as a treatment modality for grey hair. However this is an incidental finding, so far not reported in the literature.

Link: http://dx.doi.org/10.7243/2054-717X-2-3

The World Health Organization (WHO) position on aging is, as noted a few months back, well-written, incoherent, bureaucratic garbage. In essence it is a call to do nothing meaningful to treat the causes of aging, produced by people distant from the research community, who disregard the last decade of work and current scientific views on aging and longevity. This is unfortunately par for the course for large governmental organizations of this nature. Some researchers and advocates, such as those involved with the International Longevity Alliance, are keen on using the WHO as a megaphone to amplify advocacy for the treatment of aging as a medical condition, however, and so have been working behind the scenes to try to make the WHO position statement less terrible.

The World Health Organisation has revised its Draft Global Strategy and Action Plan on Aging and Health after the consultation with a delegation of experts as well as an extensive online survey. Here we report on the developments of the consultation where some members of our parent organization the International Longevity Alliance (ILA) attended and many of our organization participated in the online survey about aging. The Consultation meeting was organized at WHO headquarters in Geneva following the survey on October 28-30, which brought together all regional WHO offices, delegates from 75 member states and around 35 non governmental organizations. The delegations included a wide range of research institutions, regional, national and international organizations, as well as experts from various WHO technical departments and other leaders in the field of aging research.

Based on the findings of this Global consultation meeting and survey, a new revised Draft Global Strategy and Action Plan on Aging and Health, has been proposed for consideration by the WHO Executive Board. A summary of this consultation is available to view at the WHO website and a PDF of the proposed action plan can be downloaded directly. There is now clear evidence that the longevity community is having a decisive impact. This includes the work done by the Russian and Kazakhstanian delegations and, of course, the ILA letter writing campaign! There were interventions in favor of longevity and biomedical research promotion by many delegations including experts from Algeria, Belarus, Brazil, Finland, Germany, India, Nigeria, Norway, Qatar, Sri Lanka, Switzerland, and the United Kingdom.

The good news is that it looks like the WHO agrees that biological aging leads to many of the recognised diseases of aging, whether or not that means aging is a disease itself! So now let's take a look at some of the highlights of this consultation below.

1. The WHO Strategy Vision is reworded here: "25. The strategy's vision is a world in which everyone can live a long and healthy life" instead of "A world in which everyone experiences Healthy Aging" as per the initial draft. This is a historical recognition of healthy longevity as a priority goal at the UN level.

2. The destructive and complex nature of the biological aging process is described, perhaps for the first time at the UN level: "15. The changes that constitute and influence aging are complex. At a biological level, the gradual accumulation of a wide variety of molecular and cellular damage leads to a gradual decrease in physiological reserves, an increased risk of many diseases and a general decline in capacity. But these changes are neither linear nor consistent, and they are only loosely associated with age in years".

This demonstrates that despite using the controversial term "healthy ageing" (while some researchers are calling for acknowledging ageing as a disease), the WHO recognises ultimately that biological aging is counter to good health. The Revised Draft Global Strategy and Plan puts greater emphasis on the goal of maintaining people's health while they grow chronologically older, while keeping functional ability maintenance in case of age-related disabilities as another priority. It is a promising change in stance, that recognises biological aging as a factor of ill health. This seems to proceed a changing view on how aging should be viewed and the consideration that it is amenable to intervention.

Of course we aren't quite finished yet, but all the same there is clear movement in established opinions. Now we have established impetus in the right direction, it is hopefully only a matter of time, before our hard work pays off in terms of medical interventions that will be available to people worldwide. It is becoming increasingly obvious that things cannot remain the same, that aging is a problem to public health, and that it is indeed desirable to do something about it.

Link: http://www.majormouse.org/?q=node/164

The SENS Research Foundation will be seven years old this year. It is one of the very few organizations to aggressively pursue a campaign of research and advocacy aimed at bringing an end to aging and age-related disease, and one of perhaps only two or three at most that focus on rejuvenation research, an approach to the treatment of aging based on repair of the known forms of cell and tissue damage that cause aging. The SENS rejuvenation research project has been very successful over the course of its lifespan to date, moving from nothing more than a vision in the early 2000s to today's network of allied researchers, research programs, new startups, and the first prototype implementations of SENS therapies such as those under development for senescent cell clearance. Over that time the research community has been swayed from its former hostility to any mention of treating aging to much greater support for the goal of enhanced human longevity. To be clear, however, this is still a tiny field. There is a long way to go to produce a SENS research community as large and well supported as the cancer or stem cell research communities.

If you look back a couple of years here at Fight Aging!, you'll find a post on the strategic future of the SENS Research Foundation. The SENS Research Foundation is producing results, persuading researchers, and generating the foundations of new medical technology, and we want to see this successful team continue to achieve its goals. That, however, requires funding. To summarize the older post: half of the $4-5 million yearly budget of the SENS Research Foundation is provided by founder Aubrey de Grey, and those funds come to an end relatively soon. We all owe him a debt of gratitude for what he has achieved in this field with his own money. This is the nature of research and business; every success in finding a source of funding must be treated as a runway and a countdown to the next source of funding.

There are many ways to go from here, and the next decade looks to be a time of great opportunity in funding for longevity science of all sorts, given the large investments that are starting to arrive in the space. Even if, as seems plausible given the recent market activity, we're about to plunge into a couple of years of a bear market, that doesn't dampen the prospects all that much. Given the time taken for any meaningful research effort, the start of a bear market is actually a great time to invest in a research program; it'll just be getting somewhere when the economic picture turns around.

Crowdfunding

Crowdfunding of scientific research is something that we as a community do quite well. It is a hard problem, and crowdfunding ventures like Experiment are only just starting to make inroads into sustainable platforms. The past few years have seen a slow growth in the community of supporters willing to materially support the SENS Research Foundation every year. So far, as much as a few hundred thousand dollars each year have been raised this way, and I don't see why that number can't keep growing as the public support for longevity science grows.

Investment in SENS Rejuvenation Therapy Startups

Selective, targeted investment worked out very well for the Methuselah Foundation. The Foundation wes an early investor in Organovo a long time back, and that provided a healthy return in the years since. The important thing is to invest in those companies that can also be incubated and supported, so as to provide the best chance of success. The SENS Research Foundation is very well placed to do this. It is in the center of a web of connections to researchers and the Bay Area venture community, and also a source of technologies for new therapies, such as senescent cell and cross-link clearance. The transition from funding a scientific group to seed funding the startup that results from that work is a logical one, and indeed the SENS Research Foundation is already doing this for Oisin Biotechnology and Human Rejuvenation Technologies.

An early stage startup investment is a lottery ticket, of course, even when the investor happens to be well placed to help its progress, but at least it is a lottery ticket that has the side-effect of funding additional research and development regardless of the outcome. Perhaps more important than the risk inherent in any such investment is the timeline: one should expect a biotechnology startup to take five years or longer to come to initial fruition even should it succeed as well as Organovo did. The SENS Research Foundation investments were made last year, so there is a way to go yet.

Deeper Integration with the Non-Profit Funding Ecosystem

A massive non-profit funding ecosystem exists, just as rife with formalism, barriers, and the need for connections as the venture capital ecosystem. There are many different players involved, ranging from high net worth individuals to large foundations to government bodies. Any demonstrably successful non-profit with a yearly budget of only a few million dollars has a lot of room for growth in this space. The folk at the SENS Research Foundation agree, and are looking for a guide:

Job Opportunity: Head of Major Gifts

SENS Research Foundation (SRF) is a 501(c)(3) public charity that is undertaking one of the most ambitious goals in history: ending the human suffering resulting from age-related diseases such as Alzheimer's, diabetes, cancer, and heart disease. Our goal is to apply the principles of regenerative medicine to build a rejuvenation biotechnology industry; what makes us unique is that rather than developing more sophisticated ways to treat disease, we are developing more sophisticated ways to preserve health, and thereby prevent such diseases from ever taking hold.

Since our founding in 2009 we've grown into a significant force for change in medical research. SRF's current annual funding - over $4M - comes roughly one-half from renewable sources and one-half from a multi-year trust which will expire next year. The challenge we now face is to build quickly upon our successes, and to be able to create our truly transformational next generation of research, education and outreach programs without losing momentum. The role of the Head of Major Gifts will be to raise at least $2M/annum in new funding, and to guide us in developing new channels sufficient to create sustainable income of $5-10M/annum, from high net worth individual, foundation, corporate and government sources.

This is a great opportunity for someone coming from a large non-profit, with a packed rolodex and knowledge of the way things work. It represents the option to carve out a name in this space, to become a well-know leader in an organization that is out to change the world for real. There is no greater impact to human life than to speed progress towards the medical control of aging and all age-related disease. It is the largest cause of death and suffering by a wide margin, and every day gained is a hundred thousand lives saved.

The immediate benefits of targeted systems of cancer treatment are fairly straightforward: if a clinic can deliver cell-killing payloads directly to cancer cells, then far lower doses are necessary. This is why the development of targeting methodologies that can reach and accurately distinguish cancer cells is in many ways more important at the present time than the development of actual therapeutics. There are a lot of existing ways to kill cancer cells, and many can be used in a targeted way, reducing their unpleasant and debilitating side-effects in cancer patients while achieving the same or better outcomes.

The cancer drug paclitaxel just got more effective. For the first time, researchers from the have packaged it in containers derived from a patient's own immune system, protecting the drug from being destroyed by the body's own defenses and bringing the entire payload to the tumor. "That means we can use 50 times less of the drug and still get the same results. That matters because we may eventually be able to treat patients with smaller and more accurate doses of powerful chemotherapy drugs resulting in more effective treatment with fewer and milder side effects."

The work is based on exosomes, which are tiny spheres harvested from the white blood cells that protect the body against infection. The exosomes are made of the same material as cell membranes, and the patient's body doesn't recognize them as foreign, which has been one of the toughest issues to overcome in the past decade with using plastics-based nanoparticles as drug-delivery systems. "Exosomes are engineered by nature to be the perfect delivery vehicles. By using exosomes from white blood cells, we wrap the medicine in an invisibility cloak that hides it from the immune system. We don't know exactly how they do it, but the exosomes swarm the cancer cells, completely bypassing any drug resistance they may have and delivering their payload."

In their experiment, the team extracted exosomes from mouse white blood cells and loaded them with paclitaxel. They then tested the treatment - which they call exoPXT - against multiple-drug-resistant cancer cells in petri dishes. The team saw that they needed 50 times less exoPXT to achieve the same cancer-killing effect as formulations of the drug currently being used, such as Taxol. The researchers next tested the therapy in mouse models of drug-resistant lung cancer. They loaded the exosomes with a dye in order to track their progress through the lungs and found that the exosomes were thorough in seeking out and marking cancer cells, making them a surprisingly effective diagnostic tool in addition to being a powerful therapeutic.

Link: http://uncnews.unc.edu/2016/01/14/unc-chapel-hill-researchers-kill-drug-resistant-lung-cancer-with-50-times-less-chemo/

Researchers here argue that the common study methodology of assessing weight only at a single point in time greatly underestimates the increased mortality rate produced by choosing to become overweight, or worse, obese. The trajectory of weight over time is a significant factor, and being overweight at any time in life increases risk even if that weight is lost later. The longer an individual is overweight, the more damage is done:

Researchers have found that prior studies of the link between obesity and mortality are flawed because they rely on one-time measures of body mass index (BMI) that obscure the health impacts of weight change over time. The new study maintains that most obesity research, which gauges weight at only a single point in time, has underestimated the effects of excess weight on mortality. Studies that fail to distinguish between people who never exceeded normal weight and people of normal weight who were formerly overweight or obese are misleading because they neglect the enduring effects of past obesity and fail to account for the fact that weight loss is often associated with illness. When such a distinction is made, the study finds, adverse health effects grow larger in weight categories above the normal range, and no protective effect of being overweight is observed.

Researchers tested a model that gauged obesity status through individuals' reporting of their lifetime maximum weight, rather than just a "snapshot" survey weight. They found that the death rate for people who were previously overweight, but reported normal weight at the time of survey was 27 percent higher than the rate for people whose weight never exceeded that category. The researchers used data from the large-scale National Health and Nutrition Examination Survey, linking data available from 1988 to 1994 and 1999 to 2010 to death certificate records through 2011. The survey asked respondents to recall their maximum lifetime weight, as well as recording their weight at the time of the survey. Of those in the normal-weight category at the time of the survey, 39 percent had transitioned into that category from higher-weight categories.

The study used statistical criteria to compare the performance of various models, including some that included data on weight histories and others that did not. The researchers found that weight at the time of the survey was a poor predictor of mortality, compared to models using data on lifetime maximum weight. "The disparity in predictive power between these models is related to exceptionally high mortality among those who have lost weight, with the normal-weight category being particularly susceptible to distortions arising from weight loss. These distortions make overweight and obesity appear less harmful by obscuring the benefits of remaining never obese."

Link: http://www.bu.edu/research/articles/obesitys-link-to-mortality-understated-in-prior-research/

AMP-activated protein kinase (AMPK) is one one of the usual suspects whenever the research community considers calorie restriction, exercise, increased cellular quality control, and other ways to slightly slow the pace of degenerative aging. Search the Fight Aging! archives and you'll find many mentions over the years. In the publicity materials and paper linked below researchers take a modest step forward to better understand why AMPK is important: it appears a lynchpin regulator linking nutrient intake and one of the mechanisms of mitochondrial quality control.

All of the fundamental cellular responses to the environment are linked, and any given protein tends to play many different roles. Thus AMPK is a nutrient sensor, activated by low energy intake, which explains the link to calorie restriction. It also responds to changes that occur with exercise in much the same way, however. Once AMPK is more active, a grand cascade of varied mechanisms are set in motion, and researchers spend a great deal of time sifting through this immense complexity to understand how it produces modest benefits to health and longevity. Many interesting connections have been made. For example, calorie restriction requires functional autophagy in order to extend life, and calorie restriction is associated with raised levels of autophagy. AMPK activation, achieved artificially in absence of environmental changes, increases levels of autophagy. It all ties together in this way, but there is still much to be done to fill in the details.

Autophagy is the name given to a collection of mechanisms that clear out damaged proteins and cellular components, delivering them to locations in the cell capable of breaking down and recycling the parts for later use. One of the more important cellular components are mitochondria, the swarming bacteria-like power plants responsible for creating chemical energy stores, among other tasks. Many lines of evidence link mitochondrial damage to the pace of aging, and mitochondrial dysfunction to age-related disease. Anything that impacts mitochondria is interesting to the aging research community, and here AMPK is shown to have a fairly profound effect:

How the cell's power station survives attacks

Mitochondria, the power generators in our cells, are essential for life. When they are under attack - from poisons, environmental stress or genetic mutations - cells wrench these power stations apart, strip out the damaged pieces and reassemble them into usable mitochondria. Scientists have uncovered an unexpected way in which cells trigger this critical response to threats, offering insight into disorders such as mitochondrial disease, cancer, diabetes and neurodegenerative disease - particularly Parkinson's disease, which is linked to dysfunctional mitochondria.

In an average human cell, anywhere from 100 to 500 mitochondria churn out energy in the form of ATP molecules, which act like batteries to carry power to the rest of the cell. At any given time, one or two mitochondria fragment (fission) or reform (fusion) to cycle out any damaged parts. But when a poison - like cyanide or arsenic - or other dangers threaten the mitochondria, a mass fragmentation takes place. Researchers have known for years that mitochondria undergo this fragmentation when treated with drugs that affect the mitochondria, but the biochemical details of how the mitochondria damage is sensed and how that triggers the rapid fission response has not been clear until now.

Researchers found that when cells are exposed to mitochondria damage, a central cellular fuel gauge, the enzyme AMPK, sends an emergency alert to mitochondria instructing them to break apart into many tiny mitochondrial fragments. Interestingly, AMPK is activated by the widely used diabetes therapeutic metformin, as well as exercise and a restricted diet. The new findings suggest that some of the benefits from these therapies may result from their effects in promoting mitochondrial health. This new role of rapidly triggering mitochondrial fragmentation "really places AMPK at the heart of mitochondria health and long-term well-being."

To uncover exactly what happens in those first few minutes, the team used the gene editing technique CRISPR to delete AMPK in cells and showed that, even when poison or other threats are introduced to the mitochondria, they do not fragment without AMPK. This indicates that AMPK somehow directly acts on mitochondria to induce fragmentation. The group then looked at a way to chemically turn on AMPK without sending attacks to mitochondria. To their surprise, they found that activating AMPK alone was enough to cause the mitochondria to fragment, even without the damage.

AMP-activated protein kinase mediates mitochondrial fission in response to energy stress

Mitochondria undergo fragmentation in response to electron transport chain (ETC) poisons and mitochondrial DNA-linked disease mutations, yet how these stimuli mechanistically connect to the mitochondrial fission and fusion machinery is poorly understood. We found that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with ETC inhibitors. Moreover, direct pharmacological activation of AMPK was sufficient to rapidly promote mitochondrial fragmentation even in the absence of mitochondrial stress.

Another interesting topic to consider in this context is the ability of cells to rejuvenate their mitochondria completely in response to reprogramming. The creation of induced pluripotent stem cells has been shown to regenerate damaged mitochondria. Either the same or a similar process occurs in the very early stages of embryonic development, as the damage of aging is near-completely wiped away by the internal transformations of the few cells present at the time. Thus there are clearly mechanisms capable of this in the space of states that a cell can adopt, though this doesn't necessarily mean that any of them are accessible to an adult without the accompaniment of severe adverse consequences. Profound cellular transformations are generally not something you'd want to happen to large proportions of your cells at any one time.

The trend for cancer, like the trend for longevity, is heading slowly in the right direction. Large investments in research produce incremental reductions in cancer mortality, but the shape of this relationship results from the present dominant approaches to cancer treatment, producing therapies that are each limited in their application to only one or a few narrow categories of cancer. Cancer is a spreading tree of variants, and all of the outer branches differ from one another in the details of their cellular biochemistry. Researchers tend to focus on attacking the particular distinctive biochemistry of one branch. This is inefficient and expensive, but it is going to change. The future of cancer treatment will hinge on approaches under development that are capable in principle of application to near all cancers, in particular methods of interfering in the lengthening of telomeres that all cancers rely upon. Once those treatments are a going concern, reduction in cancer mortality will no longer be an incremental trend.

Every year, the American Cancer Society estimates new cancer cases and deaths in the U.S. for the current year and compiles the most recent data on cancer incidence, mortality, and survival. Steady reductions in smoking combined with advances in cancer prevention, early detection, and treatment have resulted in a 23% drop in the cancer death rate since its peak in 1991. Overall cancer incidence is stable in women and declining by 3.1% per year in men (from 2009-2012), with one-half of the drop in men due to recent rapid declines in prostate cancer diagnoses as PSA testing decreases. Cancer mortality continues to decline; over the past decade of data, the rate dropped by 1.8% per year in men and 1.4% per year in women. The decline in cancer death rates over the past two decades is driven by continued decreases in death rates for the four major cancer sites: lung, breast, prostate, and colon/rectum.

Death rates for female breast cancer have declined 36% from peak rates in 1989, while deaths from prostate and colorectal cancers have each dropped about 50% from their peak, a result of improvements in early detection and treatment. Lung cancer death rates declined 38% between 1990 and 2012 among males and 13% between 2002 and 2012 among females due to reduced tobacco use. Even as cancer remains the second leading cause of death nationwide, steep drops in deaths from heart disease have made cancer the leading cause of death in 21 states. Heart disease remains the top cause of death overall in the United States. "We're gratified to see cancer death rates continuing to drop. But the fact that cancer is nonetheless becoming the top cause of death in many populations is a strong reminder that the fight is not over. Cancer is in fact a group of more than 100 diseases, some amenable to treatment; some stubbornly resistant. So while the average American's chances of dying from the disease are significantly lower now than they have been for previous generations, it continues to be all-too-often the reason for shortened lives, and too much pain and suffering."

Link: http://pressroom.cancer.org/Cancer-Stats2016

Researchers here demonstrate one of a number of approaches to instruct native cells to regenerate more tissue damage than would otherwise have taken place, in this case by delivering a specific microRNA molecule that regulates patterns of gene expression and as a result increases bone regrowth. This is of interest beyond the repair of injuries, as bone mass and strength are progressively lost over the course of aging to produce the condition known as osteoporosis; compensating for this loss will reduce frailty in old age. As the scientific community becomes ever more proficient at cellular programming, this sort of therapy will likely replace the present state of the art in stem cell transplants. Stem cell therapies largely work because the newly introduced cells deliver signals to native cells, but if all of those signals were known and their effects on cells fully understood, the stem cells would not be necessary to achieve beneficial results.

Scientists have developed a polymer sphere that delivers a molecule to bone wounds that tells cells already at the injury site to repair the damage. Using the polymer sphere to introduce the microRNA molecule (miRNA-26a) into cells elevates the job of existing cells to that of injury repair by instructing the cells' healing and bone-building mechanisms to switch on. Using existing cells to repair wounds reduces the need to introduce foreign cells - a very difficult therapy because cells have their own personalities, which can result in the host rejecting the foreign cells, or tumors. The microRNA is time-released, which allows for therapy that lasts for up to a month or longer.

The technology can help grow bone in people with conditions like oral implants, those undergoing bone surgery or joint repair, or people with tooth decay. "The new technology we have been working on opens doors for new therapies using DNA and RNA in regenerative medicine and boosts the possibility of dealing with other challenging human diseases." It's typically very difficult for microRNA to breach the fortress of the cell wall, but the polymer sphere easily enters the cell and delivers the microRNA. Bone repair is especially challenging in patients with healing problems, but researchers were able to heal bone wounds in osteoporotic mice. Millions of patients worldwide suffer from bone loss and associated functional problems, but growing and regenerating high-quality bone for specific applications is still very difficult with current technology. The next step is to study the technology in large animals and evaluate it for use in humans.

Link: http://ns.umich.edu/new/releases/23403-nano-shells-deliver-molecules-that-tell-bone-to-repair-itself

Progress in gathering support for rejuvenation research has long been hampered by a number of widespread false beliefs. Every time we pitch someone unfamiliar with the topic, seeking material assistance in the long process of developing clinical treatments to control aging and thus extend life, the same initial hurdles must be overcome: the false belief that longevity assurance therapies would make people older for longer, not younger for longer; the false belief that overpopulation is inevitable if life spans increase; the false belief that only extremely rich people would benefit or have access to therapies. These are resilient myths, surviving in spite of the fact that they are easily disproved, and despite the fact that scientists explain over and again in detail as to why they won't come to pass.

No-one aiming at the treatment of aging is trying to build treatments that will make old people linger in increasing decrepitude. It isn't even possible to do that with a rejuvenation treatment that repairs damage: aging is an accumulation of damage, and reductions in that damage translate directly into a longer maintenance of youthful physiology. Researches have published countless papers on overpopulation in the general sense to show that what people see as overpopulation is simply poverty resulting from bad choices and bad governance, people choosing to make a wasteland in the midst of plentiful resources. Malthusians predicting vanishing resources have always been wrong; resources are created and replaced the moment that price increases look likely. Where researchers have created models of future population growth under the influence of radical life extension, populations do not grow rapidly. Wealth, security, and longevity produce incentives that reduce population growth.

As to only the wealthy having access: every mass-produced medical technology is initially briefly expensive, and then later affordable, and then later again dirt cheap. You don't have to take my word for it. Go out and look at the price histories of thousands of drugs and other treatments. Treatments to repair the damage that causes aging will be the same for everyone, infusions and injections that are turned out in bulk from pharmacological assembly lines, or available in tens of thousands of clinics where cell samples are needed to produce personalized therapies from a standard template. These treatments will be similar in manufacture and distribution to drugs that today range in cost from a few dollars to a few thousand dollars. The challenge will be delivery to the third world, because that is a challenge for every technology, not delivery to the average person in the first world. It is nonsensical to think that treating aging will be any different from the past treatment of disease in its logistics.

There are many other resilient persistent false beliefs that impact the ability to talk sensibly about the development of medicine for aging. The idea that multivitamins and antioxidants are a good thing, for example. The supplement industry continues to drown out the voice of the scientific community in this matter. It is done and settled in medical science that high dose vitamins and antioxidants do nothing or cause a modest level of harm, but you wouldn't know that from a tour of any shopping center. When people fixate on supplements, they tend to shy away from consideration of supporting research: doing something, anything, now satisfies the need. Of course it does nothing to actually help matters when it comes to living a longer life, but no-one should claim that we humans are particularly rational or consistent in our approach to life.

The science myths that will not die

Scientists once rallied around the free-radical theory of ageing, including the corollary that antioxidants, molecules that neutralize free radicals, are good for human health. By the 1990s, many people were taking antioxidant supplements, such as vitamin C and β-carotene. It is "one of the few scientific theories to have reached the public: gravity, relativity and that free radicals cause ageing, so one needs to have antioxidants."

Yet in the early 2000s, scientists trying to build on the theory encountered bewildering results: mice genetically engineered to overproduce free radicals lived just as long as normal mice, and those engineered to overproduce antioxidants didn't live any longer than normal. It was the first of an onslaught of negative data, which initially proved difficult to publish. The free-radical theory "was like some sort of creature we were trying to kill. We kept firing bullets into it, and it just wouldn't die." Then, one study in humans showed that antioxidant supplements prevent the health-promoting effects of exercise, and another associated them with higher mortality. None of those results has slowed the global antioxidant market, which ranges from food and beverages to livestock feed additives. It is projected to grow from US$2.1 billion in 2013 to $3.1 billion in 2020. "It's a massive racket. The reason the notion of oxidation and ageing hangs around is because it is perpetuated by people making money out of it."

Fears about overpopulation began with Reverend Thomas Malthus in 1798, who predicted that unchecked exponential population growth would lead to famine and poverty. But the human population has not and is not growing exponentially and is unlikely to do so. The world's population is now growing at just half the rate it was before 1965. Today there are an estimated 7.3 billion people, and that is projected to reach 9.7 billion by 2050. Yet beliefs that the rate of population growth will lead to some doomsday scenario have been continually perpetuated.

The world's population also has enough to eat. According to the Food and Agriculture Organization of the United Nations, the rate of global food production outstrips the growth of the population. People grow enough calories in cereals alone to feed between 10 billion and 12 billion people. Yet hunger and malnutrition persist worldwide. This is because about 55% of the food grown is divided between feeding cattle, making fuel and other materials or going to waste. And what remains is not evenly distributed. "Overpopulation is really not overpopulation. It's a question about poverty. Even people who know the facts use it as an excuse not to pay attention to the problems we have right now."

The Major Mouse Testing Program is a non-profit initiative setting up to run life span studies for potential age-slowing treatments that the rest of the research community isn't going to get to any time soon. The gold standard of life span studies are those carried out by the Interventions Testing Program at the NIA, but that group is poorly funded, slow, and conservative in their choices. The ITP staff won't be testing senolytic drug candidates or combinations of everything shown to modestly slow aging in mice any time soon, for example. So there is room for others to cut to the chase:

The field of regenerative medicine is becoming increasingly important for the future of healthcare and even how we view aging. With stem cell technology, gene therapy and other longevity technology on the horizon humanity can finally consider living longer, healthier lives. Some drugs already tested have been found to increase mouse lifespan such as metformin and rapamycin. These drugs are even now moving into human clinical trials to see if the above benefits translate into people. However, there are many more promising substances that have never been properly tested and we do not know if they could extend healthy lifespan. How fast science advances depends on how much quality research is being conducted. Currently there are few high impact studies investigating lifespan initiated each year ­ and with so many promising substances to test this is all a painfully slow process. The Major Mouse Testing Project (MMTP) is aiming to help by rapidly testing compounds and speeding up progress.

A significant problem with longevity research and testing in the past has been a lack of robust results. Small animal cohorts and questionable husbandry, combined with poor metrics or protocols, have lead to inconsistent or even conflicting results. In a field as poorly funded as longevity research currently is, we cannot afford to waste money and effort on flawed experiments that do not provide solid evidence of efficacy and high potential for human clinical trials. The Major mouse testing program is working to redress this situation with the help of an international team of dedicated researchers. We hope to deliver the kind of consistent and quality data required to provide definite confirmation of longevity interventions. We plan to initiate large scale testing on already aged mice - the approximate equivalent of a human aged sixty. This means we can produce consistent, accurate and notably faster results to drive progress.

It is also plausible that some interventions, when combined, could have a synergy where the effects are greater than the individual compounds, such as the case with dasatinib and quercetin for the clearance of senescent cells. It is possible there are more synergies to be discovered and this is where the MMTP plans to push forward, not only testing single interventions but also in testing combinations to seek out these powerful synergies. Our researchers are working on a practical solution to test these combinations and at the same time hope to provide the kind of accurate data science demands to prove efficacy.

Link: https://www.singularityweblog.com/the-major-mouse-testing-program/

The enhancement of stem cell activity is a very broad theme in medical research and development. It encompasses most present stem cell therapies, treatments that largely work through their effects on native stem cell populations, the parabiosis studies in search of blood-borne factors that both influence stem cells and change with age, and research such as the open access paper here, in which more traditional drug screening is used to search for candidates that can increase stem cell activity in a specific tissue of interest:

Advances in adult tissue stem cell biology have led to the idea that pharmacological activation of resident stem cells might represent a therapeutic strategy for tissue repair. Indeed, pharmacological candidates that regulate tissue stem cells have been identified. Here, we asked whether this is a viable strategy for skin repair. Skin is a complex tissue with many endogenous tissue stem cells. These include epidermal stem cells and a population of dermal stem cells called skin-derived precursors (SKPs). Cultured SKPs can clonally reconstitute the dermis and induce hair follicle morphogenesis, suggesting key roles for the endogenous precursors in dermal maintenance and hair follicle biology.

Here, we have tested the idea that increasing the number or self-renewal of endogenous SKPs would enhance skin repair. To do so, we screened libraries of compounds that are used clinically in humans, looking for drugs that enhance SKP self-renewal. We identified two compounds, alprostadil and trimebutine maleate, that increased SKP self-renewal, likely by activating the MEK-ERK pathway. Both compounds enhanced wound healing when applied topically. These findings provide proof of principle for the idea that compounds that regulate SKPs in culture have therapeutic efficacy in vivo, and identify potential drug candidates that can be repositioned for use in humans.

Link: http://dx.doi.org/10.1016/j.stemcr.2015.12.002

The research I'll point out today is an investigation of some of the detailed mechanisms by which the immune cells called macrophages fail in their tasks and as a result cause the bulk of the pathology of atherosclerosis, a disease in which fatty plaques build up in blood vessels. The cardiovascular system deforms and remodels over the years as a result of these deposits, contributing to hypertension and related issues, but the more dangerous outcome is for sections of a plaque to break off and block blood vessels, leading to serious injury or death due to loss of the oxygen supply to critical tissues.

Atherosclerosis starts with very small-scale irritations of the blood vessel wall caused by the presence of damaged lipid molecules, such as those generated by the small population of dysfunctional cells that have been overtaken by broken mitochondria. This population grows with age as ever more mitochondria become randomly damaged in just the right way to spread within their cell, and so does the level of damaged lipids in the bloodstream, from this and other sources. If that was all there was to atherosclerosis, however, we probably wouldn't consider it a significant threat in comparison to everything else that can fall apart in aging. The small battles fought as cells cleaned up damaged lipids probably wouldn't rise to the level of killing people.

The real reason that atherosclerosis is a dangerous medical condition is that macrophages attempt to clean up the lipids and macrophages are weak. They have a limited capacity to digest damaged lipids and other debris resulting from the presence of damaged lipids in a blood vessel wall. Their cellular recycling mechanisms, the lysosomes, become overwhelmed and the macrophage cells die. That creates more debris, which attracts more macrophages. Small areas of damage can thus spiral out of control into battlegrounds marked by growing inflammation and fatty plaques composed of the remains of countless macrophages, lured in to their doom. None of this would happen if macrophages were indomitable, capable of digesting much, much more of the problem lipids and other wastes.

It is possible to create indomitable macrophages? In principle of course. Somewhere in the future lies the mass production of diamondoid medical nanorobots, each thousands of times more effective than evolved cells at a few specific tasks, such as digesting damaged lipids or macrophage remains. But if thinking of the near future, the bounds of the possible are much more limited. Efforts to alter cells to produce better, artificial operational states that do not appear in nature have proven slow and expensive, and produce largely marginal results where there is any success in this direction. The best outcomes to date have come from coercing cells into adopting existing naturally occurring states and patterns of behavior that are more helpful to the present situation - see stem cell medicine, for example. Trying to build a better macrophage, an entirely new state of cellular operation, by iterating on the present design is not likely to stop atherosclerosis, though with great effort it is probably possible to modestly slow its progression.

To my eyes, the better and more cost-effective approach is that of periodic repair after the SENS model for the treatment of aging, which in this case means cleaning up after this macrophage-induced disaster on a regular basis and before the debris builds up to pathological levels. The approach taken to date is to find natural enzymes capable of breaking down the materials of atherosclerotic lesions and plaques. Graveyards are not seeping lipid compounds, so we know that bacteria in the soil can digest these problem molecules. Somewhere in that vast and largely uncharted range of bacterial species can be found the basis for drugs to clear out damaged lipids and the remains of doomed macrophages. This is in fact the longest running SENS rejuvenation research program, and not so long ago the first candidate bacterial enzymes were licensed to Human Rejuvenation Technologies for commercial development; we'll have to wait and see how that goes.

Repair remains a minority position in the research community, though hopefully not for too much longer as good results from other repair approaches such as senescent cell clearance start to emerge. Most researchers would first seek to build a better macrophage, a model with a more resilient garbage disposal system:

Atherosclerosis is Alzheimer's disease of blood vessels, study suggests

In atherosclerosis, plaque builds up on the inner walls of arteries that deliver blood to the body. Researchers suggest this accumulation is driven, at least in part, by processes similar to the plaque formation implicated in brain diseases such as Alzheimer's and Parkinson's. A look behind the scenes in the process of plaque accumulating in arteries, the new study is the first to show that another buildup is taking place. Immune cells attempting to counteract plaque formation begin to accumulate misshapen proteins. This buildup of protein junk inside the cells interferes with their ability to do their jobs. "In an attempt to fix the damage characteristic of atherosclerosis, immune cells called macrophages go into the lining of the arteries. The macrophage is like a firefighter going into a burning building. But in this case, the firefighter is overcome by the conditions. So another firefighter goes in to save the first and is likewise overcome. And another goes in, and the process continues to build on itself and worsen."

The researchers showed that this protein buildup inside macrophages results from problems with the waste-disposal functions of the cell. They identified a protein called p62 that is responsible for sequestering waste and delivering it to cellular incinerators called lysosomes. To mimic atherosclerosis, the researchers exposed the cells to types of fats known to lead to the condition. The researchers noted that during atherosclerosis, the macrophages' incinerators become dysfunctional. And when cells stop being able to dispose of waste, p62 builds up. In a surprise finding, when p62 is missing and no longer gathers the waste in one place, atherosclerosis in mice becomes even worse.

The researchers also found these protein aggregates and high amounts of p62 in atherosclerotic plaque samples taken from human patients, suggesting these processes are at work in people with plaque building up in the arteries. "That p62 sequesters waste in brain cells was known, and its buildup is a marker for a dysfunctional waste-disposal system. But this is the first evidence that its function in macrophages is playing a role in atherosclerosis." In atherosclerosis, and perhaps in the brain disorders characterized by protein accumulation, such evidence suggests it would be better to focus on ways to fix the cells' waste-disposal system for getting rid of the large protein aggregates, rather than on ways to stop the aggregates from forming.

Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis

The release of proinflammatory cytokines, such as IL-1β, by macrophages increases the size and number of atherosclerotic plaques. Macrophages in atherosclerotic plaques have a defect in autophagy, a process that eliminates dysfunctional proteins, and it has been shown that p62, a chaperone protein involved in autophagy, sequestered polyubiquitinated proteins in cytoplasmic inclusion bodies in macrophages. Macrophages lacking p62 released more IL-1β, and one of the proteins required for the production of IL-1β partially colocalized with these inclusion bodies.

In a mouse model of atherosclerosis, p62 deficiency increased macrophage infiltration in atherosclerotic plaques and exacerbated atherosclerosis. Thus, enhancing the function of p62 to promote the sequestration of polyubiquitinated proteins could prevent macrophages from exacerbating atherosclerosis.

Over the course of aging, proteins of many different varieties form aggregates in and around cells - this is one of the characteristic differences between old tissue and young tissue, which leads to the SENS rejuvenation research point of view that we should work to remove all of these aggregates. Any difference between old and young tissue should be reverted. Some aggregates are metabolic waste, some are misfolded or damaged protein machinery, and few are well understood at the detail level of their relationship with aging and disease. Where that understanding exists it is pretty clear that aggregates are causing pathology, but the present state of knowledge still leaves the door open to suggestions that at least some of these aggregates are helpful. Their presence perhaps compensates for other forms of age-related damage, or is the result of other compensatory behavior while the aggregates themselves are not particularly harmful. Still they are not present in young tissue, and this should perhaps remain the guide for development of rejuvenation therapies:

We age because the cells in our bodies begin to malfunction over the years. This is the general view that scientists hold of the ageing process. For example, in older people the cells' internal quality control breaks down. This control function usually eliminates proteins that have become unstable and lost their normal three-dimensional structure. These deformed proteins accumulate in the cells in a number of diseases, such as Parkinson's and Alzheimer's. For some researchers, however, the view of the ageing process as a consequence of flawed cell function and disease is too narrow. It ignores the fact that the mentioned so-called prion-like protein accumulations could have a positive effect, too, and therefore should not be referred to as cellular malfunction.

The researchers drew this conclusion based on research on yeast cells. They recently found in these cells a new type of protein aggregate, which appears as the cells get older. As the scientists were able to show, these protein aggregates do not arise as the result of a cell's malfunctioning internal quality control. On the contrary: in yeast cells with such aggregates, quality control functions even better. "It certainly seems that these aggregates help yeast cells to cope with the physiological changes caused by ageing. We are very exited to learn what type of information is stored in these structures." The scientists assume that these age-associated aggregates are formed by several different proteins. The researchers have already identified one prion-like protein that is part of the accumulations. What other proteins are involved and why the aggregates remain in the parent cells during cell division are subjects of further research.

"We're still a fairly small group of scientists who say: aggregate proteins are not pathological - they are neither an accident nor a defect." Rather, these proteins aggregate because it is their normal function. Diseases such as Parkinson's and Alzheimer's only arise when the system becomes imbalanced and too many prion-like proteins accumulate in the wrong place in the cells. "There are two aspects to ageing. Yes, you die at the end of the process, and this is negative. But you die wise. And Alzheimer's is perhaps a bad end to a good thing."

Link: https://www.ethz.ch/en/news-and-events/eth-news/news/2016/01/in-defence-of-pathogenic-proteins.html

Increased production of FGF21 via genetic engineering has been shown to extend life in mice, and calorie restriction appears to also increase FGF21 levels to some degree. Here researchers link FGF21 to the thymus and the immune system in aging. The thymus is an unusual organ in that it atrophies in early adulthood. It plays a limiting role in the pace of production of new immune cells, and thus restoring its structure and activity to youthful levels is an approach to at least partially reversing the age-related decline of the immune system. That might be achieved through tissue engineering or altered levels of FOXN1, among other methods.

A hormone that extends lifespan in mice by 40% is produced by specialized cells in the thymus gland, according to a new study. The team also found that increasing the levels of this hormone, called FGF21, protects against the loss of immune function that comes with age. When functioning normally, the thymus produces new T cells for the immune system, but with age, the thymus becomes fatty and loses its ability to produce new T cells. The researchers studied transgenic mice with elevated levels of FGF21. The team knocked out the gene's function and studied the impact of decreasing levels of FGF21 on the immune system. They found that increasing the levels of FGF21 in old mice protected the thymus from age-related fatty degeneration and increased the ability of the thymus to produce new T cells, while FGF21 deficiency accelerated the degeneration of the thymus in old mice.

FGF21 is produced in the liver as an endocrine hormone. Its levels increase when calories are restricted to allow fats to be burned when glucose levels are low. FGF21 is a metabolic hormone that improves insulin sensitivity and also induces weight loss; therefore it is being studied for its therapeutic effects in type-2 diabetes and obesity. "We found that FGF21 levels in thymic epithelial cells is several fold higher than in the liver - therefore FGF21 acts within the thymus to promote T cell production. Elevating the levels of FGF21 in the elderly or in cancer patients who undergo bone marrow transplantation may be an additional strategy to increase T cell production, and thus bolster immune function." Further studies will focus on understanding how FGF21 protects the thymus from aging, and whether elevating FGF21 pharmacologically can extend the human healthspan and lower the incidence of disease caused by age-related loss of immune function.

Link: http://news.yale.edu/2016/01/11/life-extending-hormone-bolsters-body-s-immune-function

Therapies for senescent cell clearance as a treatment for aging are going to be an ongoing concern within the next few years. Multiple different methods have been demonstrated to selectively kill senescent cells in mice, including the genetic engineering approach used a few years ago and the various senolytic drug candidates discovered more recently. These have variable effectiveness in different tissues, with some tissue types retaining all of their senescent cells, suggesting that no initial clinical treatment is going to be perfect. Even these prototypes are, however, clearing as much as a quarter of senescent cells in some tissues. In the case of senolytic drugs this is enough for old mice to display lasting health benefits after even a single treatment.

Why is the destruction of senescent cells an important goal? In short because cellular senescence is a contributing cause of aging. When damaged or faced with a toxic, stressed environment, cells tend to become senescent. A senescent cell stops replicating and secretes signals that both adjust the behavior of surrounding cells, making them more likely to become senescent, and make the senescent cell itself a target for destruction by the immune system. This is probably a defense against cancer, removing from play those cells most likely to become cancerous. Evolution likes reuse, and senescent cells are also transiently involved in wound healing and structural control over embryonic development. Nonetheless, having too many senescent cells is a bad thing, and that is exactly what happens with advancing age: senescent cells that evade destruction linger indefinitely, and their numbers grow over time, especially once the immune system starts to decline in old age. In large numbers senescent cells cause chronic inflammation and their collective signaling actively harms tissue structure and function. Their presence contributes to all of the common age-related diseases via these and a range of other, similar mechanisms. Periodic removal of senescent cells would solve all of these problems.

Senescent cell clearance treatments could be made much more efficient than the prototypes demonstrated so far in mice. That seems inevitable, based on some combination of innovation in delivery methods and innovation in kill mechanisms. We should always expect the first approaches to be weak in comparison to those that come later, with the benefit of more funding and attention. It is, however, quite possible for a therapy to be too good at killing senescent cells. Consider the study from some years back that showed as many as 20% of the skin cells in old baboons exhibited the signature for senescence. Now, what do you imagine would happen to you if 20% of the cells throughout your body died in a matter of a day? It wouldn't be pleasant. Clearing cells isn't a magical clean sweep of a process: a dead cell leaves behind debris and lot of frantic signaling in its last moments, and in volume that can be far worse than just leaving the cells alone. This is a well known problem in the cancer research community, a section of the medical establishment very focused on selectively killing cells. The condition that can result from having a significant number of cells die in a short period of time as the result of treatment is known as tumor lysis syndrome. At the mild end of the spectrum the outcome is sickness and metabolic dysregulation, while severe cases bring kidney failure and death, the systems of blood filtration utterly overwhelmed by a flood of cell debris and toxins.

Thus, naively, a hypothetical highly efficient senescent cell clearance therapy might work just fine in a 40-something adult, with tissues containing comparatively few senescent cells, while having a strong chance of killing patients in their 70s, with tissues containing many more senescent cells and also possessed of less resilient organs. Fortunately this issue is well understood in the research community, so no such highly efficient therapy is ever going to be produced. Approaches that could be this efficient in theory will be diluted or otherwise limited and delivered over a number of spaced treatments, producing a steady or stepped destruction of senescent cells at a safe pace. What that safe pace will turn out to be in humans is an open question, to be answered by experimentation, trials, and further studies, but the mouse data suggests it can be fairly rapid - just not all at once, immediately.

To go along with the recent announcement of the Longevity Dividend book, an extended argument for more government funding for the present mainstream approach to aging research, here is a position paper from one the researchers involved in this initiative:

The survival of large segments of human populations to advanced ages is a crowning achievement of improvements in public health and medicine. But, in the 21st century, our continued desire to extend life brings forth a unique dilemma. The risk of death from cardiovascular diseases and many forms of cancer have declined, but even if they continue to do so in the future, the resulting health benefits and enhanced longevities are likely to diminish. It is even possible that healthy life expectancy could decline in the future as major fatal diseases wane. The reason is that the longer we live, the greater is the influence of biological aging on the expression of fatal and disabling diseases. As long as the rates of aging of our bodies continues without amelioration, the progress we make on all major disease fronts must eventually face a point of diminishing returns.

Research in the scientific study of aging has already showed that the aging of our bodies is inherently modifiable, and that a therapeutic intervention that slows aging in people is a plausible target for science and public health. Given the speed with which population aging is progressing and chronic fatal and disabling conditions are challenging health care costs across the globe, the case is now being made in the scientific literature that delayed aging could be one of the most efficient and promising ways to combat disease, extend healthy life, compress morbidity, and reduce health care costs. A consortium of scientists and nonprofit organizations has devised a plan to initiate an accelerated program of scientific research to develop, test for safety and efficacy, and then disseminate a therapeutic intervention to delay aging if proven to be safe and effective; this is referred to as the Longevity Dividend Initiative Consortium (LDIC).

Link: http://dx.doi.org/10.1101/cshperspect.a025940

Researchers here investigate one of the more complex cell signaling mechanisms, providing evidence to link age-related changes in this mechanism to the development of osteoporosis, the loss of bone mass and strength that occurs with age. There is a growing interest in the research community in alterations to cell signaling that occur with aging. A great deal of this focuses on the changing amounts of various molecules found in the bloodstream, and arises from parabiosis studies that link the circulatory systems of old and young animals, producing benefits to measures of health in the older individual. Researchers have been isolating specific molecules of interest, showing that levels change with aging, and that reversal of those changes produces benefits in old animals.

These changes are most likely secondary reactions to forms of cell and tissue damage that accumulate over a lifespan, but in turn they are proximate causes for a range of undesirable outcomes that include the characteristic decline in stem cell activity that occurs with age. The signals that cells pass between one another are complex and varied. It isn't just a matter of releasing specific molecules into the bloodstream and surrounding tissues. For example, cells also create and emit vesicles, membrane-enclosed packages of molecular machinery that are used for a wide variety of purposes. Just as simple signals vary with age, so too do the number and contents of these vesicles, and here researchers provide evidence to suggest that there is to be found one of the proximate contributing causes to the loss of bone that occurs with age:

The capability of stem cells to regenerate tissue by differentiating into specialized cells has been shown to decrease with age. One organ that is notably affected by this loss in stem cell functionality is the skeleton. Bone is a highly dynamic organ that is constantly remodeled and maintained by the coordinated activity of bone forming osteoblasts and bone excavating osteoclasts. This balance is particularly important at older age, as too high osteoclast activity versus too few osteoblasts is considered to give rise to lower bone strength. The molecular mechanisms by which the imbalance is caused in the elderly are still incompletely understood. However, it is clear, that after skeletal maturation a constant number of mesenchymal stem cells (MSCs) and a reduced number of mature osteoblasts are observed with increasing age. This indicates that the functionality or the osteogenic commitment of MSCs might be impaired. Supportingly, the numbers of pre-osteoblasts, pre-osteoclasts and osteoclasts do not change with age per unit bone length, at least in elderly rats. However, a strong decline of mature osteoblasts has been described, as well as impaired osteoblastogenesis in age associated osteoporosis. This supports the hypothesis that impaired osteoblastogenesis contributes to age-related bone loss and loss of mechanical strength.

Since it has been proposed recently that the systemic environment of young versus elderly individuals can influence stem and progenitor cell functionality in different tissues, such as bone repair, specific focus is put on secreted circulating factors, in particular with regard to extracellular vesicles (EVs), small vesicles released by many if not all cell types. The cargo of EVs, consisting of proteins, mRNAs and non-coding RNAs, including miRNAs, is selectively packaged and delivered to specific recipient cells over short and long distances.

In the present study we set out to determine whether circulating factors, in particular human plasma-derived EVs from the elderly, contribute to the age-dependent loss of stem cell functionality. We observed that vesicles isolated from young donors enhance osteoblastogenesis in vitro compared to elderly-derived EVs. While searching for factors mediating this donor-age-dependent vesicular effect, we identified Galectin-3 to be enriched in EVs from young individuals. Indeed, we found that increased levels of Galectin-3 have a positive impact on the osteogenic differentiation capacity of MSCs and that extracellular vesicles enriched in Galectin-3 enhance osteoblastogenesis of MSCs. We elucidated its molecular mechanism of action by showing that this protein protects β-Catenin from degradation and that its Serine-96 (S96) phosphorylation site is crucial to mediate this effect. Finally, we demonstrated that cell-penetrating peptides fused to a 13 amino acid sequence, mimicking Galectin-3's Serine-96 phosphorylation site, are able to enhance osteoblastogenesis.

Link: http://www.impactaging.com/papers/v8/n1/full/100865.html

So you want to observe complexity. You might start with the obscure, rapidly moving collection of human endeavors that boil and ferment at the boundary of late medical research and early clinical development. Advocacy, fundraising, research, networking, non-profits, for-profits, and academics, a multi-level debate of a thousand opinions, and the foundations of new medicine are all mixed into one heated cauldron. In one sense it has always been this way. Figuring out what was happening in aging research and the quest for longer, healthier lives was a real challenge fifteen years ago, back at the turn of the century, let me tell you. But at least back then you could ground every investigation in the truth that if someone was trying to sell you something, then that something was irrelevant: snake oil and wishful thinking and nothing more. The serious science of aging and longevity was restricted to the laboratories, not yet to the point at which meaningful therapies could be constructed. Even stem cell treatments for narrow aspects of age-related degeneration or late-stage age-related disease had barely started to emerge back then.

Nowadays it remains a sizable task to make sense of the science and the state of development if you are coming in as an outsider. Where to even start? That is one of the reasons I continue to write Fight Aging! - because signposts are needed, and for better and worse this is one of them. If people find it hard to make sense of where things stand, how can we ask them to give us their support and their funds to move forward towards rejuvenation therapies? Education, in the sense of providing resources and making matters comprehensible for those who are interested in learning more, is an important part of advocacy.

There is one fundamental way in which understanding longevity science has become much harder today: you can no longer draw the line between the laboratory and the commercial world to say that only in the lab can you find legitimate, useful efforts to build treatments for the causes of aging. A limited number of actual, real rejuvenation treatments that clear or repair one specific root cause of aging are in development, in clinical trials, in biotech startups. There will be more with each passing year. As a result you have to know a lot more about what is going on, and must be prepared to evaluate the basis for the treatments that will be available via medical tourism, long in advance of any regulatory approval, just a few years from now.

The popular press article I've linked below is written by an outsider in the context of a time of great change, when the approach to aging in the research community has undergone a fundamental shift, SENS rejuvenation research and any number of gene therapies that might compensate for aspects of degenerative aging are moving from lab to development, or and many of these treatments will pour directly into the global medical tourism marketplace. These treatments are not all of the same class, however, and their usefulness will vary greatly: repairing the damage that causes aging and age-related disease, such as via SENS treatments, is very different from modestly compensating for the harm that damage causes, such as via most of the plausible near-future gene therapies. However: it isn't a joke to say that if you know the right people, you can go to an overseas clinic and pay a few tens of thousands of dollars to undergo a gene therapy today. It probably won't be terribly efficient at obtaining a good percentage of cells affected, but that issue is already pretty much solved back in the labs, and will also be solved in the field in a few years. The avalanche is underway, and loud enough that even normally oblivious sections of the media are pricking up their ears:

Special Series: Is Silicon-Valley Birthing the Next Set of Pro-Lifers

Elizabeth Parrish is 44, the tough-gunning, sharp-talking CEO of life-sciences startup BioViva, and seemingly full of life herself. But she says she suffers from a deadly disease. Hoping to stave off the sickness, Parrish recently journeyed to a clinic in Colombia, where she underwent a course of therapy that the FDA hasn't touched with a 10-foot pole. One treatment would alter her telomeres - the stuff at the end of her DNA. The other would inhibit a protein that stops muscle growth. Her affliction? Aging - and all the nasty diseases that come with it, from Alzheimer's and heart trouble to "basic muscle deterioration." Parrish, though perhaps unorthodox, is not alone in her insistence that aging is an evil we have a right to combat. Rather, she's part of a whole generation of futurists talking eagerly of the right to grow old in a better way. At a time when we're living longer - the average life expectancy in 2013 was nearly 80 years old, according to the CDC - this cohort wants even more. They want to live not a few years longer, but tens, even hundreds, of years longer, and what's more, they believe they - and one day all of us - are entitled to do so.

The burgeoning interest in long life isn't mere academic fodder: It has implications for public policy, law, and the health care system as we know it. The central question around which this explosive new debate will churn: Is aging itself a disease? Or is it, as the dominant thinking goes today, just the unfortunate condition that gives rise to a bunch of other nasty illnesses? If societies decided that old age was not a sad yet inevitable fact of life and that it - like malaria, like cancer - demanded a bevy of dollars and doctors battling it, then your primary care doctor and insurers, palliative care providers and government agencies would all have to adjust to a brand-new gravity. This is a whole new iteration of the term "pro-life."

The aging haters have a reasonable spiel down: It's health, pure and simple. That's the line researcher Aubrey de Grey, one of the most prominent scientists working on anti-aging issues, gives me. We're not talking about a right to never die, in his view, or even a right to live on and on. It's the right to have your health taken care of, your diseases ebbed away. It's just that aging happens to be an "uber-disease" we've not yet started to fight. Rather, if we live longer, well, that'll just be a rather nice side effect of researchers like him solving aging diseases.

Despite controversy over certain methods, some spine-tingling peer-reviewed research has lately appeared from hospitals, universities and privately funded groups like de Grey's Mountain View-based SENS Research Foundation - which just had its first paper in Science this year - or Google's biotech company Calico (which is still stealthy as hell and said they couldn't speak to us yet). Nonetheless, progress so far has come at a pace far slower than the private sector likes, and is laden with all the annoyances of bureaucracy and peer review. The National Institute on Aging (NIA) doesn't have much money, and the way it gets distributed is "inherently biased against revolutionary work," he huffs. A spokeswoman for the NIA pointed us to some examples of NIA-supported research in aging biology and in the "burgeoning field" of geroscience (which doesn't treat aging as a disease, but offers a kind of interdisciplinary approach).

And so, as with so many of our grand inventions of the future, the wealthy and the adventurous of the world will enter the fray first, potentially paying exorbitant amounts to be patient zero over and over again. Does that mean the right to a long life won't trickle down to the masses? No, de Grey insists, obviously tired of this question of access. "Once people get over the psychological stranglehold that humanity has" when they talk about death, "there's not going to be any problem at all." People will see the tech and demand it; doctors, insurers and the government will have to cave. It'll get cheaper, as technology does. Anti-aging therapies, de Grey predicts, are "going to be as available as water."

Researchers have recently shown that suppressing inflammation in brain tissue reduces the symptoms of Alzheimer's disease in a mouse model, and does this without producing any impact on the amyloid build up associated with the condition. A range of past studies have provided evidence for the significant role of inflammation in the brain in the development of Alzheimer's disease. Portions of the specialized subdivision of the immune system in central nervous system tissue are vital to the support of nerve cells, not just involved in attacking pathogens. Consider the populations of microglia and astrocytes, for example, cell types for which the full list of roles remains to be cataloged. Thus dysregulation of the immune system, as is associated with rising levels of chronic inflammation, can have complex effects in the brain that are unlike those elsewhere in the body.

Blocking a receptor in the brain responsible for regulating immune cells could protect against the memory and behaviour changes seen in the progression of Alzheimer's disease. It was originally thought that Alzheimer's disease disturbs the brain's immune response, but this latest study adds to evidence that inflammation in the brain can in fact drive the development of the disease. The findings suggest that by reducing this inflammation, progression of the disease could be halted. The team hope the discovery will lead to an effective new treatment for the disease, for which there is currently no cure.

The researchers used tissue samples from healthy brains and those with Alzheimer's, both of the same age. The researchers counted the numbers of a particular type of immune cell, known as microglia, in the samples and found that these were more numerous in the brains with Alzheimer's disease. In addition, the activity of the molecules regulating the numbers of microglia correlated with the severity of the disease.

The researchers then studied these same immune cells in mice which had been bred to develop features of Alzheimer's. They wanted to find out whether blocking the receptor responsible for regulating microglia, known as CSF1R, could improve cognitive skills. They gave the mice oral doses of an inhibitor that blocks CSF1R and found that it could prevent the rise in microglia numbers seen in untreated mice as the disease progressed. In addition, the inhibitor prevented the loss of communication points between the nerve cells in the brain associated with Alzheimer's, and the treated mice demonstrated fewer memory and behavioural problems compared with the untreated mice.

Importantly, the team found the healthy number of microglia needed to maintain normal immune function in the brain was maintained, suggesting the blocking of CSF1R only reduces excess microglia. What the study did not find is a correlated reduction of the number of amyloid plaques in the brain, a characteristic feature of Alzheimer's disease. This supports previous studies that argue other factors may play more of a role in cognitive decline.

Link: http://www.southampton.ac.uk/news/2016/01/blocking-brain-inflammation.page

An interesting study on the mechanisms of cell death in stroke came out today. The damage caused by a stroke is the result of cellular reactions to first loss and then restoration of blood flow and thus oxygen supply. Many of these reactions are, strictly speaking, unnecessary and actually directly harmful. Thus tinkering with the regulating mechanisms of these processes may produce benefits by increasing resistance to cell death due to ischemic injuries like stroke. The specific approach taken by researchers here has uncovered an unusually large effect. They propose their findings as a basis for stroke treatment after the fact, but in this new era of cheap genetic engineering, one has to wonder whether a permanent genetic alteration to human patients prior to old age is feasible in this case:

Scientists have identified the oxygen sensor PHD1, also known as EGLN2, as a potential target for the treatment of brain infarction (ischemic stroke). Of all organs in our body, the brain is unique because it needs the highest levels of oxygen and glucose to function and to survive. The simple reason herefore is that brain cells absolutely rely on oxygen and glucose to generate energy, necessary to function normally. In stroke, reduced blood supply therefore threatens this energy balance, causing neurons to die.

Researchers discovered that brain cells sense and adapt to a shortage of oxygen and nutrients via PHD1. They observed that mice lacking the oxygen sensor PHD1 were protected against stroke induced by an obstruction of a main blood vessel supplying oxygen and glucose to the brain. Not only was their infarct size reduced by more than 70% (which is an unusually large beneficial effect), but mice lacking PHD1 also performed much better in functional tests after stroke.

A critical problem when brain cells are deprived of oxygen is that they generate damaging side-products, "oxygen radicals", which kill brain cells. Most previous stroke treatments are unsucessful, because they are based on the principle to target the consequences rather than the cause of these oxygen radicals. Researchers focused on a completely new concept, i.e. utilizing the endogenous power of brain cells to enhance the neutralization of these toxic side-products. The researchers now discovered that inhibition of the oxygen sensor PHD1 protects brain cells against these toxic side-products by reprogramming the use of sugar in low-oxygen conditions. "By reprogramming glucose utilization, neurons lacking PHD1 have an improved capacity to detoxify damaging oxygen radicals, protecting the brain against stroke. This is a paradigm-shifting concept in the field of stroke protection."

Link: http://www.vib.be/en/news/Pages/-VIB-researchers-discover-possible-strategy-against-stroke.aspx

A most interesting paper surfaced today, after spending more than a year in the peer review process. The current press coverage is in Spanish only, but we all have access to automated translation these days. The authors of the paper report that the muscle stem cell population known as satellite cells, responsible for regeneration and tissue maintenance, relies upon autophagy to evade the onset of cellular senescence. Unfortunately autophagy fails with age, a decline that is linked to the accumulation of metabolic waste in long-lived cells, but probably has other less direct contributing factors as well. When stem cells fall into senescence, their activity and effectiveness declines. The researchers demonstrated that restoring youthful levels of autophagy in old satellite cell populations can restore them from senescence and return their regenerative capabilities. This has its analogies in earlier work, such as the approach taken to restore function in aged liver tissue back in 2008.

Autophagy is an collection of cellular maintenance processes, focused on clearing out waste and recycling damaged components. Greater autophagy taking place in tissue should mean fewer damaged and disarrayed cells at any given moment in time, which in turn should translate to a longer-lasting organism. The paper linked below is one of the more compelling of recent arguments for putting more effort into treatments based on artificially increased levels of autophagy. This has been a topic in the research community for some time, as many of the methods known to modestly slow aging in laboratory species are associated with increased levels of autophagy. It is a vital component in hormesis, wherein causing a little damage leads to a lasting increase in autophagy and a net gain.

Stem cells spend much of their time in a state of quiescence, only springing into action when called upon. This helps to preserve them for the long term. In older tissues with greater levels of molecular damage, ever more stem cells slip from quiescence into an irreversible senescent state. These senescent cells are no longer capable of generating new cells, and start to secrete all sorts of harmful signal molecules. Cellular senescence is thought to be a response to damage or a toxic environment, so you can probably see how this might be expected to tie into repair processes such as autophagy. There is some debate over the degree to which cellular senescence is irreversible in the normal course of events inside a living organism. When reductions in senescence are observed in a cell population as a result of changing circumstances or a treatment, it may simply be that the relative number of senescent cells falls without any such cell returning to a non-senescent status. Cell populations are dynamic, after all.

Scientists discover how to keep the body young despite age (Spanish)

Muscles have a cleaning system that eliminates waste and preventing degenerate over the years, as scientists have discovered. When this cleaning system stops working properly, the muscles go into senescence. Then, stem cells lose the ability to regenerate tissue and muscle is weakened. It's something that happens gradually from the fifth decade of life and that in elderly people forces them into frailty. But when the cleaning system is restored, as have researchers with drugs, muscle tissue can regenerate again and retrieves the lost vigor. So far the experiments have been performed in mice and in human cells in the laboratory.

The cleaning system, technically called autophagy, removes components of cells that have stopping functioning properly and become toxic. These components range from individual molecules (free radicals or damaged proteins) to whole organelles (such as mitochondria or ribosomes). Since all organs and tissues of the human body depend on autophagy, researchers believe that the same system could be key to slow aging in other organs, and it could be useful to increase their regenerative capacity and rejuvenate. "I think it must be so because every house has to be cleaned, and autophagy is a very fundamental cleaning mechanism in living organisms, but we have not proven that our research is not limited to muscle tissue."

In muscle, autophagy has been shown to maintain the ability of stem cells to regenerate tissue. And when autophagy is no longer efficient and cells begin to accumulate waste, stem cells enter senescence and lose their regenerative capacity. "We were surprised to discover this. When you stop to think about it, it makes sense, because the stem cells need to break free of waste accumulate every day to work properly." But despite intensive research in the last decade on the biology of aging, "this is the first time a relationship between aging and declining autophagy in mammalian tissue is observed. Although senescence due to aging is often seen as an inevitable and irremediable process, we demonstrate that the internal clock of aging stem cells can be manipulated with drugs."

Autophagy maintains stemness by preventing senescence

During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.

Researchers here demonstrate the ability to efficiently produce islet cells of the pancreas to order from a skin sample. One of the near term goals for the stem cell research community is to develop reliable, low-cost recipes for turning out patient-matched cells of any desired type. This is a necessary starting point for most of the future of regenerative medicine and tissue engineering: lower cost and higher quality cell sources mean faster development and cheaper clinical treatments. There are more than 200 different types of cell in the body, with that number being somewhat fuzzy around the edges and still subject to change. Thus far it has been clear that different cell types require quite different approaches to growth and culturing, so this is clearly a large project, but progress is ongoing:

Researchers have successfully converted human skin cells into fully-functional pancreatic cells. The new cells produced insulin in response to changes in glucose levels, and, when transplanted into mice, the cells protected the animals from developing type 1 diabetes in a mouse model of the disease. The new study also presents significant advancements in cellular reprogramming technology, which will allow scientists to efficiently scale up pancreatic cell production and manufacture trillions of the target cells in a step-wise, controlled manner. "Our results demonstrate for the first time that human adult skin cells can be used to efficiently and rapidly generate functional pancreatic cells that behave similar to human beta cells."

In the study, the scientists first used pharmaceutical and genetic molecules to reprogram skin cells into endoderm progenitor cells - early developmental cells that have already been designated to mature into one of a number of different types of organs. With this method, the cells don't have to be taken all the way back to a pluripotent stem cell state, meaning the scientists can turn them into pancreatic cells faster. The researchers have used a similar procedure previously to create heart, brain, and liver cells. After another four molecules were added, the endoderm cells divided rapidly, allowing more than a trillion-fold expansion. Critically, the cells did not display any evidence of tumor formation, and they maintained their identity as early organ-specific cells. The scientists then progressed these endoderm cells two more steps, first into pancreatic precursor cells, and then into fully-functional pancreatic beta cells. Most importantly, these cells protected mice from developing diabetes in a model of disease, having the critical ability to produce insulin in response to changes in glucose levels.

Link: https://gladstone.org/about-us/press-releases/insulin-producing-pancreatic-cells-created-human-skin-cells

One approach to organ engineering is to create lineages of chimeric pigs, a species with organs of a similar enough size and shape for transplant into humans, in which the organs of interest are made up of human cells rather than pig cells. This may or may not turn out to be harder than the alternative of taking ordinary pig organs, decellularizing them, stripping them of harmful remaining proteins, and then repopulating the remaining structure with human cells. There is some degree of irrational hysteria surrounding the creation of chimeras, which only makes the real challenges harder to surmount. Still, it seems to me that these are stopgap technologies that will have a short practical life span. They will be overtaken in cost and efficiency by the ability to generate organs from a patient's own cells in a bioreactor:

Braving a funding ban put in place by the NIH, some U.S. research centers are moving ahead with attempts to grow human tissue inside pigs and sheep with the goal of creating hearts, livers, or other organs needed for transplants. Based on interviews with three teams, two in California and one in Minnesota, it is estimated that about 20 pregnancies of pig-human or sheep-human chimeras have been established during the last 12 months in the U.S., though so far no scientific paper describing the work has been published, and none of the animals were brought to term.

The extent of the research was disclosed in part during presentations made to the NIH at the agency's request. One researcher showed unpublished data on more than a dozen pig embryos containing human cells. Another provided photographs of a 62-day-old pig fetus in which the addition of human cells appeared to have reversed a congenital eye defect. The experiments rely on a cutting-edge fusion of technologies, including recent breakthroughs in stem-cell biology and gene-editing techniques. By modifying genes, scientists can now easily change the DNA in pig or sheep embryos so that they are genetically incapable of forming a specific tissue. Then, by adding stem cells from a person, they hope the human cells will take over the job of forming the missing organ, which could then be harvested from the animal for use in a transplant operation.

Other kinds of human-animal chimeras are already widely used in scientific research, including "humanized" mice endowed with a human immune system. Such animals are created by adding bits of liver and thymus from a human fetus to a mouse after it is born. The new line of research goes further because it involves placing human cells into an animal embryo at the very earliest stage, when it is a sphere of just a dozen cells in a laboratory dish. This process, called "embryo complementation," is significant because the human cells can multiply, specialize, and potentially contribute to any part of the animal's body as it develops. In 2010 researchers used the embryo complementation method to show that they could generate mice with a pancreas made entirely of rat cells. "If it works as it does in rodents, we should be able have a pig with a human organ."

Link: http://www.technologyreview.com/news/545106/human-animal-chimeras-are-gestating-on-us-research-farms/

Calorie restriction has been rigorously demonstrated to slow aging in mammals for eighty years, but only in the past thirty years has research on this topic picked up. Since calorie restriction has a sizable and very reliable effect in comparison to most other interventions that can modestly slow aging, and requires no advanced technology or expensive treatments, the fact that it does extend life has been the starting point for many researchers interested in the mechanisms of aging. One of the most important tools in the sciences is the comparison of two similar things in order to pinpoint differences that are important, in this case animals of the same species and lineage with varied dietary calorie intake.

The primary goal of the scientific community is to map the changing molecular biochemistry of aging, with doing something about aging a distant second where it is considered at all. The calorie restriction response is at once useful and frustrating because it changes near everything in the operation of metabolism and slows near every measure of aging. Since all aspects of cellular biology are intertwined, this makes it enormously difficult to figure out chains of cause and effect. Understanding calorie restriction is more or less equivalent to fully understanding and mapping a large swathe of cellular biochemistry. This is a task that is expected to run for decades yet at the present pace. There are a lot of details and blank spots left to be filled in, and the closer researchers look, the more there is to find.

It is useful to understand that complex descriptions of what goes on in a calorie restricted individual are still really only sketches. There are lines drawn, and the high level picture is mostly in place in outline at least, but the full details are yet to be cataloged, and there may yet be surprises. If researchers waded through all the work required, and were to develop drugs that accurately mimicked the calorie restriction response - a tall order - the benefits would still be modest. This is not rejuvenation, repair of damage, but only a slowing of the progression of damage in aging. It is something worth doing when it is free, since every healthy year counts in a time of rapid progress, but the price tag for the scientific community to produce drugs that achieve that end seems excessive to me, at least when considering the marginal outcome. At least a billion dollars has been spent on this so far, and there is nothing much to show for it aside from new knowledge of narrow slices of our biology: see the much hyped work on sirtuins for example. We'd be better off supporting SENS-like rejuvenation research, such as senescent cell clearance, as that has already produced more impressive results in the first studies in mice than calorie restriction mimetics ever have.

None of that means that calorie restriction research is uninteresting. Far from it. Take this open access review, for example. Just bear in mind the costs and the benefits of various approaches when reading the literature:

Calorie restriction as an intervention in ageing

Ageing is not a disease and therefore, disease-oriented research and treatment approaches are not adequate. It has thus been proposed that the use of health-oriented and preventive strategies is more beneficial than disease-oriented treatments. Calorie restriction (CR) is, to date, the most successful intervention to delay ageing progression or the development of age-related chronic diseases. CR has been defined as the reduction of energy intake without malnutrition. During the last few years it has been demonstrated that CR extends lifespan, extending the healthspan by delaying the onset of age-related diseases in many of the animal models studied. This effect of CR on longevity was explained in a unified theory of ageing as not a simple and passive effect but an active, highly conserved stress response that increases the organism's chance of surviving adversity. Thus, CR produces a response that modifies key process in cell protection, reparation mechanisms and modulation of metabolism that permits a higher survival against adversity. This has been supported by the 'Hormesis hypothesis of CR' that suggests that the induction of a moderate stress causes adaptive responses of cells and organs, preventing further damage due to a stronger stress

There are no detailed reports about the effect of CR on longevity in humans. The longer life expectancy of humans in comparison with other animals and the low number of persons tested makes it difficult to reach conclusions about the effect of CR on human longevity. It is not yet clear if the reported effects on longevity and healthspan found in humans are due to the decrease in the calorie intake or are the result of a high quality diet. However, it seems clear that a reduction in calorie intake in humans improves healthspan, and delays cardiac ageing, improving cardiovascular function, one of the main causes of death in humans.

Mitochondrial activity and ROS production are modulated by CR

In spite of the enormous number of articles published about the mechanism involved in the effect of CR on longevity, these mechanisms have not been clarified to date, although an important role of the maintenance of a balanced activity in mitochondria is supported by a large body of evidence. Ageing is associated with the impairment of mitochondria, with a significant increase in reactive oxygen species (ROS) generation and a decrease in antioxidant defences, causing accumulation of mitochondrial DNA and oxidative damage. An important factor involved in the accumulation of damaged mitochondria during ageing is the decline of the mitochondrial turnover by inhibition of mitophagy; the specific autophagy process that removes damaged mitochondria. It is clear that the renovation of mitochondrial network plays a key role in healthspan increase after CR.

Importance of membrane lipid composition on the CR effect

The decrease in the oxidative damage in organic structures is one of the main factors contributing to lifespan extension induced by CR. The fatty acid composition of cell membranes is another important factor involved in ageing progression because it influences the lipid peroxidation rate during ageing. Thus, several findings indicate that the increase in lipid peroxidation during ageing. It is still unclear whether lifespan extension induced by CR can also be explained by changes in membrane fatty acid composition conferring higher resistance to peroxidation. We have recently found that lipid composition in the diet can modulate the effect of CR on longevity, for example.

Antioxidant activities in ageing and CR

Oxidative damage is prevented by endogenous antioxidant activities in cells and organs. Although one of the most popular theories to explain the prolongevity effect of CR on different organisms is based on higher protection against the increase in oxidative stress and subsequent cell damage, the role of antioxidants in CR effect is not clear. Many lines of evidence indicate that CR reduces age-associated accumulation of oxidized molecules. However, the lack of lifespan extension in antioxidant enzyme overexpression experiments casts doubt on the importance of antioxidants in the CR effect. Higher levels of antioxidants do not necessarily indicate a higher antioxidant protection and imbalances produced by the overexpression or higher activity of one antioxidant enzyme must be taken into consideration.

IGF-I

Among the hypotheses to explain ageing, several findings indicate that changes in the insulin-IGF-I receptor signalling system are involved in the modulation of ageing. CR reduces plasma levels of IGF-I, insulin and glucose in rodents and also in humans.

Target of Rapamycin (TOR)

TOR protein members are a conserved family of kinases that respond to stress, nutrient and growth factors. TOR stimulates cell growth when food is available. TOR inhibits autophagy and stimulates protein synthesis and cell proliferation. The importance of TOR in longevity induced by CR was also demonstrated in invertebrates. In these organisms, down-regulation of TOR produces an increase in lifespan.

AMP-dependent protein kinase (AMPK)

AMPK is a very sensitive energy sensor in cells and organisms. AMPK is activated in response to an increase in the AMP/ATP ratio, for example, when cells are deprived of glucose, whereas its activity decreases when cells are full of energy, indicated by a lower AMP/ATP ratio. As in the case of other regulators such as sirtuins, its effect on longevity has been observed in several organisms from yeast to mammals. It has been clearly demonstrated that an increase in AMPK activity is associated with a longer lifespan while its inhibition shortens it. However, in mammals, the importance of this kinase is under debate since it has been reported that its activity is not affected by CR or is even reduced. However, other studies indicate an increase in AMPK activity in heart and skeletal muscle. These discrepancies could be due to differences in the amount of time under CR or the degree of CR which can play an important role in nutrient balance.

Sirtuins

Some time ago it was demonstrated that the orthologue of mammalian SIRT-1, Sir2, was able to increase lifespan in invertebrates. In mammals, it is clear that CR induces the expression and the activity of sirtuins in many organs and their activities are associated with many of the metabolic effects found in these organisms after CR. Interestingly, sirtuins seem to play a central role in the response to CR. Sirtuins act as nutrient and metabolic sensors by detecting fluctuations in the NAD+/NADH ratio. When nutrients, especially glucose, decrease, NAD+ accumulates and sirtuins are activated. Thus sirtuins have an opposite effect to TOR activation after glucose input. The complexity of sirtuins in mammals has promoted the idea that they can show both pro- and anti-ageing capacities in mice.

Mitochondrial modifications induced by CR

Several studies found that mitochondrial biogenesis is impaired during ageing, especially in high-energy-demanding tissues such as muscle, brain or heart. CR and other interventions such as exercise or nutraceuticals such as resveratrol induce mitochondrial biogenesis in heart and skeletal muscle in humans and other organisms, indicating their role in the maintenance of the mitochondrial activity in these organs during ageing.

CR mimetics

During the past few years, a group of molecularly unrelated compounds have emerged as CR mimetics, able to produce, at least partially, similar effects in different organisms. In general, all these compounds have a common denominator, the activation of the above-described molecular pathways involved in the response to CR such as AMPK and sirtuins. All these compounds have shown, at least in part, similar effects to CR on cells, tissues and organs and all of them have produced mitochondrial regulation by increasing turnover and activating oxidative metabolism through activation of the AMPK/SIRT1 axis and inhibition of TOR. It seems clear then that the regulation of mitochondrial metabolism by these nutrient sensors is at the centre of the effect of CR and its mimetics on healthspan and longevity.

CR and inflammation

Inflammation is also an important factor in ageing. Proinflammatory factors such as TNF-α increase systemically during ageing. It has been shown that the increase in oxidative stress during ageing can be involved in the incidence of age-related diseases and the induction of a chronic inflammatory process. It is likely that the maintenance of mitochondria biogenesis by CR can increase the resistance of muscle against inflammation.

Effect of CR on age-associated diseases in humans

Two of the main age-associated diseases in humans are type 2 diabetes and cardiovascular disease (CVD). In both cases, models of CR, dietary interventions or exercise have shown important improvements in the onset and development of these diseases.

Concluding remarks

The broad effect of CR on healthspan and longevity occurs through multiple mechanisms that involve most of the metabolic pathways in tissues and organs. The major effectors are sirtuin deacetylases, AMPK and PGC-1α. CR improves aerobic metabolism by increasing efficient mitochondrial metabolism, lowering endogenous ROS production at the same time as it increases the amount and activity of endogenous antioxidant enzymes. These molecular and physiological effects have also been found with some nutraceuticals and compounds that act as CR mimetics such as resveratrol, rapamycin or metformin. CR also affects the lipid composition of membranes by lowering oxidative damage. Further, the study of the mechanisms involved in the prevention of chronic inflammation induced by CR, probably through similar mechanisms to those found in mitochondrial regulation, is increasing and offers new opportunities to understand how CR prevents endogenous damage in the organism.

Immunosenescence is the term given to the aging of the immune system. In old age the immune system falls into a state of chronic inflammation coupled with a lack of effectiveness: it is overactive to the point of damaging tissues, but lacks the capacity to achieve the goals of destroying pathogens and potentially dangerous cells. Researchers here theorize that the progressive deterioration of the immune system is one contributing factor to the characteristic decline in stem cell activity that also accompanies aging, at least where it involves mesenchymal stem cells (MSCs). They propose that this effect is mediated through the interaction of hematopoietic stem cells, responsible for generating immune cells, and mesenchymal stem cells in the bone marrow where they both reside:

Several lines of evidence indicate that the decline in stem cell function during ageing can involve both cell intrinsic and extrinsic mechanisms. The bone and blood formation are intertwined in bone marrow, therefore, haematopoietic cells and bone cells could be extrinsic factors for each other in bone marrow environment. There is growing evidence in animal studies and invertebrate models that the stem cell niche, one of the extrinsic mechanisms, is important for the regulation of cellular ageing in stem cells. We uncovered that there are age-related intrinsic changes in human mesenchymal stem cells. In this study, we assess the paracrine interactions of human bone marrow haematopoietic cells on mesenchymal stem cells.

Our data demonstrate that there are paracrine interactions of haematopoietic cells, via soluble factors, such as TNF-α, PDGF-β or Wnts, etc., on human mesenchymal stem cells; the age-related increase of TNF-α in haematopoietic cells suggests that immunosenescence, via the interactions of haematopoietic cells on mesenchymal stem cells, may be one of the extrinsic mechanisms of skeletal stem cell function decline during human skeletal ageing. TNF-α has a central role in bone pathophysiology and its action in the skeleton results in increased bone resorption by stimulation of osteoclastogenesis and impaired bone formation by suppressing recruitment of osteoblasts from progenitor cells, inhibiting the expression of matrix protein genes, and stimulating expression of genes that amplify osteoclastogenesis.

Our data implied that besides the current approaches to intervene in osteoporosis, such as targeting on osteoclasts to stop bone resorption or osteoblasts to increase bone formation, there may be a new approach that targets the interactions of haematopoietic cells on osteoblast precursors to identify potential intervention for osteoporosis and bone fracture, and to develop therapeutic strategies to prevent or restore skeletal tissue degeneration and loss in the ageing population.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450757/

Yet another noted organization in the space is echoing calls from researchers and advocates in recent years for regulatory bodies to classify aging as a disease:

Disease classification is too often dependent on social and cultural context, and separating 'normal' progression from 'healthy' aging lacks coherence and hinders efforts to ameliorate age-related suffering. For example, several currently recognized diseases, such as osteoporosis, isolated systolic hypertension, and senile Alzheimer's disease, were in the past ascribed to normal aging. Recognising aging as a unique, but multisystemic disease would provide a framework to tackle and prevent many chronic conditions; alleviating both financial, social and moral burden.

Researchers have called for a task force to be created to classify ageing as a disease with a granular and actionable set of disease codes in the context of the 11th International Statistical Classification of Diseases and Related Health Problems (ICD-11). Classifying aging as a disease is a highly debated topic, where there is clear disagreement among demographers, gerontologists and biogerontologists on the subject, classification of aging as a disease is likely to unite both scientists and medical practitioners in the effort to prevent the pathological age-related processes and attract more resources to aging research.

In part, the researchers call for creating a task force of scientists to more thoroughly evaluate whether to provide a more granular and actionable classification of aging as a disease in ICD-11. "A more granular classification of ageing as a disease with a set of "non-garbage" ICD disease codes will help put it in the spotlight and help attract resources to accelerate research. Also, like with any disease, acceptance of the disease is the first step to treatment."

Link: http://www.eurekalert.org/pub_releases/2016-01/brf-brf010516.php

It was going on a decade ago that I first noticed research on antioxidant compounds that target mitochondria in cells. That was the Russian research team of Vladimir Skulachev and their family of plastinquinone compounds, with SkQ as the canonical example. They started off with a demonstration that SkQ modestly extended healthy life span in mice, which is the source of interest in mitochondrially targeted antioxidants in the longevity science community.

Why would we expect antioxidants in mitochondria to extend healthy life to some degree? Mitochondria are the power plants of the cell, generating chemical energy stores that power other cellular processes. In the course of doing this the mitochondria also create reactive oxidizing molecules that can damage molecular machinery. That damage is usually quickly repaired, but some of it can slip through the gaps to linger, multiple, and cause harmful consequences in the long-term. There is no direct relationship between the level of oxidative stress generated in a cell by its mitochondria and the pace of aging: both slight reductions (less damage) and slight increases (the cell reacts with more repair efforts, so less damage overall) have been shown to extend life in short-lived laboratory animals. Some of the most important potential damage caused by oxidizing molecules is inside mitochondria themselves, however, right at the source. This is probably why antioxidants localized mitochondria can modestly alter the progression of aging, but antioxidants everywhere else do not. There are in fact natural antioxidants produced within cells that localize to mitochondria, and researchers have demonstrated some degree of slowed aging in mice through genetic engineering that results in increased production of these mitochondrially targeted antioxidants.

The types of antioxidant you can go out and buy in a store do not localize to mitochondria and do nothing for your health. That is in fact the scientific consensus on supplements in general, derived from numerous large studies. In fact taking a lot of antioxidants is probably mildly harmful, since it interferes with the oxidative signaling that is a necessary part of the chain of mechanisms that produce benefits from exercise. Exercise causes mild cellular stress, and the raised levels of oxidative molecules generated by mitochondrial activity is a signal for cells to wake up and do something about the situation. Suppress that signal with antioxidants and exercise benefits vanish.

Over the past decade Skulachev's researchers have tested plastiquinone compounds in a variety of laboratory species. As is often the case in these matters, early life span figures settled down to a lower 10% gain or less in more careful studies, much less than can be achieved via calorie restriction, to pick one example. However, they also tested for results in the treatment of range of specific medical conditions. They eventually settled on bringing a drug to market for eye conditions shown to benefit from the actions of mitochondrial antioxidants. Unlike the life extension, these results seem much more robust and transformative. Regardless, translating research to the clinic is a slow business at the best of times, thanks to heavy-handed regulation, and at the present time the only way forward within the system is to treat a specific disease rather than the causes of aging itself. This is the case even if you happen to have an approach to hand that works somewhat better than mitochondrially targeted antioxidants.

Vladimir Skulachev isn't the only researcher with a background in mitochondrial antioxidants, and the Russian teams are not the only groups working in this area. The link I have for you today is related to a US group and their mitochondrially targeted molecule SS-31, also known as MTP-131, Bendavia, and Ocuvia. These researchers are also well down the path of commercial development via the startup Stealth Biotherapeutics. Interestingly, as this article notes, SS-31 may not even be an effective antioxidant but instead reduces oxidant levels via other means:

New Mitochondrial Therapy Based on Bioenergetics Advancing in Range of Clinical Trials

In the pipeline at Stealth Biotherapeutics is a new therapy, MTP-131, with the potential to treat individuals with mitochondrial disease and other diseases affected by mitochondrial dysfunction. The systemic version of MTP-131 (also known as Bendavia) is in clinical trials for skeletal muscle and cardio-renal diseases. The topical eye drop version (also known as Ocuvia) is on track to initiate clinical trials into Fuchs' corneal endothelial dystrophy and Leber's hereditary neuropathy in early 2016. "In collaboration with mitochondrial experts, we are looking at the organs with the most mitochondria (e.g., the heart) or that produce the most energy (e.g., muscle tissue and the eye). Mitochondrial function is involved in many different diseases. The key is which disease areas to focus."

"MTP-131 crosses the plasma membrane of cells and localizes specifically to the mitochondria." Probing further into the mechanism of action, the research team discovered that MTP-131 associates with the inner membrane of the mitochondria, where the respiratory complexes that generate ATP are located. "What's unique about that inner membrane? As it turns out, it's the only place where the phospholipid cardiolipin is found." Cardiolipin, a molecule that composes approximately 20% of the inner mitochondrial membrane's phospholipid content, differs from other phospholipid molecules such as phosphatidylcholine because it has two "phospho" head groups and four acyl chains. This unique structure gives cardiolipin a conical shape that forms a curve in the inner membrane of the mitochondria when the molecules are adjacent to each other, and helps hold the respiratory complexes in place. The binding of MTP-131 to cardiolipin may help the respiratory complexes operate more efficiently, in addition to other potential effects.

This mechanism of action sets MTP-131 apart from other investigational mitochondrial disease therapies because it directly affects bioenergetics rather than scavenges reactive oxygen species (ROS). Whereas therapeutics that neutralize ROS can potentially decrease ROS to harmfully low levels (some ROS activity is necessary in cells for signaling purposes), MTP-131 normalizes ROS levels by increasing the efficiency of mitochondria. In one experiment with old and young mice, it was shown that the mitochondria of old mice reached nearly the same level of ATP generation as that of young mice an hour after treatment with MTP-131, rising from approximately two-thirds the level of young mice. MTP-131 appears to have therapeutic effects only in abnormal or stressed mitochondria, potentially reducing the risk for side effects in patients. Additional safety studies in clinical trials are needed to determine any adverse effects of treatments.

The advent of small, cheap accelerometers - such as the one found inside every mobile device these days - has profoundly changed the nature of the data used in scientific studies of the relationship between health and exercise. As in the study I'll point out here, it has been noted that self-reported exercise levels bear only a modest correlation to accelerometer data gathered from those same individuals. There are definitely questions on the interpretation of this data, however. This all starts to suggest that some of the results from older studies are based on artifacts in the data, not reality. For example, that there is a large difference in outcomes between no exercise and some exercise, but little further gain in health and reduced mortality for increased exercise past that point. Is that curve of benefits real, or does it result from the muddiness of self-reported levels of exercise?

Self-reported physical activity questionnaires remain the primary assessment method for large observational studies despite their limitations. Physical activity questionnaires rank participant physical activity levels moderately well, but are less precise assessing the absolute volume of physical activity (e.g. the total amount of time spent in moderate-to-vigorous physical activity (MVPA)) compared to objective measures. Objective measures of physical activity, such as those obtained from accelerometers, may allow for a more precise assessment of physical activity volume.

It is important to understand the relationship between accelerometer-assessment and self-report. Accelerometers, due to their decreasing cost and size, have become increasingly prevalent in both research settings and as commercial products, but are unlikely to fully replace self-report as the primary MVPA assessment method in large observational studies. Self-report questionnaires may be preferred due to fewer logistical challenges as well as to examine specific activities or domains of activity (such as leisure-time, transportation, occupational, and home-based physical activity). Finally, the majority of the existing research examining physical activity and health is based on self-reported physical activity.

Previous studies have shown a low to moderate correlation between self-report questionnaires and uniaxial accelerometer measures, as well as significant differences in absolute volume of MVPA measured. A challenge to describing accelerometer-assessed physical activity is determining the appropriate cutpoint to translate accelerometer measures into physical activity carried out at different intensities. Numerous accelerometer cutpoints for MVPA, all using data collected from the vertical axis, have been proposed based on calibration studies primarily carried out under laboratory settings. Since no 'gold standard' cutpoint for older adults exists, studies have used a variety of cutpoints to describe accelerometer-assessed time in MVPA.

Perhaps the largest challenge in comparing data collected using accelerometers or questionnaires lies in what each method truly measures. Accelerometers measure accelerations in physical motion, and do not directly measure behavior. While accelerometers offer the possibility of greater characterization of physical activity (e.g., identification of short bouts), innovative analytical methods hold promise but are still under development.

According to self-reported physical activity, 67% of women met the US federal physical activity guidelines, engaging in ≥150 minutes per week of MVPA. The percent of women who met the guidelines varied widely depending on the accelerometer MVPA definition (≥760 cpm: 50%, ≥1041 cpm: 33%, ≥1952 cpm: 13%, and ≥2690 cpm: 19%). The main strength of this study is a large sample of more than 10,000 older women, in whom we simultaneously examined assessments from self-report and accelerometer across a range of cutpoints. We show that the choice of accelerometer cutpoint impacts MVPA estimation. Among the cutpoints examined, the triaxial accelerometer MVPA cutpoint compared to self-report yields the most similar median, and lowest interquartile range of MVPA minutes per week. However, use of uniaxial and triaxial cutpoints yielded similar correlations when compared with self-reported physical activity. Although cutpoints may be a simplistic use of the rich accelerometer data, this is the only well-studied metric available today, pending further development of methods.

Link: http://dx.doi.org/10.1371/journal.pone.0145950

In recent months a number of studies on Janus kinases (JAK) have been published, focusing on their effects on senescent cells, inflammation, and stem cell activity. In animal studies JAK inhibitors seem to reduce the harmful activities of senescent cells, which leads to modest benefits in old individuals, though it is unclear as to the degree to which these treatments are removing senescent cells via programmed cell death versus merely altering their behavior. Reports in the research literature vary on this count, but lean towards modulation. Trying to alter the behavior of senescent cells is in my eyes a poor substitute for a definitive targeted elimination of those cells, but there is value in all sound demonstrations of cellular senescence as an important contribution to degenerative aging, as they increase support for the development of treatments that can measurably impact aging.

Researchers have taken what they hope will be the first step toward preventing and reversing age-related stem cell dysfunction and metabolic disease. "Our work supports the possibility that by using specific drugs that target senescent cells - cells that contribute to frailty and disease associated with age - we could stop human senescent cells from releasing toxic proteins that are contributing to diabetes and breakdowns in stem cells in older individuals."

Researchers found that human senescent fat cells release a protein called activin A that impairs the function of fat tissue stem cells and fat tissue. They discovered an activin A increase in the blood and fat tissue of the aged mice. Treatment with Janus kinase (JAK) inhibitor drugs in aged mice, equivalent to 80-year-old people, decreased the amounts of activin A and partially reversed the fat tissue insulin resistance that contributes to diabetes in old age. In aged mice that are engineered to express a drug-activated gene in their senescent cells (called INK-ATTAC mice) treatment triggering the gene removed senescent cells, decreased activin A and increased the proteins that promote insulin sensitivity and reduce diabetes. This paralleled effects of the JAK inhibitor in normal, naturally aged mice. "The treated animals had improved glucose and insulin tolerance tests, tests that indicate the severity of diabetes. Our work suggests that targeting senescent cells or their products could be a promising avenue for delaying, preventing, alleviating or treating age-related stem cell and tissue dysfunction and metabolic disease."

Link: http://newsnetwork.mayoclinic.org/discussion/reducing-stem-cell-dysfunction-and-metabolic-disease/

Antibiotics are the drugs used to control bacterial infections. Here I'll point out a couple of recent articles relating to antibiotics research, as counterpoints to the prevailing view that we're in danger of running out of antibiotics that work at some unspecified future date. That would be an existential threat to our desired future of extended healthy longevity, were it to happen, but fortunately I think it is a mirage, as are so many of these predictions of doom. As a general rule predictions of doom rely upon people doing nothing to prevent said doom, and that is never the case.

We humans have trouble thinking rationally about progress. We live in an age of profound technological change: it is everywhere, fast enough to see sweeping differences from decade to decade, and yet it is human nature to look at the present state of things and predict a future that is just today with a few of the deckchairs shuffled around. You have to think carefully on a topic to step beyond this instinct, to consider how the fundamental aspects of the picture will change, not just the fiddling details. The moment that you stop paying attention, you'll backslide into making assumptions that are, in essence, based on the belief that nothing important is going to change.

This aspect of our nature gives rise to Malthusian visions of an end to present resources, and a dismal future world that falters because of it. In practice this end never comes to pass because people react to the threat of scarcity, far in advance, by creating new resources and more efficient ways to use existing resources. The moment that price increases due to scarcity emerge as a possibility on the horizon, scores of entrepreneurs start on their varied visions for a better replacement resource. So we have progress, and in our age that is self-evidently continual, rapid, driven progress.

Present popular views on the future of antibiotics are essentially Malthusian in nature: a trend in drug-resistant bacterial species is observed, and if continued it leads to a scarcity of effective antibiotics in the future. That trend is then projected all the way down to zero, to no working antibiotics and a world of rampaging bacterial infections. That grim result will never happen, however, just as any number of other predicted grim results failed to emerge over the past few hundred years. In this case, as always, entrepreneurs both inside and outside the scientific community have been at work for years on varied solutions to bacterial resistance to antibiotics. A few are mentioned here:

Antibiotics Are Dead; Long Live Antibiotics!

We've been hearing the tales of doom for quite a few years now: the breathtaking promiscuity of bacteria, which allows them to mix and match their DNA with others' to an extent that puts Genghis Khan to shame, has increasingly allowed them to accumulate genetic resistance to more and more of our antibiotics. But this pessimism rests entirely on one assumption: that we have no realistic prospect of developing new classes of antibiotics any time soon, antibiotics that our major threats have not yet seen and thus not acquired resistance to. And it now seems that that assumption is unwarranted. It is based on history - on the fact that no new antibiotic class with broad efficacy has been identified for decades. But very recently, a novel method was identified for isolating exactly those - and it seems to work really, really well.

Antibiotics are generally synthesised in nature by bacteria (or other microbes) as defences against each other. We have identified antibiotics in the lab, and thus necessarily only those made by bacterial species that we can grow in the lab. Yet almost all bacterial species cannot be grown in the lab using present day practical methods. Knowing these points, researchers built a device that allowed them to isolate and grow bacteria in the soil itself, with molecules freely moving into and out of the device, thereby sidestepping our ignorance of which such molecules actually matter. And then they were able to isolate the compounds that those bacteria were secreting and test them for antibiotic potency. And it worked. They found a completely new antibiotic that has already been shown to have very broad efficacy against several bacterial strains that are resistant to most existing antibiotics.

And as if that were not enough, here's the kicker. This was not some kind of massive high-throughput screen of the kind we so often hear about in biomedical research these days. The researchers tried this approach just once, in essentially their back yard, on a very small scale, and it still worked the first time. What that tells us is that it can work again - and again, and again.

Viral Soldiers

Researchers on the hunt for more-effective therapies that preserve a healthy microbiome are taking a closer look at the many different viruses that attack bacteria. Bacteriophages (literally, "bacteria eaters") punch holes through the microbes' outer covering and inject their own genetic material, hijacking the host's cellular machinery to make viral copies, then burst open the cell with proteins known as lysins, releasing dozens or hundreds of new phages. The cycle continues until there are no bacteria left to slay. Phages are picky eaters that only attack specific types of bacteria, so they're unlikely to harm the normal microbiome or any human cells. And because phages have coevolved with their bacterial victims for millennia, it's unlikely that an arms race will lead to resistance. This simple biology has led to renewed interest in the surprisingly long-standing practice of phage therapy: infecting patients with viruses to kill their bacterial foes.

While most research is still in the preclinical phase, a handful of trials are underway, and a growing number of companies are investing in the treatment strategy. Phage therapy is receiving as much attention now as it did in the pre-antibiotic era, when it flourished in spite of the dearth of clinical tests or regulatory oversight at the time. "Bacteriophage therapy will have its day again. It sort of had one, before antibiotics came along, but it wasn't well understood then."

On that topic, what to do about the many types of viruses that we don't want to engage with? This is a very different area of research in comparison to the matter of controlling bacterial infection, but again there are numerous promising strategies that look capable of fundamentally changing the picture for the treatment of viral infections. One of those you might be familiar with is DRACO, double-stranded RNA activated caspase oligomerizer, a technology that can in principle control near any type of viral infection by destroying infected cells before viruses can multiply effectively.

This is an example of ongoing work on one narrow slice of the exceptionally complex mechanisms of Alzheimer's disease. It is worth considering that while Alzheimer's is the high level call to action, the real work is the business of understanding the fine details of the brain. This is the often the way in medical research: treating cancer was the call to action that funded research leading to our present understanding of cellular biochemistry in regeneration, replication, and development. The hue and cry of AIDS activism was the call to action that funded the development of our present understanding of viruses, much increased these past three decades. So it is for Alzheimer's and the biochemistry of the mind.

A new study has identified activity of brain proteins associated with memory impairments in Alzheimer's disease, and has also found that "repairing" this activity leads to an improvement in memory. "In the study we found that the nerve cells in the mouse models of Alzheimer face a type of metabolic stress. When a cell faces such metabolic stress, it is logical that it will reduce its activity level in order to survive. The problem is that this stress is chronic and leads to impairment of cognitive functioning."

In a previous study, researchers found a connection between abnormal activity of the elF2 protein, which is known to regulate the formation of new proteins needed for the creation of long-term memories, and mice that carried the human gene APOE4, which is known as a key risk factor for sporadic Alzheimer's. In the present study, a group of young mice carrying the human gene APOE4 showed cognitive impairment on the behavioral level - in other words, they showed signs of damage on the level of spatial memory. A molecular examination showed that the protein elF2 had undergone phosphorylation, changing its action and leading to several processes, including elevated expression of the RNA on another protein, ATF4. This elevation delayed the expression of additional genes associated with the consolidation of memory - i.e. the creation of long-term stable memory.

"The abnormal activity in the regulation of the activity of the ATF4 probably causes the cell to 'feel' that is under stress, that is - overactive. A cell that is in stress reduces its activity in order to survive with the goal of restoring it to a normal condition after the stress passes. The problem is that in Alzheimer's the stress is probably chronic, and accordingly there is no return to normal activity." In order to reinforce the connection they found, the researchers performed an additional intervention in which they prevented eIF2 from causing an increase in the RNA of the ATF4. When they examined these mice, they found an improvement in their cognitive capabilities.

Link: http://www.newswise.com/articles/activity-of-brain-proteins-associated-with-memory-impairment-in-alzheimer-s-identified

In the open access paper linked below, researchers discuss DNA repair differences between long and short-lived species, a part of the broader debate over the degree to which nuclear DNA damage contributes to degenerative aging beyond the matter of cancer risk. The comparative biology of aging, in which researchers catalog differences in molecular biology between close relative species with large longevity differences, it is often a search for longevity assurance mechanisms. Why is it that the one long-lived species in a collection of similar species is in fact long-lived? When pondering what can be done with that knowledge, it is worth bearing in mind that we are the exceptionally long-lived species in our own family of primates, and thus longevity assurance mechanisms discovered in other groups of mammals may be things that we already possess, not things that can potentially be turned into therapies.

Differences in DNA repair capacity have been hypothesized to underlie the great range of maximum lifespans among mammals. However, measurements of individual DNA repair activities in cells and animals have not substantiated such a relationship because utilization of repair pathways among animals - depending on habitats, anatomical characteristics, and life styles - varies greatly between mammalian species. Recent advances in high-throughput genomics, in combination with increased knowledge of the genetic pathways involved in genome maintenance, now enable a comprehensive comparison of DNA repair transcriptomes in animal species with extreme lifespan differences. Here we compare transcriptomes of liver, an organ with high oxidative metabolism and abundant spontaneous DNA damage, from humans, naked mole rats, and mice, with maximum lifespans of ~120, 30, and 3 years, respectively, with a focus on genes involved in DNA repair.

The results show that the longer-lived species, human and naked mole rat, share higher expression of DNA repair genes, including core genes in several DNA repair pathways. A more systematic approach of signaling pathway analysis indicates statistically significant upregulation of several DNA repair signaling pathways in human and naked mole rat compared with mouse. The results of this present work indicate, for the first time, that DNA repair is upregulated in a major metabolic organ in long-lived humans and naked mole rats compared with short-lived mice. These results strongly suggest that DNA repair can be considered a genuine longevity assurance system.

Link: http://www.impactaging.com/papers/v7/n12/full/100866.html

There is a prevailing public disinterest in medical research to extend healthy life. The open access survey linked here is an attempt to understand which of the present widespread beliefs on medicine, aging, and longevity is a more important determinant of this public disinterest. Note that the paper is only available in PDF format at the moment. Also note that this is a project of the Health Extension folk in the Bay Area - so good for them for stepping up, doing the work, and getting it published.

The longevity science community has long known that the public appears indifferent or even hostile to the prospect of treating aging and extending healthy life spans. I and others believe this goes a long way towards explaining why the funding situation for aging research is particularly bad, even for a world in which near all useful medical research is poorly funded and given little attention by people outside the scientific community. There are a number of schools of thought as to why people don't appear to want to live longer, which include the mistaken belief that only wealthy people would benefit from longevity assurance therapies, the mistaken belief that overpopulation and dystopia would result, and the mistaken belief that greater longevity would mean more years of being ill, frail, and decrepit. There is also the role of conformity to the norm to consider, where the norm is what happened to your parents and grandparents, and the open question of why all of these widespread erroneous beliefs persist though year after year of numerous scientists telling the public that they are incorrect.

I'm sure many long-time readers here will not be surprised to find that the survey linked below identified the primary problem as being the fear of frailty, the unfounded assumption that being older as a result of new medical treatments must mean being having more of the characteristics of people who are presently old. Perhaps it is that many people see all medicine as equal, and make no practical distinction between (a) the present patching over of age-related illness without addressing its causes, an approach that allows survivors to struggle on, to age and decline some more and die later rather than die sooner, and (b) a future treatment that reverses and repairs some of the causes of aging and thus postpones or reverses all age-related disease and decline. This is one of the challenges of standing at the point at which the approach to aging and medicine is fundamentally changing: the old common wisdom is not longer correct, and the expectations among researchers for the near future are not yet widely appreciated.

Great desire for extended life and health amongst the American public

Recent advances in aging research and regenerative medicine may soon translate into dramatically increased human lifespans. But does the American public want to live longer? Popular press argues the answer is no, e.g. a recent survey on desired lifespan reported in the New York Times found 60% of respondents voted for the shortest option, an 80 year lifespan, while fewer than 1% opted for an unlimited lifespan. Here, we show that negative attitudes to longer lives are a consequence of erroneously equating extended life with an extended period of frailty. When we stipulated continued health to the original survey question, responses dramatically favored longer life: only 20% wish to die at age 85, while 42% want an unlimited lifespan. Since funding for aging research depends on its perceived value, better science communication is needed to align public policy with public interests.

We surveyed 1000 individuals about how long they wished to live (to age 85, 120, 150, or indefinitely), under 3 scenarios: (1) sustained mental and physical youthfulness, (2) mental youthfulness only, (3) physical youthfulness only. While responses to the two partial youthfulness conditions recapitulated the results of previous surveys - i.e., most responders (65.3%) wished to live to age 85 only - under scenario (1) the pattern of responses was completely different. When guaranteed mental and physical health, 797 of 1000 people wanted to live to 120 or longer, and 53.1% of the 797 desired unlimited life spans. Furthermore, 70.1% of the people who responded 85 to scenario (2) or (3) changed their answer to 120 or longer in scenario (1). Full survey response data are publicly available. We also reproduced our primary finding - that most people wish to live far longer than the average human lifespan so long as they stay healthy - using Google Surveys. In this replication cohort of 1500 respondents, we found that 74.4% wished to live to 120 or longer if health was guaranteed, but only 57.4% wished to live that long if it wasn't. Full survey data and results are publicly available in an interactive browsable format.

The public wants to live long, and live healthy. Human supercentenarians give some of the best evidence for the possibility of increased healthspan and healthy aging, or compression of morbidity. Making healthy aging a reality for the rest of the population will be scientifically challenging. Nevertheless, it is becoming increasingly more necessary: chronic age-related diseases account for 75% of Medicare spending, and these numbers are projected to rise as baby boomers age. The National Institute on Aging currently receives less than 1% of the National Institutes of Health's overall annual budget, or less than 0.05% of annual Medicare spending; this is a misallocation of resources. There is a growing demand for more awareness and more funding for basic aging research, and new initiatives such as the Healthspan Campaign and the trans-NIH Geroscience Interest Group are helping lead the way forward. Investing in scientific research and development that targets aging, the process underlying multiple chronic diseases, can offer uniquely high potential returns.

Gene therapy is going to be very influential in medicine of all types in the next few years, and this is due to the advent of CRISPR, a cheap and reliable genetic editing technology. However, while it is reliable in embryos, since researchers only have to ensure coverage of a small number of cells to create a change that will later be present throughout the whole of the adult body, obtaining that same coverage in a therapy delivered to adults has been a challenge. If a gene therapy fails to change a large enough percentage of cells in an adult individual, then it will have no useful effect. Hence we should be watching for progress on this front.

The research results linked here focus on an inherited disorder with no relevance to aging, but the importance lies in the delivery mechanism and its demonstration, not the therapeutic goals. It is an example of a methodology for adult gene therapy with CRISPR that is (a) easy to carry out for existing labs and (b) generates good tissue coverage in adults. This is significant: it means that all of the gene therapies we might like to carry out as treatments to compensate for age-related damage and decline, such as myostatin deletion to boost muscle growth, adding extra lysosomal receptors to better clear out damage in old tissues, or moving mitochondrial genes to the cell nucleus, are now much more technically feasible. Progress is presently very rapid in this space.

Researchers had previously used CRISPR to correct genetic mutations in cultured cells from Duchenne muscular dystrophy patients, and other labs had corrected genes in single-cell embryos in a laboratory environment. But the latter approach is currently unethical to attempt in humans, and the former faces many obstacles in delivering treated cells back to muscle tissues. Another approach, which involves taking CRISPR directly to the affected tissues through gene therapy techniques, also faces challenges, particularly with delivery. In the new study, researchers overcame several of these obstacles by using a non-pathogenic carrier called adeno-associated virus, or AAV, to deliver the gene-editing system.

To use viruses as delivery vehicles for gene therapy, researchers take all the harmful and replicative genes out of the virus and put in the therapeutic genes they want to deliver. While early virus types didn't work well for various reasons, such as integrating into the genome and causing problems or triggering immune responses, AAV thus far has proven special. It's a virus that many people are exposed to anyway and is non-pathogenic, but still exceptionally effective at getting into cells. AAV is in use in many late-stage clinical trials in the United States, and has already been approved for use in one gene therapy drug in the European Union. There are also different versions of AAV that can preferentially go to different tissues, such as skeletal and cardiac muscle, so researchers can deliver them systemically.

But there's always a catch. "AAV is a really small virus and CRISPR is relatively large. It simply doesn't fit well, so we had a packaging problem." The solution came from a CRISPR system in a different bacterium than the one commonly used. In the natural bacterial immune system, CRISPR is the mug shot that helps identify the target DNA, and Cas9 is the blade that slices the strands. The large Cas9 protein typically used by researchers comes from the bacterial species Streptococcus pyogenes. After scouring the bacterial kingdom, researchers discovered the much smaller Cas9 protein of Staphylococcus aureus - small enough to fit comfortably inside of AAV.

In the study, researchers worked with a mouse model that has a debilitating mutation on one of the exons of the dystrophin gene. They programmed the new CRISPR/Cas9 system to snip out the dysfunctional exon, leaving the body's natural repair system to stitch the remaining gene back together to create a shortened - but functional - version of the gene. Researchers first delivered the therapy directly to a leg muscle in an adult mouse, resulting in the restoration of functional dystrophin and an increase in muscle strength. They then injected the CRISPR/AAV combination into a mouse's bloodstream to reach every muscle. The results showed some correction of muscles throughout the body, including in the heart - a major victory because heart failure is often the cause of death for Duchenne patients.

Link: http://today.duke.edu/2015/12/crisprmousedmd

Researchers here uncover more details of the role of SOD1 in killing cells in amyotrophic lateral sclerosis (ALS). Many degenerative conditions are associated with proteopathy, cell damage and death caused by the abnormal clumping or misfolding of specific proteins. The caveat with this research, as for many similar lines of work, is that it results from investigations of individuals with a mutation that predisposes them to suffer the disease. The mechanisms outlined here may or may not also be central and important to the development of ALS in genetically normal individuals, but given what is known to date it seems promising.

Patients with ALS suffer gradual paralysis and early death as a result of the loss of motor neurons, which are crucial to moving, speaking, swallowing, and breathing. The study focuses on a subset of ALS cases - an estimated 1 to 2 percent - that are associated with variations in a protein known as SOD1. However, even in patients without mutations in their SOD1 gene, this protein has been shown to form potentially toxic clumps. The researchers discovered that the protein forms temporary clumps of three, known as a "trimer," and that these clumps are capable of killing motor neuron-like cells grown in the laboratory. "This is a major step because nobody has known exactly what toxic interactions are behind the death of motor neurons in patients with ALS. Knowing what these trimers look like, we can try to design drugs that would stop them from forming, or sequester them before they can do damage. We are very excited about the possibilities."

Researchers zeroed in on SOD1 after genetic mutations affecting the protein were linked with ALS in the early 1990s. But the exact form of aggregated protein that is responsible for killing neurons has been hard to identify, and many of the clumps that are thought to be toxic disintegrate almost as soon as they form, making them exceedingly difficult to study. "It is thought that part of what makes them so toxic is their instability. Their unstable nature makes them more reactive with parts of the cell that they should not be affecting." Until now, researchers did not know what these fleeting clumps looked like or how they might affect cells.

To crack the mystery, the research team used a combination of computational modeling and experiments in live cells. Researchers spent two years developing a custom algorithm to determine the trimers' structure, an aspect of the study akin to mapping the structure of a ball of yarn after taking snippets of just its outermost layer and then figuring out how they fit together. Once the trimers' structure was established, the team spent several more years developing methods to test the trimers' effects on motor neuron-like cells grown in the laboratory. The results were clear: SOD1 proteins that were tightly bound into trimers were lethal to the motor neuron-like cells, while non-clumped SOD1 proteins were not. The team plans to further investigate the "glue" that holds the trimers together in order to find drugs that could break them apart or keep them from forming.

Link: http://news.unchealthcare.org/news/2015/december/new-study-opens-new-door-for-als-drug-discovery