Evidence for the Importance of Mitochondrial Function in Rat Longevity

There is a lot of evidence to indicate the great importance of mitochondria, the power plants of the cell, in aging and longevity. Mitochondrial composition and resistance to oxidative damage correlates well with the varied life spans of different mammalian species, for example. Many measures of mitochondrial activity and function correlate with natural variations in longevity within a species, such as the balance between ongoing mitochondrial fission and fusion examined in the paper here. Taken together, these are signposts that should lead us to prioritize work on the SENS approach to making mitochondria resistant to damage and dysfunction. Mitochondria have their own DNA, separate from that in the cell nucleus, and it can become damaged in ways that produce spreading cellular malfunctions and consequent oxidative damage to proteins and tissues throughout the body. Using gene therapies to make backup copies of the vital parts of this DNA in the cell nucleus will prevent this type of age-related damage from causing harm: even if these copied genes are deleted from mitochondria, the relevant protein will still be generated in the nucleus and put to work.

Extremely interesting for aging research are those individuals able to reach older ages still with functions similar to those of younger counterparts. We examined liver samples from ad libitum-fed old (28-month-old, AL-28) and ad libitum-fed very old (32-month-old, AL-32) rats for a number of markers, relevant for mitochondrial functionality and mitochondrial DNA (mtDNA) content. As for the mtDNA content and the protein amounts of the citrate synthase and the antioxidant peroxiredoxin III there were no significant changes in the AL-32 animals. No significant longevity-related change was found for TFAM amount, but a 50% reduction in the amount of the Lon protease, responsible for turnover of TFAM inside mitochondria, characterized the AL-32 rats. No longevity-related change was observed also for the amounts of the mtDNA repair enzymes OGG1 and APE1, whereas the intra-mitochondrial amount of the cytochrome c protein showed a 50% increase in the AL-32 rats, indicating a likely reduced initiation of the intrinsic apoptotic pathway.

Totally unexpected was the doubling of two proteins, very relevant for mitochondrial dynamics, namely MFN2 and DRP1, in the AL-32 rats. This prompted us to the calculation of all individual mitochondrial fusion indexes that grouped together in the AL-32 rats, while in the AL-28 animals were very different. We found a strong positive correlation between the fusion indexes and the respective mtDNA contents in two AL-28 and four AL-32 rats. This supports the idea that the limited prevalence of fusion above a still active mitochondrion fission should have ensured a functional mitochondrial network and should have led to a quite narrow range of high mtDNA contents, likely the best-suitable for extended longevity. Our findings strongly suggest that, among the multiple causes leading to the longevity of the AL-32 rats, the maintenance of an adult-like balance of mitochondrial dynamics seems to be very relevant for the regulation of mtDNA content and functionality.

Link: http://dx.doi.org/10.1016/j.exger.2016.09.010

Generating Cartilage Grafts with Properties Closer to those of Natural Cartilage

Cartilage tissue wears with age, and this is a significant source of issues for older people. The challenge in cartilage tissue engineering lies in the structural properties of the tissue. Researchers have struggled to find a methodology for culturing three-dimensional tissue that recaptures a significant portion of the load-bearing strength and resilience of natural cartilage. Some inroads have been made, however, and in the research here, a better quality of graft is produced:

Articular cartilage is the tissue on the end of a bone that cushions the surface of the joint and is vital for painless movement. Because the tissue doesn't have its own blood supply, it has limited capacity to repair itself once damaged, leading to degenerative joint conditions like osteoarthritis. Traditional methods to prevent or delay onset of cartilage degeneration following traumatic events like microfracture surgery don't create the healthy cartilage needed to endure the forces of everyday movement. Even novel medical advances using patients' own articular cartilage cells (chondrocytes) have been unable to predictably restore cartilage structure and function in the long term.

Researchers investigated an alternative approach using engineered cartilage tissue grown from patients' own cartilage cells from the nasal septum which have a unique capacity to grow and form new cartilage tissue. This phase 1 study included 10 patients with full-thickness cartilage lesions of the knee. The researchers extracted a small biopsy specimen (6mm in diameter) from the nasal septum under local anaesthetic using a minimally invasive procedure. The harvested cells were multiplied by exposing them to growth factors for 2 weeks. The expanded cells were then seeded onto collagen membranes and cultured for 2 additional weeks, generating a 30 x 40mm cartilage graft. The engineered graft was then cut into the right shape and used to replace damaged cartilage that was surgically removed from the recipient's knee. Despite variable degrees of defect filling, MRI scans at 2 years revealed the development of new tissue with similar compositional properties of native cartilage. Moreover, nine recipients (one was excluded because of several independent sports injuries) reported substantial improvements in the use of their knee and in the amount of pain compared to before surgery. No adverse reactions were reported.

The researchers say that the small number of participants and the relatively short follow-up time will mean further studies will be needed. Similar to other early phase surgical studies, the trial did not involve a control group, so other studies will be needed to establish a comparison in effectiveness with currently available treatments, and to assess the possible bias of a placebo effect. "Our findings confirm the safety and feasibility of cartilage grafts engineered from nasal cells to repair damaged knee cartilage. But use of this procedure in everyday clinical practice is still a long way off as it requires rigorous assessment of efficacy in larger groups of patients and the development of manufacturing strategies to ensure cost effectiveness. Moreover, in order to extend the potential use of this technique to older people or those with degenerative cartilage pathologies like osteoarthritis, a lot more fundamental and pre-clinical research work needs to be done."

Link: https://www.eurekalert.org/pub_releases/2016-10/tl-tls101916.php

Nauk1 Inhibition as a Treatment for Tauopathies

Tauopathies are conditions in which altered forms of tau protein accumulate into solid deposits in the brain. How this causes cell death and dysfunction is comparatively poorly understood, or at least well debated, but researchers are making inroads into mapping the relevant mechanisms. As is the case for other types of misfolded or altered protein that show up in aged tissues, it isn't so much the protein itself, but rather aspects of the surrounding processes that are the cause of harm. Still, getting rid of the altered tau would be a good way to reduce all of these problems, even in absence of understanding: young tissues don't have tau and work just fine, old tissues do have it and don't work so well, and the logic moves forward from there. If in doubt, identify the fundamental differences and remove them. Alzheimer's disease is the the most familiar of tauopathies, for all that much of the research community is focused on the form of amyloid that accumulates in Alzheimer's patients. Amyloid-β in Alzheimer's is another example of a protein that forms solid deposits and is accompanied by a surrounding set of mechanisms that harm cells when the amyloid is present in large amounts. For all that amyloid-β and tau are completely different, there are many high level similarities in their separate relationships with neurodegenerative conditions. It is becoming clear that the neurofibrillary tangles of tau in Alzheimer's disease are just as important as the amyloid, though the full story of how the disease starts and progresses, and how its components interact with one another, has yet to be written.

Everyone ends up with tau and amyloid in the brain to some degree as they age; even those that live to a very late age accumulate a fair amount of the stuff. The interesting question is why some people end up with so very much more than others and slip into full blown dementia as a result. Based on the clearly established risk factors, which are much the same as those for most age-related conditions, being obesity, lack of exercise, and so forth, the triad of chronic inflammation, cardiovascular health, and metabolic syndrome are important. As for other age-related conditions, it seems to me that one of the best courses to produce near term results is to aim at the production of safe methods to clear out amyloid and tau. The research community is working hard on the former, with most of the effort going towards immunotherapies that are just now starting to produce meaningful results, but tau clearance is a fair way behind in funding and progress.

Behind doesn't mean lacking in paths forward, however, as illustrated here. The research presented below isn't clearance, however, but rather a reduction in the pace of creation of unwanted tau, achieved through mechanisms yet to be explored in great depth. For preference we'd want to see a therapy that removed tau without altering the operation of cellular metabolism - this is why immunotherapies are attractive, putting immune cells to work on the problem of clearing out the junk in a selective way, while other cells keep on doing exactly what they were doing beforehand. The problem with therapies that only slow the accumulation of damage or metabolic waste rather than removing it outright is that they are inefficient and limited in the scope of the good they can do. You have to keep taking the treatment on an ongoing basis, and you still end up in the same place in the end, just later. A therapy that removed tau could be undergone once every few years, or even less frequently, repeated only as needed to prevent pathological levels of tau from ever arising. One of the fundamental and very important problems in medicine today is that far too much research and development is focused on slowing damage rather than repairing damage.

Study reveals potential new strategy to prevent Alzheimer's disease

"Scientists in the field have been focusing mostly on the final stages of Alzheimer's disease. Here we tried to find clues about what is happening at the very early stages of the illness, before clinical irreversible symptoms appear, with the intention of preventing or reducing those early events that lead to devastating changes in the brain decades later." The scientists reasoned that if they could find ways to prevent or reduce tau accumulation in the brain, they would uncover new possibilities for developing drug treatments for these diseases. Cells control the amount of their proteins with other proteins called enzymes. To find which enzymes affect tau accumulation, the scientists systematically inhibited enzymes called kinases.

The scientists screened the enzymes in two different systems, cultured human cells and the laboratory fruit fly. Screening in the fruit fly allowed the scientists to assess the effects of inhibiting the enzymes in a functional nervous system in a living organism. "We inhibited about 600 kinases one by one and found one, called Nuak1, whose inhibition consistently resulted in lower levels of tau in both human cells and fruit flies. Then we took this result to a mouse model of Alzheimer's disease and hoped that the results would hold, and they did. Inhibiting Nuak1 improved the behavior of the mice and prevented brain degeneration. Confirming in three independent systems - human cells, the fruit fly and the mouse - that Nuak1 inhibition results in reduced levels of tau and prevents brain abnormalities induced by tau accumulation, has convinced us that Nuak1 is a reliable potential target for drugs to prevent diseases such as Alzheimer's. The next step is to develop drugs that will inhibit Nuak1 in hope that one day would be able to lower tau levels with low toxicity in individuals at risk for dementia due to tau accumulation."

In the future it might be possible to treat people at risk for Alzheimer's disease by keeping tau low. Think of how taking drugs that lower cholesterol has helped control the accumulation of cholesterol in blood vessels that leads to atherosclerosis and heart disease. "When people started taking drugs that lower cholesterol, they lived longer and healthier lives rather than dying earlier of heart disease. Nobody has thought about Alzheimer's disease in that light. Tau in Alzheimer's can be compared to cholesterol in heart disease. Tau is a protein that when it accumulates as the person ages, increases the vulnerability of the brain to developing Alzheimer's. So maybe if we can find drugs that can keep tau at levels that are not toxic for the brain, then we would be able to prevent or delay the development of Alzheimer's and other diseases caused in part by toxic tau accumulation."

Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model

Many neurodegenerative proteinopathies share a common pathogenic mechanism: the abnormal accumulation of disease-related proteins. As growing evidence indicates that reducing the steady-state levels of disease-causing proteins mitigates neurodegeneration in animal models, we developed a strategy to screen for genes that decrease the levels of tau, whose accumulation contributes to the pathology of both Alzheimer disease (AD) and progressive supranuclear palsy (PSP). Integrating parallel cell-based and Drosophila genetic screens, we discovered that tau levels are regulated by Nuak1, an AMPK-related kinase. Nuak1 stabilizes tau by phosphorylation specifically at Ser356. Inhibition of Nuak1 in fruit flies suppressed neurodegeneration in tau-expressing Drosophila, and Nuak1 haploinsufficiency rescued the phenotypes of a tauopathy mouse model. These results demonstrate that decreasing total tau levels is a valid strategy for mitigating tau-related neurodegeneration and reveal Nuak1 to be a novel therapeutic entry point for tauopathies.

Why the Lingering Pockets of Hostility Towards SENS Rejuvenation Research?

There are still people who really don't like SENS rejuvenation research, both within and outside the scientific community. This contingent has faded over time as the funding for SENS-related research programs increased and more teams produced meaningful results in SENS-related areas such as allotopic expression of mitochondrial genes and senescent cell clearance. There are numerous research groups working on aspects of that latter project at the moment, as well as funded startup companies moving towards clinical translation of therapies. These days one has to have a very selective memory and view of the world to mock SENS, since the SENS proposals have included senescent cell clearance as a potential treatment for aging since the beginning, based on the broad range of evidence available in the scientific community even then. SENS advocates have for near fifteen years been calling for greater funding and progress in selective senescent cell destruction as one possible and plausible method of rejuvenation - and with mouse life span studies in hand now, that has been shown to be the case. Nonetheless, there are those who still propagate the irrational view that SENS isn't a legitimate part of the medical science community. One has to wonder what the true motivation is here; perhaps these people are one reason or another are uncomfortable with the idea that aging is a medical condition amenable to treatment. That seems to me a rather sad, resigned, and limited conceptual space to find oneself in, if it is the case.

You probably are not aware that, earlier this month, there was a bit of a Facebook flamewar between a few SENS opposers and some life-extensionists, some (or even all, I don't know) of whom were SENS supporters. This incident got me thinking. Why does SENS face such a fierce opposition? Why all these clearly emotional, gut-driven reactions? A lot of people over the years have raged against SENS and labelled it as quack science, a fraud, nonsense, and what you have, while having no evidence that this was the case. Sure, SENS is not fully established science yet, and who knows, maybe it will never be; we don't know for a fact. But isn't this case with tons of other research projects? Isn't the very purpose of research to establish what works and what doesn't? If SENS critics are so sure that SENS will never work, they really don't need to bother throwing challenges to disprove it and attacking it so ferociously. They could just sit back and watch as the SENS Research Foundation prove themselves wrong through their own research. On top of that, even if SENS were wrong, all the data coming from their work will certainly prove itself invaluable for future research endeavours. Win-win.

Personally, I came to the conclusion that what caused SENS to be so unpopular (at least initially) amongst the experts of the field might be its clearly stated goal of curing ageing. Biogerontologists are not immune to the pro-ageing trance by default; also, as far as I know, at the time when Aubrey de Grey first introduced SENS to the world he was practically unknown and quite new on the scene. To top it all, he was from a different field. I can see how other experts would be rather pissed at an outsider who comes out of nowhere and claims he's got the solution to a problem they mostly weren't even trying to solve. Maybe SENS wouldn't have faced any opposition if it had kept a low profile and disguised itself as mere research-for-the-sake-of-research, as it was customary in the field of gerontology back in the day.

On the other hand, people like David Sinclair and Bill Andrews too are set on bringing ageing under medical control, and to the best of my knowledge, they don't face nearly the same opposition as SENS does. Maybe it's because they followed a more traditional career path than Aubrey de Grey. Maybe their approaches are more orthodox, or maybe SENS has more media exposure and thus is more likely to be criticised. Maybe it's because of Aubrey's bold claim that the first person to reach 1000 years of age has already been born. People generally don't get this one right. He does not say that we will soon develop therapies that will make us live 1000 years. That doesn't even make sense in the context of SENS, which is a panel of therapies that would need to be periodically reapplied. What Aubrey says is that we'll probably get around 30 extra years of healthy life with the first round of SENS; during this time, perfected versions of the same therapies are likely to have been developed, granting even more extra years of healthy living, and so on. This concept is known as longevity escape velocity. I don't know for a fact why SENS faces such fierce criticism. All I know is that, quite likely, if Aubrey de Grey hadn't been shouting from the rooftops for the past 16 years that we can and should cure ageing, this tremendous problem wouldn't be receiving nearly as much attention as it does today.

Link: https://rejuvenaction.wordpress.com/2016/10/20/why-so-much-hostility-towards-sens/

Exploring the Mechanisms of Neural Regeneration in Zebrafish

Highly regenerative species such as zebrafish can regrow limbs and organs, and are also capable of far greater regrowth in response to damage in the brain than is the case in mammals. Researchers here explore the mechanisms involved in the zebrafish response to an Alzheimer's-like environment and neural cell death. As is the case for many research projects involving zebrafish, the goal is to pin down enough of the biochemistry of exceptional regeneration to understand how it differs from humans, and thus how this capability might be recreated in our species.

Zebrafish have an extensive ability to replenish the lost neurons after various types of damage, and the researchers have shown that it can also do so after Alzheimer-like neurodegeneration. This is an ability humans do not have. Evolutionarily, the zebrafish and human beings are very similar: the cell types in the zebrafish brain and their physiological roles are very similar to humans, and more than 80 percent of the genes humans have are identical in the zebrafish. Therefore, zebrafish are an ideal model for studying complex diseases of humans in a very simplistic way. "We believe that understanding how zebrafish can cope with neurodegeneration would help us to design clinical therapy options for humans, such as for Alzheimer's disease. Within this study, we observed Alzheimer-like conditions in the fish brain. We found that zebrafish can impressively increase the neural stem cell proliferation and formation of new neurons even after Alzheimer's-like pathology. This is amazing because to treat Alzheimer's we need to generate more neurons. And this all starts with neural stem cell proliferation, which fails in our diseased brains."

This study has shown that Alzheimer's disease symptoms can be recapitulated in the zebrafish brain using a short section of human APP protein that is a hallmark of Alzheimer's disease (Amyloid-β42). This protein part causes the death of neurons, inflammation, loss of neuronal connections and deficits in memory formation in zebrafish. The researchers found that the immune-related molecule Interleukin-4 (which is also present in the human brain) is produced by the immune cells and dying neurons in the fish brain. This molecule alerts the neural stem cells that there is danger around. Stem cells then start to proliferate through a cell-intrinsic mechanism involving another protein of central function called STAT6. The importance of this study lies in the notion that the diseased brain and the inflammatory milieu there can be modulated to kick-start neural stem cell proliferation, and this is exactly what successfully regenerating vertebrates do. The next steps towards an understanding of Alzheimer's disease are clearly defined: "We will go on identifying more factors required for a successful 'regeneration' response in fish brain after an Alzheimer's disease-like situation. By doing so, we can get a more complete picture of the molecular programs beneficial for tackling this atrocious disease. Zebrafish will tell us the candidate genes we should focus on in our brains for possible regenerative therapies."

Link: https://tu-dresden.de/tu-dresden/newsportal/news/dr-caghan-kizil-und-sein-forscherteam-erreichen-fortschritte-in-der-alzheimer-forschung

A Significant Association Between Periodontal Bacteria and Mortality Rates

It is fairly settled that periodontal disease, inflammation of the gums, increases the risk of developing cardiovascular disease, among other conditions. Chronic inflammation drives faster progression of all of the common age-related diseases, and gum disease is a potent source of inflammation. To pick one example from the many supporting research results, you might look to a recent study that demonstrated reduced markers of chronic inflammation achieved through nothing more than better dental hygiene. People better equipped to remove dental plaque on a daily basis exhibited reduced inflammation as a result, and that reduced inflammation will translate to a modestly lower risk and severity of a range of age-related conditions. If you dig further in the Fight Aging! archives, you'll find all sorts of unpleasant correlations involving gum disease, such as with the amyloid deposits associated with Alzheimer's disease, and with cognitive decline in general. Thus taking greater care of your teeth and gums is just a really good idea on many fronts.

An open access paper I noticed today adds more evidence to the existing body of work on this topic. Without looking at inflammation in any depth, the researchers found that specific forms of bacteria found in the mouth are associated with an elevated risk of death. Dental plaque and gum disease of course originates in the unwanted activities of bacteria resident in the mouth, but there are many different species involved. As pointed out by the researchers, it is the interactions between these species that seem as important as the presence of one or another: specific combinations appear to produce the worst outcomes, not just one type of bacteria. This is interesting research when considered in the broader context, as there is considerable enthusiasm in the dental research community in finding ways to get rid of specific bacterial species from the mouth, such as those that cause cavities, or those that build plaque and inflame the gums. This is a challenging task, unfortunately: removing bacteria from the mouth is one thing, but doing so selectively and then keeping the unwanted species from quickly returning is quite another. This is a technological capability yet to be developed into a useful and reliable form, but the benefits of achieving this goal will clearly extend far beyond the health of teeth.

Associations between Periodontal Microbiota and Death Rates

Mucosal surfaces, including the oral mucosa, are colonized by a complex and dynamic microbial ecosystem called "microbiota" that has important implications for human health and disease. While more epidemiological evidence is warranted, periodontal microbiota has been identified as a causative agent of periodontitis, which is one of the most prevalent diseases in human population. Interestingly, some animal and human observational evidence supports that periodontitis is not just an oral, in situ disease. The disease also contributes to several systemic diseases including diabetes and cardiovascular diseases (CVD). The chronic inflammatory processes of periodontitis are considered to be responsible for the etiologies. In the oral cavity, the inflammatory and immunologic reactions following periodontitis induce the production of pro-inflammatory cytokines resulting in the breakdown of periodontal epithelium and connective tissues. Systematically, the chronic trickling of periodontal microbiota into the bloodstream elicits a systemic inflammation response resulting in elevated levels of various inflammatory mediators and cross-reactive systemic antibodies, which promote risk for many systemic diseases. Importantly, it has been shown that the increased periodontitis-related all-cause and CVD mortalities are comparable with, but independent of, diabetes-related mortality.

It is believed that complex interactions between specific periodontal pathogens and different bacterial combinations are more relevant to periodontitis than are individual species. We therefore hypothesize that a similar phenomenon exists in the association between periodontal microbiota and mortality rates. To test our hypothesis, we related 21 serum immunoglobulins G (IgGs) against periodontal bacteria to the rates of all-cause, diabetes-related, and hypertension-related mortalities in a death cohort from a representative sample of the US population, the Third National Health and Nutrition Examination Survey (NHANES III). In this study, we found that two baseline serum IgG patterns, Factor 1 and Factor 2, were significantly associated with higher all-cause and/or diabetes-related mortality rates among people without history of diabetes, CVD, and cancers. While only Factor 2 was related to all-cause mortality, both Factor 1 and Factor 2 were related to diabetes-related mortality. To our best knowledge, this is the first data showing that specific oral microbiota may have an impact on the rate of death in humans.

Serum IgGs reflected human systemic response to the corresponding periodontal bacteria and studies have shown that individual periodontal bacterial quantities were significantly correlated with corresponding serum antibody levels. Therefore, the serum IgG levels can be considered as host-related phenotypes of periodontal microbiota. Our analysis showed that, although the two mortality-related IgG patterns that we characterized featured several bacteria, which were also featured in periodontitis-related complexes, they were in different combinations. It seemed that different bacterial combinations have different impacts on human health. Interestingly, our findings coincide with the hypothesis of Porphyromonas gingivali (PG) as a keystone pathogen. It is conceived that the mere presence of a keystone pathogen, even at very low colonization levels, can modulate host response in ways that alter the amount and composition of subgingival microbiota, thereby triggering adverse effects on human health. It has been demonstrated in a periodontal model that the introduction of PG, even at low numbers, in cooperation with other dysbiotic bacteria led to a marked acceleration in pathological alveolar bone loss, but PG alone failed to induce periodontitis. Importantly, our findings from Factor 1 and Factor 2 also, respectively, suggested that active periodontitis may increase diabetes-related death rate, and that, even without clinically significant periodontitis, the presence of PG at very low colonization levels increase total and diabetes-related death rate. It seemed that the elimination of PG is crucial in reducing risk for both periodontitis and mortality.

Our findings collaborated with previous observations that periodontitis, a result of polymicrobial infection, increased the risk for several major diseases, such as diabetes, CVD, cancers, and mortalities as well. The etiologies may involve several pathological consequences leading to uncontrolled inflammation, such as elevated levels of systemic proinflammatory cytokines, oxidative stress, formation of advanced glycation end products, disturbed microbe-host nutrition and metabolism interaction, etc. These mechanisms may be responsible not only for the initiation but also for the promotion and progression of the diseases as well, and thus lead to higher death rates. However, it has been shown that periodontal microbial interactions are complex and that numerous genes related to motility, metabolism, and virulence in one bacterium are differentially regulated in the presence of others. The detailed mechanisms relating specific combinations of periodontal bacteria to specific diseases or death rates warrant further study. The information would be valuable in developing personalized therapeutic and prevention strategies.

Enhanced Mitochondrial Catalase has Different Effects in Young and Old Mice

Mitochondria are important in aging, and this appears to be related to the generation of oxidative molecules that takes place as a side-effect of the creation of chemical energy stores. A fair number of the ways to modestly slow aging in short-lived species change the operation of mitochondria so as to also change the output of oxidants. These reactive molecules can disrupt cellular machinery, but also act as signals, so it is still far from clear as to which are the most important secondary consequences in the various contexts of interest. In the longer term, it is plausible that these oxidants are causing DNA damage in the mitochondria themselves, something that has the potential to spiral out of control to lead to dysfunctional mitochondria, a dysfunctional cell, and damage that can spread out into surrounding tissues. One potential way to suppress the output of oxidative molecules is genetic engineering to increase levels of natural antioxidant compounds localized to the mitochondria, and one of the earliest attempts to do this targeted mitochondrial catalase in laboratory mice. This has produced varied outcomes, however, ranging from little effect to slowed aging. The paper noted here might go some way towards explaining why research groups have seen mixed results from this approach, as the age of the mice used in these studies appears to be a crucial factor:

Reactive oxygen species (ROS) are associated with the progression of a broad spectrum of pathologies including aging. Mechanistically, this has largely been attributed to oxidative modification of cellular macromolecules, including lipids and proteins. While ROS have been widely regarded as a major component of aging since the 'free radical theory of aging' was proposed in the 1950s, there is an increasing appreciation that ROS also serve important physiological signaling roles. It is therefore important to closely examine both negative and positive consequences of therapeutic interventions that target ROS. Given that oxidative modifications can impair the activity of macromolecules, and the well-documented correlation between oxidative damage and aging reported in almost all models studied, it has been tempting to conclude that this is a likely mechanism for aging. However, there are many observations at odds with this theory of aging. Clinical trials of dietary antioxidants have thus far shown little to no efficacy. Some have shown adverse outcomes. In mice, deletion of many antioxidant enzymes has little effect on lifespan and, importantly, overexpression of several antioxidants including superoxide dismutase and peroxisomal catalase has failed to extend lifespan.

Our group has previously shown that mice overexpressing mitochondrial-targeted catalase (mCAT), but not nuclear or peroxisomal catalase, have an approximately 20% increased median and maximal lifespan, suggesting that reducing ROS specifically in the mitochondria is key to achieving a beneficial effect on aging. mCAT has been shown to reduce oxidative modification of DNA and proteins and delays the progression of multiple pathologies. We have also demonstrated that mCAT is protective against cardiac aging. However, it has been increasingly recognized that ROS has beneficial roles in signaling, hormesis, stress response, and immunity. We therefore hypothesized that mCAT might be beneficial only when ROS approaches pathological levels in older age and might not be advantageous at a younger age when basal ROS is low. We analyzed abundance and turnover of the global proteome in hearts and livers of young (4 month) and old (20 month) mCAT and wild-type (WT) mice. In old hearts and livers of WT mice, protein half-lives were reduced compared to young, while in mCAT mice the reverse was observed; the longest half-lives were seen in old mCAT mice and the shortest in young mCAT. Protein abundance of old mCAT hearts recapitulated a more youthful proteomic expression profile. However, young mCAT mice partially phenocopied the older wild-type proteome. Age strongly interacts with mCAT, consistent with antagonistic pleiotropy in the reverse of the typical direction. These findings underscore the contrasting roles of ROS in young vs. old mice and indicate the need for better understanding of the interaction between dose and age in assessing the efficacy of therapeutic interventions in aging, including mitochondrial antioxidants.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12472/full

Calorie Restriction Protects Neurons From Excess Calcium

Calorie restriction is demonstrated to slow the progression of neurodegenerative disease in numerous species, but picking out specific relevant mechanisms from the sweeping changes in cellular behavior that occur as a result of a lower calorie intake has proven to be a challenge. The scientists involved in the research noted here focus on just one, relating to dysfunction of calcium metabolism in neurons. As might be imagined, this is the tiniest slice of the complete picture of calorie restriction and health, considered at the cellular level. A full accounting of exactly how calorie restriction works to improve health and delay aging remains to be created. It is a job of staggering size, one that must proceed in parallel with the equally large task of producing a comprehensive map of metabolism and how it changes with age. It seems plausible that researchers will still be working on this well after the first suite of rejuvenation therapies after the SENS vision are a going concern. It is fortunate that the faster and more effective approach to treating aging described in the SENS proposals exists: if it didn't, our prospects for longer, healthier lives would be far worse.

Studies of different animal species suggest a link between eating less and living longer, but the molecular mechanisms by which caloric restriction affords protection against disease and extends longevity are not well understood. The results of new in vitro and in vivo experiments include the finding that a 40% reduction in dietary caloric intake increases mitochondrial calcium retention in situations where intracellular calcium levels are pathologically high. In the brain, this can help avoid the death of neurons that is associated with Alzheimer's disease, Parkinson's disease, epilepsy and stroke, among other neurodegenerative conditions. Calcium participates in the process of communication between neurons. However, Alzheimer's disease and other neurological disorders can cause an excessive influx of calcium ions into brain cells due to overactivation of neuronal glutamate receptors. This condition, known as excitotoxicity, can damage and even kill neurons.

To verify the effect of caloric restriction on excitotoxicity, scientists compared two groups of mice and rats. The control animals were given food and water ad libitum for 14 weeks and were overweight at the end of the experiment. The other group received a 40% caloric restriction (CR) diet for the same period. In the first test, the animals were injected with kainic acid, a glutamate analogue with a similar effect in terms of inducing neuronal calcium influx, albeit more persistent. In rodents, it can cause brain damage, seizures and neuronal cell death due to overactivation of glutamate receptors in the hippocampus. It is used in the laboratory to mimic epilepsy. "We administered a small dose to avoid killing the animal. Even so, kainic acid caused seizures in the control group. It had no effect on the CR group."

The next step was to see what happened when the mitochondria isolated from each group were treated with cyclosporin, a drug known to increase calcium retention. While calcium uptake did indeed increase in the mitochondria from the control group, it remained unchanged in the CR group, eliminating the difference observed in the previous test. "Cyclosporin's target in mitochondria is well known. The drug inhibits the action of a protein called cyclophilin D, leading to increased mitochondrial calcium retention." In this case, however, cyclophilin D levels were found to be the same in both groups. The researchers therefore decided to measure the levels of other proteins that might be interfering with cyclophilin D's action in the organism. "We discovered that caloric restriction induces an increase in levels of a protein called SIRT3, which is capable of modifying the structure of cyclophilin D. It removes an acetyl group from the molecule in a process known as deacetylation, and this inhibits cyclophilin D, so that the mitochondria retain more calcium and become insensitive to cyclosporin." Just as other research groups had already found, the team also observed an increase in the activity of antioxidant enzymes such as glutathione peroxidase, glutathione reductase and superoxide dismutase in the CR rodents' mitochondria. These results suggest an enhanced capacity to manage cerebral oxidative stress, a condition that contributes to the onset of several degenerative diseases.

Link: https://www.eurekalert.org/pub_releases/2016-10/fda-crc101916.php

Senolytic Drugs Can Become a Future Regenerative Medicine

Today I thought I'd share a recent commentary on cellular senescence research to treat aging. A growing amount of work is taking place on the fundamentals of clearing senescent cells as a method of partial rejuvenation. The presence of newly founded companies pushing forward towards clinical translation, and results showing life extension and improved tissue function in normal mice are drawing more funding into the field. Folk in our grassroots community are also helping where they can, such as by crowdfunding the first studies to be carried out by the Major Mouse Testing Program earlier this year, or providing seed funding for promising companies. All of this effort is not before time: it is nearing fifteen years since SENS rejuvenation biotechnology advocates first gathered the evidence supporting senescent cell accumulation as a fundamental cause of aging, and began calling for more research on this topic. Various research groups are now focusing on different methods of clearance and their effects on specific tissues and organs, seeking to prove or disprove effects on degenerative aging. We should expect to see a mix of benefits and absence of benefits once the dust settles: senescent cells are only one of the seven broad classes of age-related damage enumerated in the SENS research proposals. Their presence may contribute to many or even all of the common age-related conditions, but they are not significant causes of all of the specific forms of secondary and later cell and tissue dysfunction in the aging body.

To pick one example, earlier this year researchers published a study of the effects of reduced senescent cell counts on aspects of vascular aging. It was indeed a mix of benefits and absence of effects: fewer senescent cells led to reduced calcification of blood vessel walls, associated with blood vessel stiffening with age, but it didn't have much of an impact on the development of atherosclerotic plaques. Both of these items are about as serious in their consequences over the long run. Stiffening of blood vessels drives hypertension, which in turn produces damage to delicate tissues such as the brain and kidneys as tiny blood vessels suffer structural failure at a greater rate. It also provokes remodeling of heart tissue, leading to heart failure, and along the way helps to turn atherosclerosis into a fatal condition. The fatty, inflamed plaques that distort blood vessels eventually grow to the point of rupture, which either blocks or breaks important large vessels. That is a frequently fatal occurrence. This mixed outcome was an interesting result, as one of the characteristics of senescent cells is that they produce greater levels of chronic inflammation via the mix of signals they generate, the senescence-associated secretory phenotype. This signaling is how small numbers of senescent cells, perhaps 1% of the cells present in an organ, can distort the function of the other 99%. Inflammation is pretty important to the pace of progression of atherosclerosis, so one might expect a reduction in the number of senescent cells to slow the pace of that condition - but apparently not in this particular scenario.

The recently published commentary linked below is a celebration of the fact that the scientific community has finally achieved some traction in the matter of a treatment for the root causes of aging, one likely to produce reliable, if partial, degrees of rejuvenation. It is not unreasonable at this point to expect senescent cell clearance to achieve larger and more robust results on aging and age-related disease than much of the rest of present day medicine, and to do so in a way that is additive to other methodologies. That capability will emerge fairly soon in clinics, a few years to a decade from now, varying with the regulatory environment and where the products are offered. This is the true benefit of focusing on reverting the fundamental damage that is the cause of aging, rather than tinkering with later stages of disease and malfunction.

Senescent cell death brings hopes to life

Life expectancy in the developed countries is continuously increasing. However, age-related diseases lead to late life complications and remain the most prevalent cause of mortality. One of the cellular components that is present in sites of age-related pathologies and accumulates during aging is senescent cells. These cells are formed when a stress signal triggers terminal cell cycle arrest in proliferating cells. Entrance to a state of senescence deprives damaged cells of their proliferative potential and thus limits tumorigenesis and tissue damage. Despite the protective role of cellular senescence, the long term presence of senescent cells is harmful to their environment. These cells secrete a plethora of pro-inflammatory factors that might aid their removal by the immune system. However, at advanced age senescent cells gradually accumulate in tissues and the secretory phenotype promotes a chronic "sterile" inflammation which is a hallmark of unhealthy aging. Elimination of senescent cells in mice by a genetic approach led to a decreased burden of age-related disorders, and an increased median survival of the mice. Therefore, pharmacological elimination of senescent cells in-vivo is a promising strategy for treatment of age-related diseases associated with accumulation of senescent cells. An attractive method to implement this strategy would be to induce apoptosis preferentially in senescent cells. The scientific basis of this approach relies on an understanding of the molecular mechanisms that distinguish the regulation of apoptosis in senescent cells from other cells.

Resistance of senescent cells to both extrinsic and intrinsic pro-apoptotic stimuli testifies for complex regulation of apoptosis in these cells. We recently demonstrated that senescent cells, induced to senesce by different kind of insults, upregulate proteins of the anti-apoptotic BCL-2 family. Combined knockdown of these proteins or their inhibition by a small molecule inhibitor, ABT-737, selectively skew cell-fate decision in senescent epithelial cells in-vivo toward apoptosis. Therefore, the expression of BCL-2 family members endowed senescent cells with resistance to apoptosis. The senolytic activity of the ABT-737 molecule was demonstrated in in-vivo models of senescence. DNA damage-induced senescent cells were formed in the lungs upon ionizing irradiation of mice. Administration of ABT-737 rapidly reduced the number of senescent cells, concomitantly with an increase in apoptosis.

Alongside with the BCL-2 family inhibitors, other approaches for selective elimination of senescent cells, also termed senolytic approaches, have been identified. For example, the combination of 2 drugs, dasatinib and quercetin, was shown to exert killing potential of senescent preadipocyte and endothelial cells. Elimination of senescent cells could also be achieved by adapting tools from the field of cancer therapy. One such possibility is utilization of common immunotherapy practices following identification of senescence-specific markers. The immune system is a natural resource that is able to recognize and eliminate senescent cells. Using its properties in combination with immunotherapy approaches or with emerging senolytic drugs might lead to more specific and efficient elimination of senescent cells. However, no matter what would be the approach of choice, it is necessary to keep in mind that senescent cells participate in variety of essential physiological functions such as in wound healing, tumor suppression, regulation of glucose levels and embryonic development. In order to develop efficient senolytic approaches it is necessary to dissect beneficial and detrimental functions of senescent cells in different physiological and pathophysiological conditions using in-vivo models.

Successful development of senolytic drugs will bring senescent cells to the forefront of anti-aging therapies. However, it is necessary to understand the effect of elimination of senescent cells on diverse cell communications in the complex tissues. Elimination of senescent cells by ABT-737 or ABT-263 was followed by increased proliferation of stem cells in both skin and haematopoietic system. These results suggest that senolytics can have an impact on tissue regeneration and can potentially be used in regenerative medicine. This approach will combine elimination of damaged cells with stimulation of proliferation of healthy progenitors, in a way that could restore tissue fitness in diseases associated with reduced tissue function. In summary, senolytic drugs can become a future regenerative medicine. Treatment with senolytic drugs results in the elimination of senescent cells, thus blocking tissue degeneration and late life complications. In turn, elimination of senescent cells leads to the proliferation of stem cells, allowing tissue regeneration. This joined effect of senolytic drugs will restore tissue fitness and will help restraining age-related pathologies.

Mitochondrially Targeted Antioxidant Slows Alzheimer's Progression in Rat Model

There has been a fair amount of news regarding the SkQ class of mitochondrially targeted antioxidant this past year, most likely because clinical development in Europe is moving ahead. Having one or more for-profit entities involved, even when they are fairly young companies, tends to bring more funding into ongoing research, both directly and indirectly. This type of antioxidant, unlike the antioxidant supplements you can buy in a store, has been shown to modestly slow aging in short-lived laboratory species. It is theorized that additional antioxidants localized to mitochondria soak up some of the oxidants produced by the mitochondria before those molecules can damage mitochondrial DNA. Alternatively, it is possible that the more important mechanism is that a reduction in the flux of oxidants at that point leads to other beneficial changes in cell metabolism, as mitochondrial oxidants are a signaling mechanism as well as a source of damage. Certainly many of the methods shown to slow aging in the laboratory involve altered mitochondrial function, especially insofar as it relates to the rate at which oxidant molecules are generated. The effects of mitochondrially targeted antioxidants on inflammation have proven to be larger and more easily measured, however, which is why present clinical development is focused on inflammatory eye conditions. Still, a steady flow of studies like the following are emerging to show benefits in a range of animal models for various age-related conditions:

Alzheimer's disease (AD) is a progressive, age-dependent neurodegenerative disorder featuring progressive impairments in memory and cognition and ultimately leads to death. According to the most widely accepted theory, the "amyloid cascade" hypothesis, AD arises when amyloid precursor protein (APP) is processed into amyloid-β, which accumulates in plaques. There is growing evidence that mitochondrial damage and oxidative stress lead to activation of the amyloid-β cascade and, accordingly, the mitochondrial dysfunction is a significant contributing factor of the onset and progression of AD. According to the "mitochondrial cascade hypothesis" amyloid-β is a marker of brain aging, and not a singular cause of AD. Many studies have confirmed that mitochondrial dysfunction is likely to be the leading cause of synaptic loss and neuronal death by apoptosis, representing the most likely mechanism underlying cortical shrinkage, especially in brain regions involved in learning and memory, such as the hippocampus. The mitochondrial changes increase amyloid-β production and cause its accumulation, which in turn can directly exert toxic action on mitochondria, thus aggravating the neurodegenerative processes.

Here, using OXYS rats that simulate key characteristics of sporadic AD, we set out to determine the role of mitochondria in the pathophysiology of this disorder. OXYS rats were treated with a mitochondria-targeted antioxidant SkQ1 from age 12 to 18 months, that is, during active progression of AD-like pathology in these animals. Dietary supplementation with SkQ1 caused this compound to accumulate in various brain regions, and it was localized mostly to neuronal mitochondria. Via improvement of structural and functional state of mitochondria, treatment with SkQ1 alleviated the structural neurodegenerative alterations, prevented the neuronal loss and synaptic damage, increased the levels of synaptic proteins, enhanced neurotrophic supply, and decreased amyloid-β protein levels and tau hyperphosphorylation in the hippocampus of OXYS rats, resulting in improvement of the learning ability and memory. Collectively, these data support that mitochondrial dysfunction may play a key role in the pathophysiology of AD and that therapies with target mitochondria are potent to normalize a wide range of cellular signaling processes and therefore slow the progression of AD.

Link: http://dx.doi.org/10.18632/aging.101054

The Potential Benefits of Better Dental Plaque Control

Improved control over plaque and unwanted bacteria in the mouth could improve long-term health. There is a demonstrated link between dental plaque, consequent gum disease, and whole-body inflammation. Higher levels of inflammation raise the risk of suffering heart disease and other conditions: chronic inflammation speeds the development and progression of all of the common age-related diseases. Thus any large improvement in everyday dental technology should also slightly slow the pace of degenerative aging via a reduction in inflammation. The results reported here are a very modest example of this type of progress, nothing to get too excited about: it is more in the way of a suggested change in the culture and methodology of brushing teeth. The researchers take an approach used by dentists, staining plaque to make it easier to remove, and package it for everyday use. Nonetheless, even something as simple as that can make some difference to inflammation. Consider this as a reminder to pay attention to the march of technology in this field, as the outcomes are relevant to much more than the health of teeth.

For decades, research has suggested a link between oral health and inflammatory diseases affecting the entire body - in particular, heart attacks and strokes. The results released today from a randomized trial of a novel plaque identifying toothpaste, show statistically significant reductions in dental plaque and inflammation throughout the body. Inflammation throughout the body is accurately measured by high sensitivity C-reactive protein (hs-CRP), a sensitive marker for future heart attacks and strokes. In this trial, all randomized subjects were given the same brushing protocol and received a 60-day supply of toothpaste containing either the plaque-identifying toothpaste or an identical non-plaque identifying placebo toothpaste. To assess dental plaque, all subjects utilized a fluorescein mouth rinse, and intraoral photographs were taken under black light imaging. For hs-CRP, levels were measured by an independent laboratory using an enzyme linked immunosorbent assay.

"While the findings on reducing dental plaque extend a previous observation, the findings on decreasing inflammation are new and novel." This is the first toothpaste that reveals plaque so that it can be removed with directed brushing. In addition, the product contains unique combinations and concentrations of cleaning agents that weaken the core of the plaque structure to help the subject visualize and more effectively remove the plaque. Based on these findings, researchers are drafting an investigator initiated research grant proposal to the National Institutes of Health (NIH). This large scale randomized trial will test whether the toothpaste reduces risks of heart attacks and strokes.

Link: https://www.eurekalert.org/pub_releases/2016-10/fau-tsr101416.php

The Option of Organ Farming

At some point in the foreseeable future, it will become possible to grow functional replacement organs and large tissue patches from a patient skin sample in bioreactors. This capability will replace the present insufficient and unreliable donor sources of organs for transplantation. The cost and logistics will be much less onerous, especially if tissue engineering is paired with reversible vitrification, allowing replacement organs to be generated and then kept in storage until needed. Given the present state of tissue engineering, in which an increasing number of functional tissues can be generated in small sizes, and the trajectory of regenerative medicine as a whole, it seems inevitable that these capacities will come to pass. Whether or not they are widely used is an economic question, a race yet to be run between organ engineering for transplantation on the one hand and in situ repair and rejuvenation of existing organs on the other. Some combination of cell therapies and first generation SENS rejuvenation treatments to clear out metabolic waste, senescent cells, and the like could well prove a better choice for patients than undergoing the major surgery of transplantation, even if the transplanted organ is of a higher quality than the repaired aged organ.

There is a way to go yet before organs can be reliably grown from cells in bioreactors, however. Yet on the way to that goal, there are a number of potential shortcuts and transitional technologies that might be (a) be realized more rapidly, (b) allow the creation of useful organs for transplantation, and (c) provide a more reliable and less expensive option than the present system of organ donation. For example, the use of decellularization may provide incremental gains in the number of organs available, and reduce some of the hazards of transplantation. Decellularization involves taking a donor organ, which might include one that wouldn't make the cut for present day transplantation due to cell damage, stripping all of its cells, and then repopulating the organ using a mix of the patient's own cells. This has been accomplished in the laboratory, and perhaps the most interesting implication of this line of research is that the organ need not be human. Pigs have organs of about the right size, for example, and genetic engineering to remove the known problem proteins that might remain in a decellularized porcine organ is a project of feasible scope. Hard, but not impossible. There are research groups working towards this goal today, some already in the commercial stage of development.

Humanized organs in gene-edited animals

Treatment of chronic diseases has resulted in the successful use of cell therapy for the treatment of hematopoietic diseases and cancers as well as device therapies for the treatment of heart disease, diabetes and osteoarthritis. These therapies, while effective, have not been broadly applied to end-stage disease. Currently, curative therapies for advanced end-stage organ failure require transplantation, which is limited by donor organ availability. While millions of patients could benefit from such therapy, the scarcity of organs severely limits the number of transplantations that are performed. This disparity has fueled intense interest focused on alternative organ sourcing and regenerative medicine.

The use of human cells or lineages in a nonhuman animal has been extensively pursued in biomedical research. For example, the incorporation of human hematopoietic stem cells into early, preimmune fetal lamb embryos was demonstrated in the 1990s. These investigators observed significant, long-term, multilineage engraftment of these cells in sheep bone marrow and blood. Additionally, in 2005, functional human neurons in the mouse were developed by injecting human embryonic stem cells into the ventricles of mice. Humanized liver models in mouse have been well established and are currently used for the study of pharmacokinetics and toxicity. In 2001, the repopulation of a mouse liver with human hepatocytes was described. In 2004, human hepatocytes were transplanted into an immunodeficient mouse model to generate chimeric mice with an 80-90% humanized liver. The utility of these chimeric mice in studying human toxicity and dosing and disease is well recognized. More recently, 3D vascularized and functional human livers have been generated by transplanting human liver buds, developed in vitro, into mice. Various studies have demonstrated the capacity for targeted organ chimeras using blastocyst-complementation strategies. For example, a rat pancreas was produced in a mouse by the process of blastocyst complementation. In these studies, blastocysts mutant for Pdx1, the master regulatory gene for pancreatic development, were injected with pluripotent stem cells from wildtype rats. Transfer of the pluripotent stem cells from wildtype rats injected blastocysts and, subsequently, into surrogate mouse dams gave rise to mouse chimeras with functional pancreata composed of rat cells. These studies emphasized the importance of generating blastocysts, deficient for a key developmental regulatory factor, in which the embryo completely lacks the target organ. The blastocyst-complementation strategy has also produced organs such as the kidney and liver in rodents, and recently, the pancreas in pigs. The results of this latter study are significant, because it supports the notion of generating human patient-specific organs in pigs that can be subsequently used for transplantation or advanced therapies.

Groundbreaking scientific advances are bringing the scientific field closer to the reality of developing human organs in nonhuman animals. First, the advances in developmental biology have identified master regulators that are both necessary and sufficient to specify stem cells and direct them to differentiate to distinct lineages. Second, the ability to reprogram human somatic cells to a pluripotent stem cell state, human induced pluripotent stem cells (hiPSCs), has revolutionized the field of regenerative science and medicine. Third, genome-editing technologies, such as clustered regularly interspaced short palindromic repeat, allow for site-specific genome editing. Fourth, the ability to successfully perform somatic cell nuclear-transfer technology (i.e., cloning) in large animals has allowed for the genetic engineering of large animal models. The intersection and combination of these four emerging technologies makes feasible the ability to delete the genes that govern tissue or organ development in a host, thereby establishing a niche for humanized cells. In addition, the use of complementation experiments, where hiPSCs are transferred to a mutant blastocyst, followed by the transfer into a pseudopregnant host, could result in the potential rescue of the host phenotype rescue with a humanized organ. Therefore, it may be possible to engineer personalized organs in large animals and/or engineer unique human disease models in a large animal for preclinical testing of potential therapeutic agents.

Thus farming may well turn out to be one noteworthy component of the organ engineering industry that will arise over the next few decades: harvesting organs from animals, probably genetically engineered lineages specifically created for this purpose. With sufficiently advanced genetic engineering and use of implanted organ seeds or other strategies, the organs being grown in these animals could be completely human. Growing the organ of one species in an individual of another is also something that has been achieved in the laboratory. If you, like most people, happen to be comfortable with the ethics of eating meat, you should probably also be comfortable with farming organs for medical use.

For my part I think that there is a lot to be said for not undertaking the mass generation and killing of entities capable of suffering purely for one's own convenience, but given that I support the necessity of laboratory animals in medical research, my objection is clearly more utilitarian than absolutist. At the present time relinquishing the use of laboratory animals in the medical sciences would be worse than continuing use. In any case, in comparison to farming for food, organ farming and other research community use of animals is a drop in the ocean. Still, to my eyes both farming and laboratory studies of living beings are things that we should use technology to do away with - to cease these activities as soon as possible. This is as much a part of the goals of the Hedonistic Imperative as is eliminating suffering in humans. To end the farming of animals is in fact already possible, and could be accomplished given the will to do so. On the other side of the house, progress in computation and simulation will eventually enable the retirement of mice, flies, worms, and other species that researchers use in their studies. So all in all, it would be pleasant should the future include less farming of animals for organs and more generation of organs in bioreactors, but it is hard to predict how these things will pan out in advance. It all depends on the twists and turns of the economics of clinical application.

Mouse Ovary Tissue and Eggs Engineered from Cells

In the context of ongoing work on the beneficial effects of young ovaries in old mice, it is interesting to note that researchers have now managed to engineer functional mouse ovary tissue that produces eggs. The starting point was a cell sample, converted into induced pluripotent stem cells. It is a good example of the current state of the art in tissue engineering, in which many types of correctly functioning organ tissue can be produced in small amounts given just a small patient tissue sample to work with. Each tissue and organ requires its own recipe of signals and environment, and the discovery of working approaches is a slow grind, but once a methodology is established then the door is open for that particular tissue type.

Scientists have for this first time reprogrammed murine embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) into fully functional oocytes in the laboratory. In mice, oocytes are derived from primordial germ cells (PGCs), which form around day 6.5 of embryonic development. In female embryos, the PGCs make their way to what will turn into the ovary and enter meiosis to form primary oocytes, which begin to mature following puberty. Previously, researchers reported the ability to differentiate murine ESCs and iPSCs into PGC-like cells - a process that takes about five days in vivo - that could then develop into oocytes when transplanted into adult mice. The researchers also showed that mouse-derived PGCs can be used to produce fertile oocytes in the lab.

In the present study, researchers have now extended their culturing technique to encompass the entire embryonic stem cell to oocyte differentiation, which takes about 30 days in vivo. Starting with either stem cell type, the researchers first created the PGC-like cells by inducing expression of several genes and then mixed these cells with female gonadal somatic cells - which support germ cell development - to create "reconstituted ovaries" in vitro. The cells gradually lost expression of PGC markers and began to express oocyte markers. By three weeks of growth in culture, the team observed primary oocytes in meiosis prophase I within structures that resembled secondary follicles. One of the key components at this stage was the need to add an estrogen inhibitor to get the early stage oocytes to build ovarian follicles in vitro. The researchers then added follicle-stimulating hormone and two other factors to the medium and separated each follicle-like structure - inside which oocytes continued to grow for 11 more days - resembling full-size germinal vesicle oocytes. In the third phase, the germinal vesicle oocytes were cultured for one day in maturation culture medium to become meiosis II-arrested oocytes. "The stumbling block for a long time that this research group finally managed to overcome is coordination of the female germ cell development with its somatic environment at every step along the way"

Altogether, the team conducted three separate culture experiments that produced 58 reconstituted ovaries and 3,198 germinal vesicle oocytes, of which 28.9 percent matured to the meiosis II stage. Testing the quality of the meiosis II-arrested oocytes, the team found that about 78 percent had the correct number of chromosomes. Then, using RNA-sequencing on pooled oocytes, the researchers observed expression in the culture-derived oocytes comparable to that of meiosis II oocytes derived from in vivo adult and newborn pup ovaries. There were 424 genes that were either up- or downregulated compared to in vivo-derived meiosis II oocytes, particularly, mitochondrial function genes. To test whether the lab-cultured meiosis II oocytes were fully functional, the team fertilized the oocytes with wild-type sperm in vitro, and implanted the embryos into surrogate females, which resulted in healthy pups that were slightly heavier compared to wild-type pups but that developed normally and were fertile at 11 months.

Link: http://www.the-scientist.com/?articles.view/articleNo/47256/title/From-Stem-Cell-to-Oocyte-In-a-Dish/

PRG3 Promotes Neural Regeneration

Researchers here identify a protein that increases regeneration in the central nervous system following injury, or to restore lost plasticity and ability to adapt in later life. Spurring greater regrowth of damaged nerves is of great interest to the research community, and a range of approaches are underway at various stages of development. Despite promising results in animal studies so far the practical outcomes for human medicine are all fairly marginal, however. This will change in the years ahead, but at this point it is hard to say just where or when, or which of the avenues will prove to be the first one that works well enough to follow through to widespread clinical availability.

Neuronal plasticity and structural remodelling are fundamental feature of the developing nervous system and plays also an essential role during learning and injury-dependent remodelling and regeneration. In development, axons extend over long distances and form contacts with their target structure and facilitate functional connections. These neuronal connections become stabilized and restricted during maturation and secure proper functioning of the brain. Conversely, sprouting and regeneration is limited after decline of intrinsic axonal remodelling activity in aging brain and in an microenvironment rich in neurite growth inhibitors after neurological injury.

Several extracellular ligands account for the neurite growth inhibitory environment after maturation and injury. These ligands converge on the RhoA-Rho kinase pathway mediating the final signal transduction for neurite retraction and axon growth inhibition. Pharmacological and genetic interfering with the ligands Nogo/NgR or LPA promotes axonal regeneration and functional recovery after central nervous system injury. An essential step during development and regeneration is the initiation of actin-rich membrane protrusions termed filopodia or microspikes. These structures are involved in cell attachment, migration and neurite growth. Filopodia initiation and neural growth depends on cytoskeletal dynamics regulated to a large extent by the small molecular weight GTPases of the Rho family. Here, we describe the individual morphogenic activity of the integral membrane proteins Plasticity Related Genes also termed Lipid Phosphate Phosphatases Related genes (PRG 1-5 or LPPR 1-5). They are differentially expressed in the developing brain and re-expressed in regenerating axons after a lesion. In particular, PRG3 induces the formation of filopodia and promotes axonal growth. The sequence of PRG3 is highly related to PRG5 which also promotes morphological changes in neurons. However, our comparative analysis revealed a hierarchy with PRG3 displaying the strongest outgrowth promoting activity among the entire PRG family.

Transgenic adult mice with constitutive PRG3 expression displayed strong axonal sprouting distal to a spinal cord lesion. Moreover, fostered PRG3 expression promoted complex motor-behavioral recovery compared to wild type controls as revealed in the Schnell swim test (SST). Thus, PRG3 emerges as a developmental RasGRF1-dependent conductor of filopodia formation and axonal growth enhancer. PRG3-induced neurites resist brain injury-associated outgrowth inhibitors and contribute to functional recovery after spinal cord lesions. Here, we provide evidence that PRG3 operates as an essential neuronal growth promoter in the nervous system. Maintaining PRG3 expression in aging brain may turn back the developmental clock for neuronal regeneration and plasticity.

Link: http://dx.doi.org/10.18632/aging.101066

The Opening Decades of an Era of Greater Health and Longevity

Life span has been steadily increasing these past three decades, a trend made clear in the paper I'll point out today. Yet when it comes to the scope of history, the state of the present, and the future ahead, most people are quite pessimistic. Millennialism never really goes away. The past is seen in rose-tinted hues, the present is experienced against a backdrop of media emphasis on the fearful and the terrible, and the future is commonly painted as a descent into the pit. Yet in truth we live in an age of tremendous positive progress, in which wealth, access to medicine, security, comfort, and healthy longevity are on average increasing year by year. This has been true for more than two centuries in some parts of the world, those first into the industrial revolution, and certainly for at least a lifetime elsewhere. When it comes to biotechnology and medicine, there is a massive shift underway, a gathering of forces for even greater progress. Computing, materials science, and the life sciences are all accelerating, and nowadays researchers are turning their attention towards the treatment of the causes of aging rather than merely patching over and slightly slowing its consequences. The future of human health will be far more than a simple continuation of the gentle upward trend of the past. Great leaps lie ahead.

We're all aware that the past few decades have seen improved health and longevity across most of the world. This is as much a matter of growing wealth as it is a combination of new medicine made better and old medicine made cheap. Many regions are far wealthier today than even a generation ago, and that makes a sizable difference in the statistics of health and mortality: better control over infectious disease, better nutrition, greater awareness of common health practices, less exposure to pollution, and so on and so forth, a longer list than simply greater access to modern medical technology throughout life. Where do the statistics of life and death come from, however? As it happens, there is a fair-sized industry of researchers who mine and manage human mortality data from around the world. It is a massive undertaking, made challenging by the poor nature of much of that data on mortality, and especially mortality due to age-related disease, in many parts of the world. Even in wealthier countries, until fairly recently data on the oldest people was notably inaccurate, characterized by a tendency for medical staff to enter "old age" or similar general category as a cause of death rather than something more specific. Cleaning up large-scale databases and obtaining good statistical results with a high confidence of correctness and utility is a specialized business.

The open access paper linked below gives some idea of the sort of toil that goes into pulling together mortality data from countless reporting bodies into a useful set of working data. You should certainly click through and take a look at the full text, particularly the explanations (complete with diagrams and flow charts) of how researchers go about building the analysis from raw data. Given the doom-laden zeitgeist of this age of ours, as much of the blurb is concerned with inequality, healthcare costs, and regional declines as it is with simply presenting the data. It is unarguably the case, however, that the state of medicine and health has greatly improved over the past three decades, and that process of improvement continues. Progress is the true spirit of the age, for all that many do not want to see it. That progress is both good and necessary, as there is much left to be accomplished in the quest to end suffering; the tools to achieve an end to disease, step by step, are both foreseeable and in some cases already under development. The more of that, the better.

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015

Comparable information about deaths and mortality rates broken down by age, sex, cause, year, and geography provides a starting point for informed health policy debate. However, generating meaningful comparisons of mortality involves addressing many data and estimation challenges, which include reconciling marked discrepancies in cause of death classifications over time and across populations; adjusting for vital registration system data with coverage and quality issues; appropriately synthesising mortality data from cause-specific sources, such as cancer registries, and alternative cause of death identification tools, such as verbal autopsies; and developing robust analytical strategies to estimate cause-specific mortality amid sparse data. The annual Global Burden of Disease (GBD) analysis provides a standardised approach to addressing these problems, thereby enhancing the capacity to make meaningful comparisons across age, sex, cause, time, and place.

Global life expectancy at birth increased by 10.2 years, rising from 61.7 years in 1980 to 71.8 years in 2015, equating to an average gain of 0.29 years per year. By 2015, male life expectancy had risen by 9.4 years, increasing from 59.6 years in 1980 to 69.0 years, whereas female life expectancy improved by 11.1 years, climbing from 63.7 years to 74.8 years. On average, an additional 0.27 and 0.32 years of life were gained per year for males and females, respectively, since 1980. Global gains in life expectancy were generally gradual but steady, although catastrophic events, including the Rwandan genocide and North Korean famines, and escalating mortality due to HIV/AIDS, had worldwide effects on longevity. Slower gains were achieved for life expectancy at 50 years, or the average number of additional years of life 50 year olds can anticipate at a given point in time. On average, 50-year-old females saw an increase of 4.5 additional years of life since 1980, and 50-year-old males experienced an increase of 3.5 years. Total deaths increased by 4.1% from 2005 to 2015, rising to 55.8 million in 2015, but age-standardised death rates fell by 17.0% during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% to 39.8 million in 2015, whereas age-standardised rates decreased by 13.1%. Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias.

At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems.

PGC-1α Gene Therapy Slows Alzheimer's Progression in Mouse Model

It is always a good idea to look closely at the biochemistry involved in any potential Alzheimer's disease therapy that shows promise in mouse models. There is perhaps more uncertainty for Alzheimer's than most other age-related conditions when it comes to the degree to which the models are a useful representation of the disease state in humans - which might go some way towards explaining the promising failures that litter the field. In the research here, the authors are aiming to suppress a step in the generation of amyloid-β, one of the proteins that aggregates in growing amounts and is associated with brain cell death in Alzheimer's disease. They achieve this goal using gene therapy to increase the level of PGC-1α, which in turn reduces the level of an enzyme involved in the production of amyloid-β. Interestingly, increased levels of PGC-1α have in the past been shown to produce modest life extension in mice, along with some of the beneficial effects to health associated with calorie restriction.

Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying amyloid-β (Aβ) pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease.

Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.

Link: http://dx.doi.org/10.1073/pnas.1606171113

Interfering in the Spread of Alpha-Synuclein to Treat Synucleopathies

Researchers here demonstrate a method of interfering in the spread of alpha-synuclein aggregates, an approach that may slow the progression of synucleopathies such as Parkinson's disease. Like a number of other age-related neurodegenerative conditions, these are associated with and probably driven by the growing presence of specific misfolded or damaged proteins. The ideal approach is to find ways to safely remove these proteins, or understand and resolve the underlying reasons for their accumulation, both of which are paths that are so far proving to be more challenging than expected. Much of the research community remains focused on attempts to alter the late stage biochemistry of disease progression, however, as is the case here, rather than taking aim at root causes. This can be effective, but it is usually going to be much harder to prevent pathology without fixing the root causes than it is by going after those root causes.

Researchers report they have identified a protein that enables a toxic natural aggregate to spread from cell to cell in a mammal's brain - and a way to block that protein's action. The new findings hinge on how aggregates of alpha-synuclein protein enter brain cells. Abnormal clumps of alpha-synuclein protein are often found in autopsies of people with Parkinson's disease and are thought to cause the death of dopamine-producing brain cells. A few years ago, researchers published evidence for a novel theory that Parkinson's disease progresses as alpha-synuclein aggregates spread from brain cell to brain cell, inducing previously normal alpha-synuclein protein to aggregate, and gradually move from the "lower" brain structures responsible for movement and basic functions to "higher" areas associated with processes like memory and reasoning. "There was a lot of skepticism, but then other labs showed alpha-synuclein might spread from cell to cell."

The researchers knew they were looking for a certain kind of protein called a transmembrane receptor, which is found on the outside of a cell and works like a lock in a door, admitting only proteins with the right "key." They first found a type of cells alpha-synuclein aggregates could not enter - a line of human brain cancer cells grown in the laboratory. The next step was to add genes for transmembrane receptors one by one to the cells and see whether any of them allowed the aggregates in. Three of the proteins did, and one, LAG3, had a heavy preference for latching on to alpha-synuclein aggregates over nonclumped alpha-synuclein. The team next bred mice that lacked the gene for LAG3 and injected them with alpha-synuclein aggregates. "Typical mice develop Parkinson's-like symptoms soon after they're injected, and within six months, half of their dopamine-making neurons die. But mice without LAG3 were almost completely protected from these effects."

Antibodies that blocked LAG3 had similar protective effects in cultured neurons, the researchers found. "We were excited to find not only how alpha-synuclein aggregates spread through the brain, but also that their progress could be blocked by existing antibodies." Antibodies targeting LAG3 are already in clinical trials to test whether they can beef up the immune system during chemotherapy. If those trials demonstrate the drugs' safety, the process of testing them as therapeutics for Parkinsons' disease might be sped up, he says. For now, the research team is planning to continue testing LAG3 antibodies in mice and to further explore LAG3's function.

Link: https://www.eurekalert.org/pub_releases/2016-10/jhm-nts101116.php

A Calorie Restricted Medical Diet, to be Filed Next to Selling Ice to Eskimos

One of the more recent innovations in calorie restriction research has nothing to do with the science, and everything to do with figuring out how to pull more funding into the field. There is never enough funding for research in any field: going by how funds flow through our societies, it is easy to say that to a first approximation no-one really cares about progress in medicine. Bread and circuses, yes. Better technologies, better understanding of biology, and less disease, no. There is also a large difference between the funds available for non-commercial research versus money available and interested in investment in for-profit ventures. The latter is at least ten times the former, and much more easily arranged as well. Writing grants and raising philanthropic funding is a considerably harder job than pitching angels and venture firms; more effort for fewer dollars at the end of the day. But without the funding for non-profit research initiatives, there will be no new technologies ready to be carried forward in for-profit companies. It is one of the great frustrations of patient advocacy to know that the owners of countless millions of dollars are sitting on their hands, waiting for viable biotech companies, while the important research projects that will generate those companies struggle to raise hundreds of thousands to sustain shoestring budgets.

Calorie restriction is a particular challenge in this context. It is a lifestyle choice, not a drug or an antibody or something else that the medical industry understands how to package, market, and sell. It is nothing more than eating sensibly and eating less. Anyone can choose to do it. It is free and straightforward and well-documented. Yet the effects on long-term health and aging in ordinary individuals are much larger than anything that can be generated by the presently available panoply of drugs and other interventions. That, I should say, is more a statement on the poor quality of present medicine when it comes to treating aging as a medical condition than it is on the benefits of calorie restriction. It is a case of something being better than nothing: no presently available medicine deliberately addresses the root causes of aging, for all that the first therapies that will do that are in development at various stages. The nature of calorie restriction means that there has been little to no for-profit investment aiming to better characterize its benefits. Rather, all that funding was directed towards mapping the biochemistry and haphazardly testing the established drug libraries to find something that triggered any of the same effects. The search for such calorie restriction mimetics is well documented elsewhere, so I won't dwell on that, beyond noting that the outcome of ten to fifteen years of work and a great deal of money is, so far, nothing of any practical use.

So to calorie restriction itself, and how to obtain for-profit funding for research into eating less, and eating less in an effective way. The innovators here are Valter Longo and colleagues, who have achieved the goal of pulling in for-profit funding on the backs of turning specific implementations of fasting and low-calorie diets into FDA-approved therapies, such as an adjuvant in cancer treatment. The magic of regulation means that companies can manufacture a medical diet on the basis of research, and then use the barriers set up via intellectual property and regulatory pronouncements to charge an inordinate amount for what is, basically, a little bit of food that anyone could throw together after reading the papers to obtain the target calories, protein, micronutrient levels, and so on. That in turn means that the principals of these companies are willing to pay for the supporting research. On the one hand it's a depressing example of the distorted priorities that emerge from regulation of medicine, on the other one feels a certain admiration for Longo et al for having successfully hacked the system to fund the useful results they have produced these past few years. Quantifying the degree to which fasting alters the immune system, and quantifying the degree to which low-calorie diets and fasting are effectively equivalent in altering metabolism, are both helpful new information for those who practice forms of calorie restriction and intermittent fasting. In any case, here is a pointer to the less useful outcome from all of this, which is to say the medical diet. It comes across as a bad parody of itself, but that seems fairly true of most medical diet products.

Introducing ProLon

Industry leading nutritechnology company L-Nutra has announced the release of ProLon, a groundbreaking 5 days per month only natural plant based meal program that nourishes the body while convincing it that it is fully fasting. This is the first time in history that 'Fasting with Food' is possible and is therefore called the Fasting Mimicking Diet (FMD). Developed at the Longevity Institute of the University of Southern California (USC) and under the sponsorship of the National Institute for Aging and the National Institute of Health, ProLon induces the body to protect itself and rejuvenate in response to 5 consecutive days of fasting.

In the latest clinical trial conducted at USC's Longevity Institute, 100 participants on 3 cycles of ProLon (5 days only per month over a 3-month period) showed statistically significant improvements on various health metrics: decrease in body fat; decrease in body weight; preservation of bone density; reduction in fasting glucose and insulin resistance; optimization of cholesterol and triglyceride levels; decrease in IGF-1 (aging marker); decrease in C-reactive protein; elevated mesenchymal/progenitor cells (rejuvenation marker). This 'fasting with food' program features meals ranging from 770 to 1,100 calories per day.

Needless to say you can do all of this yourself, and whether or not you happen to have cancer at the time. It isn't hard to construct and follow a diet to a specific target of calories and nutrients: it just takes the willingness to do it. When presented with the above, and there's more along the same lines if you want to explore the ProLon website, it has to be said that it is more of a challenge than usual to remain optimistic that the first generation of rejuvenation therapies after the SENS model, such as senescent cell clearance, will be able do without the ridiculous marketing language that characterizes present day efforts such as the one above.

Further Assessment of the Effects of Young Ovaries Transplanted into Old Mice

Not so very many years ago it was noted that transplanting young ovaries into old mice resulted in extended life. There is still no good understanding of why this happens, and which of the numerous changes produced by this transplantation are most important in determining life span, but researchers here focus on beneficial effects for the immune system. Age-related failure of the immune system negatively impacts a wide range of important functions, including wound healing, destruction of senescent and potentially cancerous cells, and maintenance and support of neural tissues. It also leads to increased levels of chronic inflammation, a factor that contributes to the development of all of the common age-related diseases. Immune system decline is an important component of frailty in old age, so it isn't unreasonable to think that meaningful benefits will be generated by immune system restoration.

As we age, our metabolism slows and our immune system runs out of steam. Older people are more likely to have severe cold and flu symptoms, probably because they have fewer fresh immune cells left. And a slower metabolism means that glucose stays in the blood stream for longer after eating a meal. Over time, high blood sugar levels can damage organs. But experiments in mice suggest that transplanting organs from a younger individual could reverse these changes. Researchers removed the ovaries of 10 mice that were 12 months old and had gone through oestropause, a transition similar to the human menopause. They replaced these with ovaries taken from 60-day old mice - roughly equivalent to people in their early 20s in terms of ageing.

Four months later, the researchers assessed the mouse immune systems. The numbers of immune cells that respond to new infections - called naive T-cells - tend to decline with age, and had already fallen in these mice before surgery. Between the ages of 6 months (before the operation) and 16 months, the number of naive cells in these mice rose by around 67 per cent. Cell counts fell by 80 per cent in untreated mice over the same period. To test metabolism, researchers injected the mice with glucose and measured how long it took for their blood sugar levels to return to normal. The mice with young ovaries removed glucose from their blood faster than untreated mice. The findings build on the team's previous work, which found that mice transplanted with young ovaries in middle age live about 40 per cent longer than their peers, and have healthier looking hearts too. How young ovaries might exert these benefits remains something of a mystery. One theory is that the hormones produced by the eggs inside these ovaries are responsible. But when researchers killed all the eggs inside young ovaries before transplanting them into another set of older mice, they still saw the same benefits. The researchers theorize that some other kind of cell inside the ovary might be responsible for the rejuvenation.

Link: https://www.newscientist.com/article/2108682-young-ovaries-rejuvenate-older-mice-and-extend-their-lifespan/

Can Rejuvenation Biotechnologies Stop Cancer from Developing in the First Place?

A supporter recently asked the SENS Research Foundation staff whether the implementation of rejuvenation therapies that follow the SENS model of damage repair would prevent the development of cancer, since cancer is predominantly an age-related disease. Would rejuvenation alone, without any progress towards a comprehensive and effective cure for cancer, be good enough to hold cancer at bay?

It's certainly a good bet that applying rejuvenation biotechnologies to remove, repair, and replace other kinds of aging damage will in some ways make us less vulnerable to cancer. Notably, ablating senescent cells would eliminate the "senescence-associated secretory phenotype" (SASP), which promotes the growth and invasiveness of cancers in several ways, including stimulating early-stage cancer cells to continue replicating, encouraging the growth of new blood vessels needed by cancer cells to supply themselves with fuel and oxygen, and breaking down the physical barriers that prevent them from metastasizing, which is when most cancers become deadly. Also, rejuvenating the aging immune system (by eliminating the dysfunctional T-cells that accumulate with age and rebuilding the atrophied thymus gland) will restore the body's ability to suss out and eliminate cancers as they emerge. But it's also clear that deploying these other rejuvenation biotechnologies won't be enough to eliminate cancer altogether, and that must be our ultimate goal.

First, we already know that cancers can evolve multiple mechanisms to avoid being hit or destroyed by antibodies and immunological factors, and the longer a person lives with proto-cancerous cells (even in the presence of a healthy, young immune system), the longer those cells have to develop ways to evade such an immune system. This is one of the reasons that cancer is an age-related disease, despite the fact that young people can and do certainly get cancer, and despite the fact that many late-life cancers originate with mutations that arise in the body decades earlier. More importantly, perhaps, there is good reason to worry that otherwise-rejuvenated tissues in a body that is still vulnerable to the core processes of cancer may actually become more vulnerable to cancer than they would be under "aging as usual." Consider the following contrasting scientific findings.

On the one hand, it has been shown in animal experiments that when you transplant a pre-formed cancer into an old host, it usually grows more quickly than the same cancer does when transplanted into a young one. This is as you'd expect from things that make the aged host more vulnerable to cancer: senescent cells make it easier for the implanted cancer to take root and spread, and a flagging immune system is less able to root out the invader. On the other hand, when you infect mice with a virus that can cause new cancers to form, it is actually less likely to happen in an old mouse than in a young one - and the tumors that do form grow more slowly, despite the weakened immune system and burden of senescent cells in the older animal. This strongly suggests that something about biological aging itself eventually makes our tissues less prone to forming cancers.

Consistent with this, consider the phenomenon of people (and mice) with mutations in DNA repair genes that cause them to accumulate mutations more rapidly than the rest of us. These people develop an "old" burden of potentially cancer-causing mutations in a body that is otherwise still young. This would be similar to having an otherwise-rejuvenated body in which the problem of age-associated mutations had not been solved by a specific rejuvenation biotechnology. Such people develop what are often very aggressive cancers at much younger ages than is typical in the general population. This suggests that once the mutations needed to form a cancer take hold, even an otherwise-young body is unable to hold the invasion back. Thus, rejuvenating the body will reduce the risk of some cancers (notably, by reversing immunosenescence, clearing out senescent cells, and restoring the structural integrity of the extracellular matrix of our tissues). In other ways, however, rejuvenation could restore the host tissues' intrinsic vulnerability to forming new cancers, and to that extent make cancer more of a risk: all those fresh, proliferation-competent cells, and a restored signaling environment full of growth factors.

Link: http://www.sens.org/research/research-blog/question-month-15-would-other-rejuvenation-biotechnologies-keep-us-cancer-free

Interfering in a Later Stage Mechanism of Tauopathy Can Restore Some Lost Cognitive and Memory Function

In the research linked below, scientists describe a potentially beneficial point of interference in a tau-related mechanism of neurodegeneration: targeted sabotage of this mechanism can restore lost cognitive function and otherwise turn back some of the effects of a tauopathy, at least in the engineered mouse lineages used. Tauopathies are neurodegenerative conditions characterized by an accumulation of altered forms of tau protein, forming solid fibrils and tangles in brain tissue. Alzheimer's disease is perhaps the most familiar of these conditions, and there is still considerable debate over the degree to which the harm to brain cells and cognitive function is caused by amyloid-β versus tau in that case. For both proteins the situation is somewhat similar: a lot of work focused on how the deposited solid aggregates relate to mechanisms of cell death and dysfunction, as well as why it is that older people have more of these aggregates, and so far frustratingly limited progress towards therapies capable of clearing out these forms of metabolic waste, despite years of large-scale investment. Many researchers are, however, focused less on clearance than on altering the operation of brain biochemistry in the presence of tau and amyloid: finding ways to short-circuit the worst consequences rather than finding ways to remove the root causes. I can't say I think that this is a wise high-level strategy, but it is very prevalent in the research community.

Why does the presence of the insoluble form of tau increase with age? One possibility is shared with amyloid, that the clearance and filtration mechanisms operating on cerebrospinal fluid decline in later life. That might include dysfunction in the choroid plexus, responsible for filtration, or dysfunction in the drainage system of small fluid passageways behind the nose. The creation and removal of these aggregates is actually fairly dynamic, and the outcome only looks like a slow and steadily increase because the imbalance between that creation and removal grows slowly and steadily. Another possible cause of growing levels of tau is the age-related decline in immune function, just as apparent in the brain as elsewhere in the body. Immune cells are responsible for clearing out waste, among many other tasks, and when they are less efficient we might expect levels of all forms of waste between cells to increase. At the detail level of biochemistry and mechanisms, however, a great deal of uncertainty remains. There is considerable debate and a great deal of published research covering efforts to catalog how and why the presence of tau increases with age, and how and why it does so to a larger degree in only some people. It is a complex field, still in progress towards definitive answers.

In the ideal world, this lack of knowledge could be treated as a Gordian Knot and cut with some form of therapy that efficiently removed tau aggregates. That would very quickly and clearly pin down the importance of the role of tau in neurodegenerative disease and cell death. It isn't the chosen strategy for much of the research community, however, and there is typically more of a focus on the class of approach illustrated below, in which downstream mechanisms in a disease brain are mapped and then manipulated. The root cause remains, able to cause harm via any of the other, yet to be mapped consequences: keeping a damaged machine running without repairing that damage is typically much harder than just focusing on repair. It is possible to achieve beneficial outcomes by following this strategy, as is the case here, but they will typically only deal with a fraction of the issue or only slow the progression of the condition. Still, within the context of the strategy chosen here, and with the caveat that work in mouse models for amyloid and tau pathologies has a poor record of success when it comes to making the leap to human medicine, this seems promising. Those in the audience who have followed research into Alzheimer's and amyloid-β over the past decade might find that there are a number of parallels in the results presented here and some of the discoveries made of how amyloid gives rise to harmful effects on cells - also quite indirect in its relationship with the aggregrated solid form of the protein.

Untangling a cause of memory loss in neurodegenerative diseases

Using a mouse model of tauopathy that produces a mutated form of human tau protein, researchers correlated memory deficits with the presence of a fragment of the tau protein. The tau fragment, which is produced when caspase-2 cuts the full-length tau protein at a specific location, was also found at higher levels in the brains of Alzheimer's disease patients compared to healthy individuals of the same age. While the standard hallmark of tauopathies is the appearance in brain tissue of large tangles of abnormal tau protein, it has recently become less clear whether the tangles of tau are actually causing cognitive decline. "In the past, many studies focused on the accumulation of tangles and their connection to memory loss, but the more we learn, the less likely it seems that they are the cause of disease symptoms. The pathological fragment of tau that we have identified resists forming tangles and can instead move freely throughout the cell. Therefore, we decided to look for other mechanisms that could affect synaptic function."

The researchers used fluorescent labeling to track and compare the behavior of normal and mutated tau in cultured neurons from the rat hippocampus, the brain region most associated with learning and memory. Unlike normal tau, both mutated tau and the short fragment produced when caspase-2 cuts tau were primarily found within structures called dendritic spines, where neurons receive inputs from neighboring cells. The overabundance of mutated tau, including the caspase-2-produced fragment, caused disruptions in synaptic function in the spines. The impact on synapses was specific, with no observed effects on the overall structure or survival of the neurons. "It appears that abnormally processed tau is disrupting the ability of neurons to properly respond to the signals that they receive, producing memory deficits independent of tangle formation. Because this effect is occurring without cell death or a loss of synapses, we have a better chance of intervening in the process and hopefully reversing symptoms of the disease."

Caspase-2 cleavage of tau reversibly impairs memory

In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.