Fight Aging!

Senescent cells accumulate with age, and secrete an unfortunate combination of signals that harms organs and tissues in numerous ways, such as via the production of increased chronic inflammation. This is one of the root causes of aging and age-related disease. Safe and effective clearance of senescent cells has been on the SENS rejuvenation biotechnology agenda for fifteen years, but only recently has progress in scientific funding and demonstrations of improved health and life spans in mice snowballed to the point at which startup companies could make a real go of it. Things are moving fairly rapidly in this field now. With the recent $116 million venture investment in UNITY Biotechnology's work on senescent cell clearance, and other companies angling for their own launch, it is fair to say that this line of research and development is underway for real. Clinical trials of senescent cell clearance will be underway soon, funded by UNITY Biotechnology, and using drug candidates such as navitoclax developed in the cancer research community, noted for their ability to induce apoptosis, a form of programmed cell death. Senescent cells are primed for apoptosis, and it takes little to tip them over the edge in comparison to a normal somatic cell, which means that there may well be quite a large stable of existing drugs that will have some useful effect.

The question here is one that is only now starting to be useful to ask: should we all be running out today to obtain and take a drug (such as navitoclax) or drug combination (such as dasatinib and quercetin) that were shown to clear some fraction of senescent cells in rodents? Certainly there have been no shortage of people chasing after whatever the current hype of the day was in past years; I'm sure you all recall resveratrol and other alleged calorie restriction mimetics or telomere length enhancers. All a waste of time and effort. The difference between the science behind those and the science behind senescent cell clearance is considerable, however. The items of the past have all been associated with altering metabolism so as to modestly slow aging, at best, and we have the very good examples of calorie restriction and exercise to show us the immediate bounds of the plausible on that front in our species. Senescent cell clearance on the other hand is legitimately and actually a form of rejuvenation, turning back one facet of the aging of your tissues to an earlier time. You probably don't have to keep taking the treatment, unlike those that slightly slow aging. An efficient senescent cell clearance treatment is something that you would undergo once every few years, perhaps. These first attempts won't be efficient, of course, but they should certainly have a sizable effect in comparison to most of the nonsense that gets peddled to the credulous.

It is helpful to look at the question of whether you and I should jump on this bandwagon through the lens of navitoclax, or ABT-263, which is a likely candidate for UNITY Biotechnology to choose for their trials. The people involved with UNITY Biotechnology have worked with it, and it has been used in a range of clinical trials for cancer, which makes it harder for the FDA to mount their usual expensive objections and requests for more data. Navitoclax can be purchased, and dosages can be established from the human cancer studies and the senescent cell clearance rodent studies (there is a fairly standard method of going from mouse or rat dosage to human dosage). There is comprehensive human safety and side-effect data to look at, but only rodent data for its effects on senescent cells - no-one was looking at that in the cancer studies, which is entirely understandable, but a pity. The current methods of senescent cell clearance with published rodent data show a degree of clearance for fairly short treatments varying from negligible to more or less 50% by tissue type, with different drugs having different profiles. So from a technical point of view, the open question is whether or not it works in people to a useful degree. It is entirely reasonable to expect some drugs to do well in mice and terribly in people when it comes to killing senescent cells, and vice versa. The only real way to find out is to try it. Since clinical trials are coming up soon, from my perspective you would have to be something of an enthusiast to jump in ahead of that right now; a year or two seems a fine amount of time to wait for more certainty.

If taking the leap now, you would have to establish the degree of effect yourself. To do that rigorously you'd need a friendly lab capable of a biomarker assay in a skin sample before and after, say, which isn't impossible to find, just quite specialized. The necessary equipment for those who know how to use it is certain readily available for sale. But without that, you might want to try before and after comprehensive bloodwork to look at markers of inflammation, or even simpler assessments such as blood pressure, given the recent suggestions that senescent cell clearance might help with tissue elasticity, and loss of elasticity in blood vessel walls drives age-related increase in blood pressure. There are other possible options to consider. The point being, don't just run the experiment and feel good about it. Prove to yourself that something happened.

The real issue that puts navitoclax on the wait and see list is that it is expensive, a fairly common problem for newer drug candidates. There is no widespread usage yet, so no-one has invested in the facilities needed for mass production at a reasonable cost, and until such time as someone invents some sort of nanotechnological universal chemical synthesis device, it will remain an expensive, people-intensive business to run up custom lots of specific drug compounds to order. In this case, replicating the doses used in cancer trials would cost something like $700-$1500 per day, which makes it less a matter of thinking carefully about costs and benefits and more a matter of being beyond affordable to anyone inclined to self-experiment. This, more than any of the other factors tells us that we're all going to be waiting on the matter of navitoclax. What if the price was $1 per day, however? Would it be worth it? I'd say probably yes as an experiment, if you were comfortable with what you read of the side effects in the results from the cancer trials, and were willing to put in the work to gather some data about its effects on your own tissues.

As a comparison, we can consider the combination of dasatinib and quercetin - which actually doesn't turn out to be much of a comparison at all. It is very similar, starting with being in much the same place as navitoclax from the point of view of data: dasatinib is used in human cancer trials, but senescent cell clearance results have been published for mice only. Based on the mouse data, you would have to use both rather than just the one: it is a synergistic effect, and just the one or the other isn't anywhere near as useful. Quercetin is a readily available supplement and pretty cheap, so there is that at least. Dasatinib is not, however. It isn't as costly as navitoclax, but still hundreds of dollars for the sort of daily dose used in human trials. Further, the side-effects for dasatinib at these dosages appear somewhat worse that those for navitoclax.

This is the sort of thing that should be going through your mind when looking into making the plunge: cost and reliability of the source; finding good data on dosage, safety, and side-effects; ability to determine whether or not it is actually doing something if you are taking it. In addition, think about what is coming down the line. Is new human data to be expected soon that would reduce the risk of trying something that works in rodents but not so well in people? Are better approaches in the works, such as the gene therapy from Oisin Biotechnologies that should have few to no side-effects? Would it hurt to wait two years, or five years, for an actual product to arrive and for the costs to fall as production increases? These are all questions that we can only answer for ourselves, for our own case.

Researchers here take what seems to be an important step forward in understanding how aggregates of altered tau protein produce forms of age-related neurodegeneration such as Alzheimer's disease. You might be more familiar with amyloid deposits in the brain in the context of Alzheimer's, but it is becoming clear that tau is probably just as important in this condition, and there are other tauopathies in which it is the dominant cause of cell death and dysfunction. Efforts to safely remove harmful forms of tau are unfortunately lagging behind efforts to clear amyloid, but that should change in the years ahead.

The distinct structures of toxic protein aggregates that form in degenerating brains determine which type of dementia will occur, which regions of brain will be affected, and how quickly the disease will spread, according to a new study. The research helps explain the diversity of dementias linked to tau protein aggregation, which destroys brain cells of patients with Alzheimer's and other neurodegenerative syndromes. The study also has implications for earlier and more accurate diagnoses of various dementias through definition of the unique forms of tau associated with each. "In addition to providing a framework to understand why patients develop different types of neurodegeneration, this work has promise for the development of drugs to treat specific neurodegenerative diseases, and for how to accurately diagnose them. The findings indicate that a one-size-fits-all strategy for therapy may not work, and that we have to approach clinical trials and drug development with an awareness of which forms of tau we are targeting."

Researchers had previously determined that tau acts like a prion - an infectious protein that can self-replicate and spread like a virus through the brain. The lab has determined that tau protein in human brain can form many distinct strains, or self-replicating structures, and developed methods to reproduce them in the laboratory. This research led the team to the latest study to test whether these strains might account for different forms of dementia. To make this link, 18 distinct tau aggregate strains were replicated in the lab from human neurodegenerative disease brain samples, or were created from mouse models or other artificial sources. Researchers inoculated the strains into different brain regions of mice and found striking differences among them. Each form created different pathological patterns, recapitulating the variation that occurs in diseases such as Alzheimer's, frontotemporal dementias, and traumatic encephalopathy. The different forms of tau caused pathology that spread at different rates through the brain, and affected specific brain regions. This experiment demonstrated that the structure of pathological tau aggregates alone is sufficient to account for most if not all the variation seen in human neurodegenerative diseases that are linked to this protein. "The challenge for us now is to figure out how to rapidly and efficiently determine the forms of tau that are present in individual patients, and simultaneously, to develop specific therapies. This work says that it should be possible to predict patterns of disease in patients and responses to therapy based on knowledge of tau aggregate structure."

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2016/oct/identifying-tau-strains.html

In the aging research community as it stands today there is much more work on approaches that can at best produce only small effects on the course of aging than there is work on approaches capable of rejuvenation and large gains in life span. The present growth of interest in supplementation with nicotinamide mononucleotide (NMN) falls into the former camp, shown to modestly slow aging in animal studies. We know that effects on aging in short-lived species are much larger than they are in humans, where there is the data to make direct comparisons of the same method or genetic alteration. The life spans of short-lived species are much more plastic in response to circumstances. Investigations of NMN, like the sirtuin research that led to it, cannot possibly produce large gains in human health. It is somewhat frustrating to see significant time and effort once again be directed towards a line of research in which the potential outcomes are so very limited, analogous to those produced by exercising a little more and eating a little less. Yes, it is more evidence for the importance of mitochondrial function in aging, but in a rational world that should be taken as nothing more than a sign that the research and development communities should put more effort into mitochondrial repair strategies, or the backup approach of allotopic expression so as to completely fix the problem in older individuals, not just slightly slow it down.

Much of human health hinges on how well the body manufactures and uses energy. For reasons that remain unclear, cells' ability to produce energy declines with age, prompting scientists to suspect that the steady loss of efficiency in the body's energy supply chain is a key driver of the aging process. Now, scientists have shown that supplementing healthy mice with a natural compound called NMN can compensate for this loss of energy production, reducing typical signs of aging such as gradual weight gain, loss of insulin sensitivity and declines in physical activity. "This means older mice have metabolism and energy levels resembling that of younger mice. Since human cells rely on this same energy production process, we are hopeful this will translate into a method to help people remain healthier as they age."

With age, the body loses its capacity to make a key element of energy production called NAD (nicotinamide adenine dinucleotide). Past work has shown that NAD levels decrease in multiple tissues as mice age. Past research also has shown that NAD is not effective when given directly to mice so the researchers sought an indirect method to boost its levels. To do so, they only had to look one step earlier in the NAD supply chain to a compound called NMN (nicotinamide mononucleotide). The new study shows that when NMN is dissolved in drinking water and given to mice, it appears in the bloodstream in less than three minutes. Importantly, the researchers also found that NMN in the blood is quickly converted to NAD in multiple tissues.

To determine the long-term effects of giving NMN, researchers studied three groups of healthy male mice fed regular mouse chow diets. Starting at five months of age, one group received a high dose of NMN-supplemented drinking water, another group received a low dose of the NMN drinking water, and a third group served as a control, receiving no NMN. The researchers compared multiple aspects of physiology between the groups, first at 5 months of age and then every three months, until the mice reached 17 months of age. Typical laboratory mice live about two years. The researchers found a variety of beneficial effects of NMN supplementation, including in skeletal muscle, liver function, bone density, eye function, insulin sensitivity, immune function, body weight and physical activity levels. But these benefits were seen exclusively in older mice. "When we give NMN to the young mice, they do not become healthier young mice. NMN supplementation has no effect in the young mice because they are still making plenty of their own NMN. We suspect that the increase in inflammation that happens with aging reduces the body's ability to make NMN and, by extension, NAD."

In skeletal muscle, the investigators found that NMN administration helps energy metabolism by improving the function of mitochondria, which operate as cellular power plants. They also found that mice given NMN gained less weight with aging even as they consumed more food, likely because their boosted metabolism generated more energy for physical activity. The researchers also found better function of the mouse retina with NMN supplementation, as well as increased tear production, which is often lost with aging. They also found improved insulin sensitivity in the older mice receiving NMN, and this difference remained significant even when they corrected for differences in body weight.

Link: https://medicine.wustl.edu/news/natural-compound-nmn-reduces-signs-aging-healthy-mice/

A fair amount of interesting research on the topic of exercise and aging passes by every month. Most is not really worth commenting on here, other than to reinforce the point that there is a very, very large body of evidence to link regular exercise with improved long-term health and reduced mortality. Since I did note a few items worth reading recently, I thought I'd bundle them together for today's post as just such a reminder. In human studies the evidence for exercise tends to be a matter of correlation more often than causation, but the corresponding animal studies, in which researchers can put individuals into groups by level of exercise and observe the results across the life span of a cohort, leave no doubt as to the benefits provided by regular exercise. The results over the long term remain better than anything a basically healthy individual can obtain from medical science today, say to say, though that statement won't be true for many more years given the progress being made towards rejuvenation therapies. You can't exercise your way to ensuring a life span of 100 years, it isn't that large of an effect, but the benefits that can be realized are available, reliable, and free. It makes sense to take advantage of them.

The high level summary of the present research community consensus on the health benefits of exercise is that it, like many things in health and medicine, appears to have a U-shaped dose-response curve with the 80/20 point somewhere around about or a little above the standard recommendations for half an hour to an hour a day of moderate aerobic exercise. While elite athletes are shown to live a few years longer than the rest of us, it remains unclear as to whether that is due to the large amount of physical exercise or due to the fact that more robust people - who would live longer anyway - tend to have a better shot at succeeding in the world of professional athletics. At the other end of the dose-response curve, the growing use of accelerometers in studies has demonstrated that even modest levels of exercise, such as infrequent gardening or cleaning or walking, have noticeable correlations with health and mortality. More is better, however, and there is a pretty clear difference in life expectancy between those who manage regular moderate exercise and those who remain sedentary. Given that a radical change in the state of medicine lies ahead, the transition from not treating the causes of aging to actually and effectively repairing those causes, it makes sense to eke out extra years of healthy life, to increase the odds of living to take advantage of the rejuvenation biotechnologies yet to come.

Mortality and heart disease: you don't have to be an athlete to reduce the risk factors

Researchers, it is hoped, will one day find a miracle cure for all kinds of diseases. Yet over and over again it has been shown that even if it takes a little more effort than swallowing a little pill, exercise is an excellent preventive and curative treatment for many diseases. A new study shows that even low physical fitness, up to 20% below the average for healthy people, is sufficient to produce a preventive effect on most of the risk factors that affect people with cardiovascular disease. To measure the impact of physical fitness on heart disease risk factors, the researchers selected 205 men and 44 women with heart disease, including coronary artery disease, stroke, congestive heart failure, and heart valve disease, and had them undergo a stationary bike stress test to determine their fitness level. The results showed that normal physical fitness, even up to 20% below the population average, is sufficient to have a preventive effect on five of the eight risk factors affecting people with cardiovascular disease - abdominal circumference, diabetes, hypertension, obesity, and excess weight. Normal physical fitness means having the physical fitness of a person of the same weight, height, sex, and age, and who is disease-free. The easiest way to achieve this is to follow the recommendations of the World Health Organization - 150 minutes per week of moderate exercise or 75 minutes of vigorous exercise.

Does it matter how long you sit-if you are fit?

More and more studies confirm that sitting is bad for our health. It increases the likelihood of developing cardiovascular disease and other lifestyle-related illnesses such as diabetes. Some studies have estimated that being sedentary kills as many people as smoking. The average adult in the Western world sits between 9 and 11 hours a day, a number that only increases as we age. In fact, in a study in older adults just published researchers found that the least sedentary third of their study participants still spent between 12 and 13 hours in sedentary behavior, while the most sedentary of the elders in the study were sedentary for up to 15 hours a day.

But how does being fit affect the health risk associated with a sedentary lifestyle, especially in older adults, who are the most likely to be sedentary? The researchers found that older women and men in the most sedentary group were correspondingly 83% and 63% more likely to have risk factors for cardiovascular disease compared to women and men who were least sedentary. But when the researchers took fitness into account, they found that having high age-specific fitness (in this case, being among the fittest 40%) reduced the likelihood of having cardiovascular risks factors posed by extended time spent being sedentary. However, no such effect was found in those who were physically active without being fit. "Our Western lifestyles necessarily involve a lot of sitting, and we spend more and more time sitting on average as we age. But our findings show that being fit plays an important part in successful ageing and may lend protection against the negative health effects of being sedentary."

Increasing muscle strength can improve brain function

Mild Cognitive Impairment (MCI) defines people who have noticeably reduced cognitive abilities such as reduced memory but are still able to live independently, and is a precursor to Alzheimer's disease. Findings from the Study of Mental and Resistance Training (SMART) trial show, for the first time, a positive causal link between muscle adaptations to progressive resistance training and the functioning of the brain among those over 55 with MCI. "What we found in this follow up study is that the improvement in cognition function was related to their muscle strength gains. The stronger people became, the greater the benefit for their brain." SMART was a randomised, double-blind trial involving 100 community-dwelling adults with MCI, aged between 55 and 86. These new findings reinforce research from the SMART trial, whereby MRI scans showed an increase in the size of specific areas of the brain among those who took part in the weight training program. These brain changes were linked to the cognitive improvements after weight lifting.

Aerobic exercise and vascular cognitive impairment

To assess the efficacy of a progressive aerobic exercise training program on cognitive and everyday function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI), this was a proof-of-concept trial comparing a 6-month, thrice-weekly, progressive aerobic exercise training program (AT) with usual care plus education on cognitive and everyday function with a follow-up assessment 6 months after the formal cessation of aerobic exercise training. Seventy adults randomized to aerobic exercise training or usual care were included in intention-to-treat analyses. At the end of the intervention, the aerobic exercise training group had significantly improved Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog) performance compared with the usual care plus education group (-1.71 point difference); however, this difference was not significant at the 6-month follow-up (-0.63 point difference). There were no significant between-group differences at intervention completion and at the 6-month follow-up in EXIT-25 or ADCS-ADL performance. Examination of secondary measures showed between-group differences at intervention completion favoring the AT group in 6-minute walk distance (30.35 meter difference) and in diastolic blood pressure (-6.89 mm Hg difference). This study provides preliminary evidence for the efficacy of 6 months of thrice-weekly progressive aerobic training in community-dwelling adults with mild SIVCI, relative to usual care plus education.

Exhausted, or anergic T cells show up in increasing numbers in the aged immune system, or in an immune system worn down by persistent infections such as HIV. Most people are in fact infected by the persistent herpesvirus CMV by the time they are old, and this is thought to have a detrimental effect on the immune system, contributing to its collapse into immunosenescence. Exhausted T cells take up space that could be hosting useful cells, but are largely ineffective at their jobs. The direct approach to fixing this problem is to find ways to selectively destroy these cells, or destroy the entire immune system and then rebuild it from a patient's own cells, something that has been shown to cure autoimmunity, and is these days looking more practical for other uses now that the scientific community is making progress on side-effect-free alternatives to chemotherapy for that destruction. In this case, the researchers involved are more interested in reprogramming exhausted T cells, to see if their exhaustion can be removed. They make a solid attempt, but find it is more challenging than hoped:

Microbes that cause diseases like HIV, malaria, and hepatitis C exploit and often activate immune checkpoint pathways - cell surface receptors such as CTLA4 and PD-1 - to slow immune cells and prevent their elimination by the host. T cells that are supposed to clear an infection, instead, become "exhausted." The cell-surface receptors naturally act like brakes to tell the immune system to not react as strongly during normal situations and help the immune system avoid damaging healthy tissue or causing autoimmunity. Blocking PD-1 can reinvigorate exhausted T cells and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram exhausted T cells into durable memory T cells is unclear. Researchers have now found that reinvigorating exhausted T cells in mice using a PD-L1 blockade caused very few T memory cells to develop. After the blockade, re-invigorated T cells became re-exhausted if antigen from the virus remained high, and failed to become memory T cells when the virus was cleared.

Epigenetics is the way chemical modifications to DNA and the proteins binding DNA determine which genes are expressed by a cell type. Epigenetic profiles can be highly stable and confer long-term identity to a cell. (In other words, the reason a liver cell stays a liver cell and doesn't become a lung cell is due largely to epigenetics since both liver and lung cells have the same genes.) "What these new findings on exhausted T cells tells us is that the unique epigenetic profile of exhausted T cells causes these cells to express a different overall set of genes compared to memory or effector T cells." However, this epigenetic pattern was only minimally changed following the PD-L1 blockade. This prevented these exhausted T cells from changing into the more protective effector or memory cell types. "We were surprised that the exhausted T cell epigenetic profile was not reprogrammed. Instead, the benefit we see after PD-1 pathway blockade is caused by only transient changes in gene expression that is not durable, rather than permanent epigenetic reprogramming." These findings suggested that exhausted T cells are a distinct lineage of T cells in and of themselves instead of just being effector or memory T cells restrained by checkpoint pathways. "We predicted that exhausted T cells would not have a distinct epigenetic profile but have the molecular flexibility to obtain immune memory. But we found that exhausted T cells are quite set in their ways. We think this shows that epigenetic fate inflexibility may limit current immunotherapies based on PD-1 checkpoint inhibitors."

Link: http://www.uphs.upenn.edu/news/News_Releases/2016/10/wherry/

The development of unstable fatty lesions in blood vessel walls that characterizes atherosclerosis is a vicious cycle of bad cell behavior once it gets going. Cells react to the presence of damaged lipids with inflammation, and macrophages arrive in response to clean up the lipids. The macrophages ingest more damaged lipids than they can handle, turn into what are known as foam cells, call for more help, then die, and their remains contribute to the growth of the lesion and the inflammation it causes. As the research here notes, it turns out that a meaningful proportion of foam cells become senescent in the course of this process, and thus strategies that remove senescent cells in a targeted manner can slow the development of atherosclerosis in addition to all of the other benefits they produce. Senescent cells accumulate with age and cause disruption to surrounding tissue structure and cell behavior through the senescence-associated secretory phenotype (SASP), a mix of secreted signal molecules is known to provoke inflammation. In the context of what is known of atherosclerosis, it makes perfect sense that senescent cells would have an important role. Their removal is one of a number of possible points at which the vicious cycle of inflammation and immune response in atherosclerotic lesions might be sabotaged.

Cells enter a state of senescence in response to certain stresses. Studying mouse models, researchers examined the role of senescent lipid-loaded macrophages (so-called "foam cells") in the pathogenesis of atherosclerosis. At early stages of atherosclerosis, senescent foam cells promoted the expression of inflammatory cytokines. At later stages, they promoted the expression of matrix metalloproteases implicated in the rupture of atherosclerotic plaque, which can lead to blood clots. Experimental removal of the senescent cells had beneficial effects at both stages of the disease.

Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice, we show that these cells are detrimental throughout disease pathogenesis. We find that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. Together, these results demonstrate that senescent cells are key drivers of atheroma formation and maturation and suggest that selective clearance of these cells by senolytic agents holds promise for the treatment of atherosclerosis.

The degredation of elastin resulting from the presence of senescent cells is an interesting point and worth dwelling on. It was also seen in a study of senescent cell removal in aged lung tissue. Loss of tissue elasticity in blood vessels is an important contribution to hypertension and consequent cardiovascular disease, but is thought to be largely a consequence of cross-linking, not cellular senescence. If it turns out that removing senescent cells significantly slows the stiffening of blood vessels with age, and perhaps this is yet another inflammatory aspect of their unwanted activity, that will probably result in an equally significant reduction in cardiovascular mortality in later life.

Link: http://dx.doi.org/10.1126/science.aaf6659

The whispers of late have had it that UNITY Biotechnology was out raising a large round of venture funding, and their latest press release shows that this was indeed the case. The company, as you might recall, is arguably the more mainstream of the current batch of startups targeting the clearance of senescent cells as a rejuvenation therapy. The others include Oisin Biotechnologies, SIWA Therapeutics, and Everon Biosciences, all with different technical approaches to the challenge. UNITY Biotechnology is characterized by a set of high profile relationships with noted laboratories, venture groups, and big names in the field, and, based on the deals they are doing, appear to be focused on building a fairly standard drug development pipeline: repurposing of apoptosis-inducing drug candidates from the cancer research community to clear senescent cells, something that is being demonstrated with various drug classes by a range of research groups of late. Senescent cells are primed to apoptosis, so a nudge in that direction provided to all cells in the body will have little to no effect on normal cells, but tip a fair proportion of senescent cells into self-destruction. Thus the UNITY Biotechnology principals might be said to be following the standard playbook to build the profile of a hot new drug company chasing a hot new opportunity, and clearly they are doing it fairly well so far.

UNITY Biotechnology Announces $116 Million Series B Financing

UNITY Biotechnology, Inc. ("UNITY"), a privately held biotechnology company creating therapeutics that prevent, halt, or reverse numerous diseases of aging, today announced the closing of a $116 million Series B financing. The UNITY Series B financing ranks among the largest private financings in biotech history and features new investments from longtime life science investors ARCH Venture Partners, Baillie Gifford, Fidelity Management and Research Company, Partner Fund Management, and Venrock. Other investors include Bezos Expeditions (the investment vehicle of Jeff Bezos) and existing investors WuXi PharmaTech and Mayo Clinic Ventures. Proceeds from this financing will be used to expand ongoing research programs in cellular senescence and advance the first preclinical programs into human trials.

The financing announcement follows the publication of research that further demonstrates the central role of senescent cells in disease. The paper, written by UNITY co-founders Judith Campisi and Jan van Deursen and published today, describes the central role of senescent cells in atherosclerotic disease and demonstrates that the selective elimination of senescent cells holds the promise of treating atherosclerosis in humans. In animal models of both early and late disease, the authors show that selective elimination of senescent cells inhibits the growth of atherosclerotic plaque, reduces inflammation, and alters the structural characteristics of plaque such that higher-risk "unstable" lesions take on the structural features of lower-risk "stable" lesions. "This newly published work adds to the growing body of evidence supporting the role of cellular senescence in aging and demonstrates that the selective elimination of senescent cells is a promising therapeutic paradigm to treat diseases of aging and extend healthspan. We believe that we have line of sight to slow, halt, or even reverse numerous diseases of aging, and we look forward to starting clinical trials with our first drug candidates in the near future."

So this, I think, bodes very well for the next few years of rejuvenation research. It indicates that at least some of the biotechnology venture community understands the likely true size of the market for rejuvenation therapies, meaning every human being much over the age of 30. It also demonstrates that there is a lot of for-profit money out there for people with credible paths to therapies to treat the causes of aging. It remains frustrating, of course, that it is very challenging to raise sufficient non-profit funds to push existing research in progress to the point at which companies can launch. This is a problem throughout the medical research and development community, but it is especially pronounced when it comes to aging. The SENS view of damage repair, which has long incorporated senescent cell clearance, is an even tinier and harder sell within the aging research portfolio - but one has to hope that funding events like this will go some way to turn that around.

From the perspective of being an investor in Oisin Biotechnologies, I have to say that this large and very visible flag planted out there by the UNITY team is very welcome. The Oisin team should be able to write their own ticket for their next round of fundraising, given that the gene therapy technology they are working on has every appearance of being a superior option in comparison to the use of apoptosis-inducing drugs: more powerful, more configurable, and more adaptable. When you are competing in a new marketplace, there is no such thing as too much validation. The existence of well-regarded, well-funded competitors is just about the best sort of validation possible. Well funded competitors who put out peer-reviewed studies on a regular basis to show that the high-level approach you and they are both taking works really well is just icing on the cake. Everyone should have it so easy. So let the games commence! Competition always drives faster progress. Whether or not I had skin in this game, it would still be exciting news. The development of rejuvenation therapies is a game in which we all win together, when new treatments come to the clinic, or we all lose together, because that doesn't happen fast enough. We can and should all of us be cheering on all of the competitors in this race. The quality and availability of the outcome is all that really matters in the long term. Money comes and goes, but life and health is something to be taken much more seriously.

Now with all of that said, one interesting item to ponder in connection to this round of funding for UNITY is the degree to which it reflects the prospects for cancer therapies rather than the prospects for rejuvenation in the eyes of the funding organizations. In other words, am I being overly optimistic in reading this as a greater understanding of the potential for rejuvenation research in the eyes of the venture community? It might be the case that the portions of the venture community involved here understand the market for working cancer drugs pretty well, and consider that worth investing in, with the possibility of human rejuvenation as an added bonus, but not one that is valued appropriately in their minds. Consider that UNITY Biotechnology has partnered with a noted cancer therapeutics company, and that the use of drugs to inducing apoptosis is a fairly well established approach to building cancer treatments. That is in fact why there even exists a range of apoptosis-inducing drugs and drug candidates for those interested in building senescent cell clearance therapies to pick through. Further, the presence of large numbers of senescent cells does in fact drive cancer, and modulating their effects (or removing them) to temper cancer progress is a topic under exploration in the cancer research community. So a wager on a new vision, or a wager on the present market? It is something to think about.

The genetics of natural variations in human longevity is an interesting subject for study, and there is great enthusiasm for genetics and gene therapy in this day and age, but nonetheless the genetics of longevity has next to no relevance to the future of medicine to treat aging. The results from a great many studies have shown that the contribution of each gene is tiny, and associations between gene variants and aging are only rarely replicated between study groups, suggesting that genetic contributions are (a) highly dependent on one another, and (b) highly dependent on environmental circumstances. The same gene in different human lineages, or the same gene in the same lineage with a different diet or lifestyle, will result in quite different tiny contributions to the pace of aging.

The effects are so small, in fact, that they are probably in many cases statistical or methodological artifacts: change the methodology used to gather or process the data, and different associations show up in the same study population, a point that is well illustrated in the research linked below. Even for the few genes in which variants do show fairly reliable associations, like FOXO3 and APOE, it is still the case that these are tiny effects in the grand scheme of things: perhaps some people have a 10% greater chance of reaching the age of 100 than would otherwise be the case. That would be enough to produce statistically significant enrichment of a gene variant in extremely old individuals. But are the mechanisms involved worth chasing in order to attempt to produce a therapy? How about if a collection of variants doubled the odds of making it to 100? No in either case. Not when there are far greater gains to be achieved via the SENS approach to human rejuvenation or similar strategies based on repair of cell and tissue damage.

In this article we clarify mechanisms of genetic regulation of human aging and longevity traits. The objective of this article is to address the issues in previous research of not reaching a genome-wide level of statistical significance and lack of replication in the studies of independent populations. We performed a genome-wide association study (GWAS) of human life span using different subsets of data from the original Framingham Heart Study (FHS) cohort corresponding to different quality control procedures, and we used one subset of selected genetic variants for further analyses. We used a simulation study to show that this approach to combining data improves the quality of GWAS with FHS longitudinal data to compare average age trajectories of physiological variables in carriers and noncarriers of selected genetic variants.

We used a stochastic process model of human mortality and aging to investigate genetic influence on hidden biomarkers of aging and on dynamic interaction between aging and longevity. We investigated properties of genes related to selected variants and their roles in signaling and metabolic pathways and showed that the use of different quality control procedures results in different sets of genetic variants associated with life span. We selected 24 genetic variants negatively associated with life span and showed that the joint analyses of genetic data at the time of biospecimen collection and follow-up data substantially improved significance of associations of 24 selected single-nucleotide polymorphisms with life span. We also showed that aging-related changes in physiological variables and in hidden biomarkers of aging differ for the groups of carriers and noncarriers of selected variants.

The results of these analyses demonstrated benefits of using biodemographic models and methods in genetic association studies of these traits. Our findings showed that the absence of a large number of genetic variants with deleterious effects may make substantial contribution to exceptional longevity. These effects are dynamically mediated by a number of physiological variables and hidden biomarkers of aging. The results of these research demonstrated benefits of using integrative statistical models of mortality risks in genetic studies of human aging and longevity.

Link: https://dx.doi.org/10.1080/10920277.2016.1178588

Calorie restriction, also known as dietary restriction, improves health and extends life in near all species and lineages tested to date. The evidence for health benefits in humans is solid, those benefits being sizable in comparison to what today's medical technology can achieve for basically healthy people, but the effects on life span are thought to be modest in our case. Calorie restriction makes sweeping changes to near every aspect of cellular metabolism, which means that pinning down how exactly it works under the hood is a challenging problem. In order to fully understand calorie restriction, it is more or less necessary to fully understand cellular metabolism and its relationship with aging. That is an enormous project, one that will likely still be in progress with decades to go when the first SENS rejuvenation therapies are widely available. It is fortunate indeed that full understanding of our biochemistry isn't needed to produce effective medicine, and that researchers can make significant progress given what is known of the root causes of aging today.

For present investigations of calorie restriction, after two decades of increasing investment, many research teams are still at the stage of deleting specific genes and proteins one at a time to find those that are important. Theories have been sketched in at the high level, but at the low level of cellular biochemistry, the gaps in understanding are enormous. The research noted here is an example of the type, but since it involves intestinal function in flies, additional caution is warranted when considering possible relevance to human calorie restriction. In recent years, researchers have demonstrated that intestinal function occupies an central position in the processes of aging in flies, far more so than appears to be the case in higher animals such as mammals.

Dietary restriction (DR), defined as a regime of limited protein intake without malnutrition, leads to increased lifespan and health span in all tested model organisms. One of the conserved fundamental adaptations to DR, or to other low-nutrient conditions such as fasting, involves a metabolic shift toward increased triglyceride (TG) utilization. DR increases the conversion of dietary carbohydrates into lipids, elevates fat storage, and accelerates lipid turnover in flies, which appears to have a profound positive impact on longevity. Drosophila has emerged as an excellent model organism to explore the mechanisms driving diet- and/or age-related changes in lipid metabolism. Importantly, Drosophila provides critical technical advantages that allow characterizing tissue-tissue coordination during metabolic adaptation. While lipids are stored in the fat body and transferred to oenocytes for mobilization, the Drosophila intestine also contributes to lipid synthesis and cholesterol homeostasis. The Drosophila intestine plays a key role in modulating health span by modulation of immune responses, metabolic homeostasis, and stress signaling.

The adult intestine is regenerated by intestinal stem cells (ISCs), which divide to replace functional enterocytes (ECs) and enteroendocrine cells when needed. The intestine is also central to longevity in Drosophila, as gut function rapidly declines in aging flies. Furthermore, in old flies, the ability of the intestine to generate and store lipids is severely compromised, and restoring the adequate metabolic function of this tissue increases health span. The age-related decline in intestinal function in flies is a consequence of complex inflammatory conditions that are associated with increased protein misfolding. How endoplasmic reticulum (ER) stress and ER stress response pathways influence diet- and/or age-related metabolic function of the intestinal epithelium remains unclear.

The ER stress transducer IRE1 triggers one of the three signaling pathways engaged by ER stress. Interestingly, IRE1 also influences lipid homeostasis. IRE1 is also required for S6K- and HIF-1-mediated lifespan extension under DR in C. elegans, though the mechanisms mediating this effect remain unclear. During ER stress, IRE1 dimerizes and splices the mRNA of XBP1, leading to translation of a functional transcription factor that induces genes involved in ER biogenesis, protein folding, and degradation to restore ER homeostasis. The role of IRE1/XBP1 in the regulation of lipid homeostasis has not been explored in the context of a DR intervention or during conditions of obligatory lipid recruitment, such as prolonged fasting/starvation. Here, we identify IRE1 as a player in DR-induced lifespan extension in flies. Our data suggest that IRE1 is required for the metabolic shift toward elevated TG turnover occurring during DR and that the absence of IRE1 is detrimental under this dietary intervention. Moreover, we identify the transcription factor Sugarbabe as a downstream target of the IRE1/XBP1 module that is required for increased lipid turnover under DR. Our results provide insights into physiological mechanisms that link tissue-specific metabolic adaptation to lifespan extension under DR conditions.

Link: http://dx.doi.org/10.1016/j.celrep.2016.10.003

The understanding that senescent cells existed and were important in human health and aging started sometime around the discovery and subsequent exploration of the Hayflick limit to cellular replication, in the 1960s. By the time that the SENS rejuvenation research proposals were first formalized, more than three decades later, a little after the turn of the century, the research community had a much better understanding of cellular senescence as a phenomenon, as well as a good deal of indirect evidence to show that (a) senescent cells accumulated with age, and (b) their presence contributed to age-related disease and dysfunction. That weight of evidence is why senescent cell clearance was included in the SENS proposals for rejuvenation therapies from the outset. In recent years, more direct evidence has been established, demonstrations of extended life and improved health in mice resulting from the targeted destruction of senescent cells. A range of methodologies are available to achieve this goal, and many of them are presently heading in the direction of clinical availability. Senescent cell clearance will likely be the first broadly available, actual, real rejuvenation treatment - a way to turn back one narrow part of the aging process.

Senescent cells cause harm through what is known as the senescence-associated secretory phenotype (SASP), the secretion of signals that spur inflammation, tissue modeling, and alterations in cellular behavior. Even a small number of senescent cells, say 1% of the cells in an organ, can alter tissue structure and the behavior of normal cells to a great enough degree to produce disease symptoms. Since there are so few senescent cells, however, their destruction is a feasible project: if removal can be accomplished in a selective manner, it will not greatly harm an organ. Some researchers are more interested in altering SASP, however, trying to minimize or block the damaging factors while leaving senescent cells present. This seems to me to be an inferior approach, one that will require a lot more work, and which is far less developed and understood than efforts to destroy these cells at the present time. The SASP is a very complex set of signals and molecules, and if a research group spends years working on removing one item from that mix, what then of all the others? Further, a SASP suppression therapy is something that would have to be taken as medicine on a continuing basis, whereas destruction of senescent cells can happen as a single treatment as needed, say once every few years.

Setting aside debates over methodologies and treatments, it is certainly the case that initial results from clearance of senescent cells have invigorated the field, pulling in greater funding and effort. It wasn't so many years ago that the few research groups involved in this work were struggling to raise any meaningful funding for studies in mice. Now, however, we're going to be seeing a whole lot more work in the years ahead on the characterization of senescent cells, improved methods of detection and targeting, and better understanding how and where these unwanted cells are contributing to specific age-related conditions. The research results linked below fall into the latter category: the researchers improve the understanding of the way in which diabetes produces blindness by showing that cellular senescence is a bridging mechanism in the retina. The metabolic alterations of diabetes produce a loss of oxygenation in the retina, which in turn produces greater numbers of senescent cells, and the SASP from those cells then causes disarray in retinal structure: inflammation and pathological growth of blood vessels that destroys the machinery of sight. It is an interesting point to consider that a range of diseases, age-related and otherwise, may provoke greater cellular senescence as a part of the progression of pathology, even though cellular senescence is not one of the main root causes of these condition. In this and similar ways all of the fundamental forms of cell and tissue damage that cause aging are linked together, feeding from one another, making up a web of interacting forms of damage and consequences.

Understanding retinopathy: Senescence-associated secretory phenotype contributes to pathological angiogenesis

Diabetic retinopathy is the most prominent complication of diabetes and the leading cause of blindness in working age individuals. The ability to control and cure this disease has been limited so far. But a study sheds new understanding on the mechanisms of the disease as it uncovered a program of accelerated aging of the neurons, blood vessels and immune cells of the retina in areas where blood vessels had been damaged. Researchers found that cells of the retina that are cut off from their main source of oxygen and nutrients during disease are resilient and do not die. Instead, they enter a state of cellular senescence where they are dormant yet start producing a series of factors that contribute the blinding disease.

The exciting work lead to the successful mapping and identification of the molecules that are activated during this process of premature aging. Interfering with the early cellular aging process occurring in mouse models of retinopathy with currently available and novel drugs resulted in improved regeneration of blood vessels within the retina and reduced retinal damage. "Currently available treatments for diabetic retinopathy are either invasive or present adverse side effects when used for long term regimens. Our study does not identify a cure, but by mapping out the events that lead to premature senescence in retinopathy, we are now able to consider novel therapeutic interventions to slow down the disease process and preserve vision."

Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy

Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a mouse model of ischemic retinopathy, we found that hypoxic regions of the retina showed only modest rates of apoptosis despite severely compromised metabolic supply. Using transcriptomic analysis and inducible loss-of-function genetics, we demonstrated that ischemic retinal cells instead engage the endoplasmic reticulum stress inositol-requiring enzyme 1α (IRE1α) pathway that, through its endoribonuclease activity, induces a state of senescence in which cells adopt a senescence-associated secretory phenotype (SASP).

We also detected SASP-associated cytokines (plasminogen activator inhibitor 1, interleukin-6, interleukin-8, and vascular endothelial growth factor) in the vitreous humor of patients suffering from proliferative diabetic retinopathy. Therapeutic inhibition of the SASP through intravitreal delivery of metformin or interference with effectors of senescence (semaphorin 3A or IRE1α) in mice reduced destructive retinal neovascularization in vivo. We conclude that the SASP contributes to pathological vessel growth, with ischemic retinal cells becoming prematurely senescent and secreting inflammatory cytokines that drive paracrine senescence, exacerbate destructive angiogenesis, and hinder reparative vascular regeneration. Reversal of this process may be therapeutically beneficial.

One of the proximate causes of osteoporosis, age-related weakening of bone, is that the balance between the constantly ongoing processes of bone formation and bone absorption becomes disrupted. There is too little formation and too much absorption in older people when compared to the activities that take place in younger bone tissue. Thus one approach to the production of compensatory therapies for this condition is to tinker with this balance in some way, push it back in the direction of more creation than destruction. There are a range of not-so-great present treatments that work along these lines, and a fair breadth of research aimed at producing much better results via the same sort of adjustment. As an example of the type, scientists here discuss one recent promising discovery, currently in the early stages of exploration:

While one currently available treatment - injections of a fragment of parathyroid hormone (PTH) - can stimulate bone formation, it also stimulates the resorption of bone. "We wanted to understand how PTH signaling affects gene expression within bone cells, particularly in osteocytes, which are buried deep within bone itself. By identifying an essential step in that signaling cascade - turning off an enzyme called SIK2 - our findings shed light on a new mechanism of PTH signaling in bone and identify a potential new treatment for osteoporosis."

Most currently available osteoporosis drugs work by slowing down the destruction of bone, but their effectiveness is limited and long-term use can occasionally have side effects. The PTH-based drug teriparatide increases bone density; but in addition to its also accelerating bone resorption, the fact that teriparatide must be administered by daily injection discourages many patients from using it to treat a symptom-free condition. To better understand the mechanisms underlying the effects of PTH on osteocytes, the research team focused on a gene called SOST, which inhibits bone formation and is known to be suppressed by PTH. The team's experiments first showed that PTH suppressed SOST expression by means of transcription-regulating enzymes called HDACs - specifically HDAC4 and HDAC5 - activation of which previous research had indicated was regulated by enzymes called SIKs. The researchers confirmed that PTH signaling turns off the activity of the SIK2 enzyme.

A series of experiments with small-molecule SIK inhibitors revealed that they regulated not only the expression of SOST but also of other PTH target genes such as RANKL, a molecule that stimulates bone resorption. The research team then showed that an SIK2-specific inhibitor called YKL-05-093 mimicked the effects of PTH on gene expression both in cells and in mice. Since repeat dosing with YKL-05-093 had adverse effects on mice, the researchers tested a closely related compound YKL-05-099 and found that daily doses safely stimulated bone formation in male mice. The team was surprised to find that YKL-05-099 also reduced levels of osteoclasts - cells responsible for the breakdown of bone - indicating that it had the desired dual effect of stimulating bone formation and suppressing bone resorption. "We don't completely understand why YKL-05-099 reduces osteoclasts, but we think the combination could be very useful therapeutically. In addition to concentrating on understanding how this compound inhibits osteoclasts - which may lead us to develop even more specific SIK2 inhibitors - we also need to see if it increases bone mass in an animal model of postmenopausal osteoporosis, such as older female mice that have had their ovaries removed."

Link: http://www.massgeneral.org/about/pressrelease.aspx?id=2004

The life spans of lower animals, such as the flies and the nematode worms commonly used in exploratory studies of the biochemistry of aging, are very plastic. They can be considerably lengthened by environmental circumstances and altered metabolism that have very little effect on longer-lived mammals. Where we have direct comparisons that are easy to make, such as for calorie restriction and growth hormone receptor dysfunction, we know that while mice with those circumstances life half again as long as usual, we humans certainly don't. Evolution has made short lives much more reactive to circumstances than long lives. So when you read about life extension in worms or flies of 10% or 30% or even a doubling or more, bear in mind that, when based on altered states of metabolism, this will not translate to any meaningful extension of human life. The degree of extension isn't anywhere near as important as the methodology of extension when it comes to whether or not it can produce usefully large effects on human longevity. This is made particularly clear by the fact that, say, aspirin produces significant life extension in lower animals. So too does vitamin D, as demonstrated here, and I think that most people are fairly comfortable acknowledging that life-long intake of either aspirin or vitamin D does not have profound effects on human longevity - if it did give us a third again as much life, that would certainly have been noted by now.

Vitamin D has much wider effects regulating calcium absorption and promoting bone growth - at least in the nematode worm, C. elegans. Research shows that vitamin D works through genes known to influence longevity and impacts processes associated with many human age-related diseases. The study may explain why vitamin D deficiency has been linked to breast, colon and prostate cancer, as well as obesity, heart disease and depression. "Vitamin D engaged with known longevity genes - it extended median lifespan by 33 percent and slowed the aging-related misfolding of hundreds of proteins in the worm. Our findings provide a real connection between aging and disease and give clinicians and other researchers an opportunity to look at vitamin D in a much larger context."

The study shines a light on protein homeostasis, the ability of proteins to maintain their shape and function over time. It's a balancing act that goes haywire with normal aging - often resulting in the accumulation of toxic insoluble protein aggregates implicated in a number of conditions, including Alzheimer's, Parkinson's and Huntington's diseases, as well as type 2 diabetes and some forms of heart disease. "Vitamin D3, which is converted into the active form of vitamin D, suppressed protein insolubility in the worm and prevented the toxicity caused by human beta-amyloid which is associated with Alzheimer's disease. Given that aging processes are thought to be similar between the worm and mammals, including humans, it makes sense that the action of vitamin D would be conserved across species as well. Vitamin D3 reduced the age-dependent formation of insoluble proteins across a wide range of predicted functions and cellular compartments, supporting our hypothesis that decreasing protein insolubility can prolong lifespan. We've been looking for a disease to associate with vitamin D other than rickets for many years and we haven't come up with any strong evidence. But if it's a more global marker of health or longevity as this paper suggests, that's a paradigm shift. Now we're talking about something very different and exciting."

Given adequate funding, researchers plan to test vitamin D in mice to measure and determine how it affects aging, disease and function - and hope that clinical trials in humans will go after the same measurements. "Maybe if you're deficient in vitamin D, you're aging faster. Maybe that's why you're more susceptible to cancer or Alzheimer's. Given that we had responses to vitamin D in an organism that has no bone suggests that there are other key roles, not related to bone, that it plays in living organisms."

Link: http://buckinstitute.org/buck-news/new-look-vitamin-d-challenges-current-view-its-benefits

The research and development community is certainly showing a great deal of interest in senescent cell clearance these days: this is one of the first working approaches to rejuvenation via reversal of a fundamental cause of aging, and it is very gratifying to see it start to take off following a series of fairly robust positive results on health and life span in mouse studies. Things are going so well that the SENS Research Foundation has of late been able to step back from this field and focus attention and resources on other parts of the rejuvenation biotechnology portfolio. For senescent cell research, things are becoming busier with each passing quarter. Even setting aside the groups that we won't hear about until they are much further along, meaning the more adventurous folk inside Big Pharma entities who have convinced their bosses to put resources into evaluating the present catalog of apoptosis-inducing drugs, there is a brace of dedicated senescent cell clearance startup companies: Oisin Biotechnologies, UNITY Biotechnology, SIWA Therapeutics, and at this point probably one or two others in the works that I'm as yet unfamiliar with. On the non-profit side, there is the Major Mouse Testing Program, and now the newcomers at CellAge:

CellAge: Your Future is Young

Imagine a future where people can enjoy their 80s in the same way they enjoyed their 20s. A future where people no longer suffer from age-related diseases. A future where we all are given more time to spend with our loved ones. We are working to make this future your future. CellAge is a dynamic startup aiming to increase human healthspan and reduce the incidence of age-related diseases by helping human body destroy aged cells. Our breakthrough technology concept harvests the promises from synthetic biology and recent findings in ageing research to deliver novel products and therapies. Our products will help to advance ageing research even further and help people live healthier lives.

Our society as a whole is getting older and as a consequence incidences of age-related diseases, such as cancer, cardiovascular diseases and osteoarthritis, are increasing at an alarming rate. Furthermore, detrimental effects of aging not only decreases the quality of life in old age but is an ever-expanding and unsustainable drain on private and national resources for health and social care. Despite these enormous problems, there are very few effective products which address these and related challenges. Recently, a new target, which could help tackle many of the mentioned problems, has been validated by a number of in vivo and in vitro studies. It has been shown that senescent cells (cells which have ceased to replicate due to stress or replicative capacity exhaustion) are linked to a number of diseases and their removal increases mouse healthspan (period of life free of serious diseases). The concept of our technology is to increase patient's health span and life expectancy by removing aged cells, also known as senescent cells, by use of combinatorially targeted senolytic gene therapy. Large number of biomarkers used in our targeting will not only allow removal of significant proportions of senescent cells but also has low off-target effects, sparing other healthy cells which sometimes closely resemble aged cells.

One of the great things about the non-profit side of the house is that the people involved feel far less constrained to temper their vision when speaking in public. This field of research is absolutely all about increasing life span as well as health span, for all that this part of the goal tends to become less visible and less vocal the more money that arrives to support it. The more that people in the scientific and biotechnology communities talk about this, the more it legitimizes oingoing work on ending aging in the eyes of those who still have doubts. Rhetoric and tone are important! They set the scene for future growth and fundraising in this industry. The CellAge principals orbit in the same portion of the scientific community as the Major Mouse Testing Program scientist Alexandra Stolzing, who is at present running a senescent cell clearance study that we all helped to crowdfund. You might take a look at this coauthored review paper from earlier this year on the topic of senescent cell biomarkers for an idea as to the CellAge areas of interest, which clearly include improving on the present methods used to identify and categorize senescent cells.

Biomarkers to identify and isolate senescent cells

Aging is the main risk factor for many degenerative diseases and declining health. Senescent cells are part of the underlying mechanism for time-dependent tissue dysfunction. These cells can negatively affect neighbouring cells through an altered secretory phenotype: the senescence-associated secretory phenotype (SASP). The SASP induces senescence in healthy cells, promotes tumour formation and progression, and contributes to other age-related diseases such as atherosclerosis, immune-senescence and neurodegeneration. Removal of senescent cells was recently demonstrated to delay age-related degeneration and extend lifespan.

To better understand cell aging and to reap the benefits of senescent cell removal, it is necessary to have a reliable biomarker to identify these cells. Following an introduction to cellular senescence, we discuss several classes of biomarkers in the context of their utility in identifying and/or removing senescent cells from tissues. Although senescence can be induced by a variety of stimuli, senescent cells share some characteristics that enable their identification both in vitro and in vivo. Nevertheless, it may prove difficult to identify a single biomarker capable of distinguishing senescence in all cell types. Therefore, this will not be a comprehensive review of all senescence biomarkers but rather an outlook on technologies and markers that are most suitable to identify and isolate senescent cells.

Researchers here report on a study in mice that suggests high blood cholesterol levels contribute to the progression of osteoarthritis, a degenerative condition of bone and cartilage in the joints. It is well known that high cholesterol is bad for health in a variety of other ways, and is one of the mechanisms linking conditions like obesity, metabolic syndrome, and diabetes to higher mortality rates. It speeds progression of atherosclerosis, for example, in which fatty deposits build up in blood vessels. The association with osteoarthritis is fairly new, however, and the researchers here suggest that mitochondrial dysfunction and oxidative stress are the mechanisms of interest in this relationship.

The contribution of metabolic factors on the severity of osteoarthritis (OA) is not fully appreciated. This study aimed to define the effects of hypercholesterolemia on the progression of OA. Apolipoprotein E-deficient (ApoE-/-) mice and diet-induced hypercholesterolemic (DIHC) rats were used to explore the effects of hypercholesterolemia on the progression of OA. Both models exhibited OA-like changes, characterized primarily by a loss of proteoglycans, collagen and aggrecan degradation, osteophyte formation, changes to subchondral bone architecture, and cartilage degradation. Surgical destabilization of the knees resulted in a dramatic increase of degradative OA symptoms in animals fed a high-cholesterol diet compared with controls. Clinically relevant doses of free cholesterol resulted in mitochondrial dysfunction, overproduction of reactive oxygen species (ROS), and increased expression of degenerative and hypertrophic markers in chondrocytes and breakdown of the cartilage extracellular matrix.

We showed that the severity of diet-induced OA changes could be attenuated by treatment with both atorvastatin and a mitochondrial targeting antioxidant. The protective effects of the mitochondrial targeting antioxidant were associated with suppression of oxidative damage to chondrocytes and restoration of extracellular matrix homeostasis of the articular chondrocytes. In summary, our data show that hypercholesterolemia precipitates OA progression by mitochondrial dysfunction in chondrocytes, in part by increasing ROS production and apoptosis. By addressing the mitochondrial dysfunction using antioxidants, we were able attenuate the OA progression in our animal models. This approach may form the basis for novel treatment options for this OA risk group in humans.

Link: http://dx.doi.org/10.1096/fj.201600600R

Researchers have for some years now studied the biochemistry and genetics of exceptional human longevity in a long-lived population of Ashkenazi Jews. In the recent paper noted here, the authors find an association between IGF-1, which is well-studied in the context of aging and natural variations in life span, and cognitive ability in the elderly. In this context, it is interesting to look back at the results of past studies on IGF-1, such as the demonstration that lower levels predict survival in women only, and observations of increased mouse life span due to lowered IGF-1. If you want to lower IGF-1 yourself, the best way to go about it is to practice calorie restriction for the long-term. Calorie restriction is known to improve health and longevity in a range of species, though it is far from clear as to how much of its effects are driven by IGF-1 levels.

Cognitive decline is a highly prevalent condition among the aging population that causes significant morbidity in the elderly and results in rising expense for the healthcare system. Although aging is a major risk factor for cognitive impairment, some individuals with exceptional longevity demonstrate delayed onset of dementia by as much as 13 years, with many not manifesting it at all. The fact that individuals with exceptional longevity possess factors that allow them to delay or avoid age related diseases make them a particularly attractive model for the study of healthy aging. One of the features identified in individuals with exceptional longevity was partial resistance to insulin-like growth factor-1 (IGF-I) resulting from a mutation in the IGF-I receptor gene. Subsequent studies have shown that lower IGF-I and IGF-I/IGF binding protein-3 (IGFBP-3) ratio are associated with extended survival in nonagenarians and better performance at activities of daily living.

Despite evidence from humans and experimental models that reduced circulating IGF-I may promote longevity and healthy lifespan, the role of peripheral IGF-I in cognition and muscle function remains unresolved. Several cross-sectional and prospective studies linked lower IGF-I to poorer cognitive function, as well as higher risk for mild cognitive impairment and Alzheimer's disease. On the other hand, a recent prospective study in older men associated IGF-I levels in the lowest quintile with less cognitive decline. Adding to this debate are the differences observed between the sexes. For example, in the Rancho-Bernardo cohort higher IGF-I was associated with better cognitive function only among men, but not women. With the understanding that healthspan extension is an important determinant of healthy aging, we set out to test the hypothesis that individuals with exceptional longevity and low circulating IGF-I levels not only exhibit extended survival, but are also healthier in cognitive and muscle function domains. Furthermore, given our prior findings that low IGF-I benefited females preferentially, we tested whether this association is sex-specific in relation to these other clinical outcomes.

IGF-I levels and cognitive assessment were available for 203 participants, 163 female and 40 male, median age 97.2 years and 97.5 years, respectively. Measured levels of IGF-I were not found to be significantly different between males and females; however, the IGF-I/IGFBP-3 ratio was significantly lower in females compared to males. Lower serum IGF-I levels were found to be associated with better cognitive function in females with exceptional longevity, but not in males. Furthermore, no detriment to muscle mass or function was observed in this cohort among women or men with IGF-I levels within the lowest tertile of IGF-I compared to individuals with IGF-I in the upper two tertiles. Our study is the first to demonstrate a gender specific negative association between IGF-I and cognition in the extremely elderly. This supports previous data showing that lower IGF-I may have protective effects in aging that may be gender specific. No association was found between tertiles of circulating IGF-I and muscle mass or muscle function in our cohorts. These results suggest that circulating IGF-I plays a minimal role in maintaining muscle mass or strength in individuals with exceptional longevity.

Link: http://dx.doi.org/10.18632/aging.101063

The 2016 year-end SENS rejuvenation research fundraiser starts next week, on November 1st. For those who give to charitable causes at the end of the year, which turns out to be a fair number of people, this is a chance to help speed progress towards therapies that can address the root causes of degenerative aging, that can postpone and turn back age-related disease, and that can greatly extend healthy life span. This is not a pipe dream! These therapies, as well the required research and development programs, are envisaged in great detail, and the first of them are already in the earliest stages of commercial development. To all of you reading this, I ask that on November 1st you show your support for continued progress by signing up as a SENS Patron - pledge a recurring monthly donation to the SENS Research Foundation. When you do, Josh Triplett and Fight Aging! will match a full year of your donations from the challenge fund we have provided.

This is a time to focus more on longer term support rather than individual fundraisers. Over the last eighteen months, a fair number of long-term projects have started, of great importance to the future of our health and longevity. These are seeds that will take a few years - or perhaps five years - to come to fruition. To pick just a few examples: the Major Mouse Testing Program got underway with their first crowdfunding campaign; companies like Oisin Biotechnologies and UNITY Biotechnology have launched to bring to the clinic their varieties of senescent cell clearance treatment, where senescent cell accumulation is one of the seven forms of fundamental damage outlined in the SENS research agenda; Ichor Therapeutics is turning SENS Research Foundation work into a therapy for macular degeneration; the SENS Research Foundation itself launched Project|21 to target the launch of further therapies by 2021, and an initial $10 million was pledged to this goal. That isn't all. There is more going on out there in the biotechnology and advocacy communities, as new groups become involved in the quest to bring an end to the pain, suffering, and disease of aging. Continuing progress in research, as well as a growing awareness of the prospects for therapies to treat the causes of aging, are building upon one another. This is a time of transformation, in which great changes lie just ahead in the field of aging research.

None of this just happened. We helped to make this happen, all of us! For years our community has raised funds and donated to support SENS rejuvenation research efforts. We've reached out to persuade and educate people - every such act counts. We have been the lantern that lights the way to attract the support of high net worth donors and established sources of institutional funding. Organizations such as the SENS Research Foundation and Methuselah Foundation have used our donations wisely to produce important progress, both in the sciences and in organizing a research and development community for rejuvenation biotechnology that encompasses both academia and industry. Together we have accomplished a great deal, and this is the time to pledge continued support for the longer term. Now that the wheel is starting to turn, our continued support will aid the years-long work of turning promising starts into therapies widely available in the clinic. The work that has been accomplished to date makes up the tip of the spear, the start of the avalanche, and there is much more ahead. Yet we're well past the hardest point in the curve of bootstrapping a new field of medicine, back when a lot of money was needed to make a small amount of progress, and when it was very hard to find new supporters who saw the potential for treating aging as a medical condition. The funds we donate to the SENS Research Foundation today can now produce greater gains: allies are easier to find, the technology has improved, and more people are willing to listen.

So what are you waiting for? You can make a difference to the future of health and longevity, not just for yourself, but for everyone else as well. You can speed up progress towards the end of aging as a cause of disability and death. This November, become a SENS Patron.

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

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

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.

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/

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

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.

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 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

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.

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

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

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.

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/

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

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.

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

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

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.

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/

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

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.

There is some evidence for the deposition of misfolded proteins into solid structures known as amyloid to contribute to the development of arthritis. Amyloid is better known for its role in Alzheimer's disease, but there are a number of types of amyloid, each a different misfolded protein, and for many of these the the relationships to age-related disease are still tentative or only partially explored. In recent years transthyretin amyloid has been recognized as important in heart disease and a range of other conditions, for example, but these are quite new discoveries despite the fact that the existence of this type of amyloid has been recognized for a long time. Still, amyloids are one of the characteristic differences between old tissue and young tissue: the research community should be aiming at the development of safe methods of removal for all of them, even in advance of a comprehensive understanding of how exactly they cause harm.

Amyloidosis is a protein conformational disorder in which amyloid fibrils accumulate in the extracellular space and induce organ dysfunction. Recently, two different amyloidogenic proteins, transthyretin (TTR) and apolipoprotein A-I (Apo A-I), were identified in amyloid deposits in knee joints in patients with knee osteoarthritis (OA). However, clinicopathological differences related to those two kinds of amyloid deposits in the knee joint remain to be clarified. Here, we investigated the clinicopathological features related to these knee amyloid deposits associated with knee OA and the biochemical characteristics of the amyloid deposits.

We found that all of our patients with knee OA had amyloid deposits in the knee joints, especially in the meniscus, and those deposits were primarily derived from TTR and/or Apo A-I. Some patients with knee OA, however, had unclassified amyloid deposits. One of our interesting observations concerned the different effects of aging on each type of amyloid formed. The frequency of formation of ATTR deposits clearly increased with age, but that of AApo A-I deposits decreased. Furthermore, we found that ∼16% of patients with knee OA developed ATTR/AApo A-I double deposits in the meniscus. Amyloid deposition may therefore be a common histopathological feature associated with knee OA. Also, aging may induce ATTR formation in the knee joint in elderly patients with knee OA, whereas AApo A-I formation may be inversely correlated with age.

Link: http://dx.doi.org/10.3109/13506129.2015.1115758

SIWA Therapeutics is one of a number of companies that have been around for some years, working away at the problem of senescent cells and their contribution to age-related disease at a slow pace. It is probably the case that some of these initiatives will raise new funding and be invigorated as a result of Oisin Biotechnologies and UNITY Biotechnology entering this area, as well as the recent research results showing life extension and other benefits in mice as a result of senescent cell clearance. The principals at SIWA, however, are in this release emphasizing cancer treatment rather than rejuvenation or slowing the pace of aging. This makes sense from a business perspective if you consider where most of the money is in medical research and development. Aging research has always been the poor cousin in comparison to the better established institutions. While effective treatments for aging will be massively more lucrative than effective treatments for cancer, as the target market is pretty much every individual over the age of 30, it requires investment to build those treatments. That is easier to obtain if cancer is involved.

SIWA Therapeutics today reports results of its recent in vivo preclinical study which showed that its monoclonal antibody for removing senescent cells, SIWA 318, significantly inhibited tumor metastasis. Importantly, there were no observable adverse effects from the treatment and no increase in tumor growth over the control group. "These results suggest that the removal of senescent cells may become a therapeutic approach against metastatic cancers. Based on data we and the rest of the scientific community have generated over the last several years, the evidence is clearly mounting that senescent cells are causally implicated in the manifestation and progression of many diseases including cancer metastasis."

The study was done in a BALBc 4T1 metastatic breast cancer mouse model. Mice were grouped to receive 5 ug/g, 10 ug/g, or saline injections two times daily for three weeks. A fourth group received no treatment. At 23 days, when the study ended, the 10ug/g group showed 30% fewer metastatic lung foci compared to the control. The new data are consistent with earlier results in which we showed that SIWA 318 significantly increased muscle mass in normally aged CD-1 mice as well as significantly reducing the level of p16INK4a expression, a validated biomarker of senescent cells. Based on the results SIWA has generated to date, the company is optimizing a humanized form of SIWA 318, and planning additional preclinical studies.

Link: http://www.siwatherapeutics.com/siwa-announces-data

Use of ultrasound as a tool is commonplace in medicine these days, with applications ranging from tissue imaging to breaking up dental plaque to destruction of kidney stones. Many of the effects, actual and potential, at the cellular level are still being explored, however, and they range from the merely intriguing to the very promising. For example, ultrasound appears to speed wound healing in aged skin. More relevant to the research presented here, ultrasound applied to the brain makes the blood-brain barrier leak a little, enough to spur the immune system into greater productive activity. In mice this has been shown to improve cognitive function as well as produce some clearance of the metabolic waste known as β-amyloid that is associated with Alzheimer's disease.

There are lengthy and poorly mapped chains of cause and effect spanning the gap between the application of ultrasound and end results such as amyloid clearance. Which mechanisms are relevant, and how exactly the ultrasound produces the end results of interest, is a line of work that remains very open to hypothesis, competing evidence, and debate. If we consider the effects on the blood brain barrier noted above, it is worth bearing in mind that growing age-related dysfunction and leakage in this structure is thought by many in the field to be a part of the problem in the aging brain. The purpose of the barrier, which lines blood vessels in the brain, is to keep the environment of the brain insulated from that of the rest of the body. Leakage encourages greater levels of neural inflammation and contributes to early development of Alzheimer's disease. So how is it that brief disruption can be as beneficial as long-term disruption is harmful? Nothing is simple when it comes to cellular biochemistry and the progression of aging.

The question of mechanisms is particular pronounced in the research linked below, in which researchers examine the fine structures of dendrites in one area of the brain and how those structures change over time. Dendrites are a part of the structure of the synapses that link neurons into networks. They are decorated with spines that some research suggests are the form in which the data of memory is encoded in the brain. Synapses, dendrites, and spines all change over time, and in characteristic ways with aging. With the application of ultrasound, this age-related change appears to be reduced, but there is no shortage of places to start fishing for the reasons why that might be the case. One could build a career simply trying to fill in the gaps in this picture.

Research finds that ultrasound slows brain ageing

Research shows that scanning ultrasound prevented degeneration of cells in the brains of healthy mice. "We found that, far from causing any damage to the healthy brain, ultrasound treatments may in fact have potential beneficial effects for healthy ageing brains. In a normal brain the structure of neuronal cells in the hippocampus, a brain area extremely important for learning and memory, is reduced with age. What we found is that treating mice with scanning ultrasound prevents this reduction in structure, which suggests that by using this approach we can keep the structure of the brain younger as we get older. We are currently conducting experiments to see if this preservation of the brain cell structure will ameliorate reductions in learning and memory that occur with ageing." In the next stage of research, the team will test the effect of ultrasound on the brain structure and function of older mice.

Scanning Ultrasound (SUS) Causes No Changes to Neuronal Excitability and Prevents Age-Related Reductions in Hippocampal CA1 Dendritic Structure in Wild-Type Mice

Recently, our group has reported that repeated scanning ultrasound (SUS) treatments reduced the amyloid plaque pathology in a transgenic mouse model of Alzheimer's disease (AD) and improved hippocampal-dependent spatial memory performance by activating brain-resident microglia. In this approach, ultrasound was combined with microbubbles to disrupt the blood-brain barrier (BBB) which is achieved by mechanical interactions between the microbubbles and the blood vessel wall as pulsed focused ultrasound is applied, resulting in cycles of compression and rarefaction of the microbubbles. This leads to a transient disruption of tight junctions and the uptake of blood-borne factors by the brain, which are likely to have a role in the activation of microglia that were found to take up amyloid into their lysosomes.

However, the short- and long-term effects of SUS treatment on individual neuronal action potential (AP) firing and dendritic morphology have not been investigated. To address this issue, we evaluated the physiological effects of both a single and multiple SUS treatments on short- and long-term neuronal excitability, dendritic morphology and dendritic spine densities in the CA1 region of the hippocampus of wild-type mice. This allowed us to determine the effect of different SUS treatments in a non-disease state system before eventually moving to a more complicated disease model, where alterations in neuronal function are already present at an early age. For example, reductions in dendritic spine density, AP firing, synaptic activity and long-term potentiation (LTP) have all been reported to occur in amyloid-depositing mouse models of AD.

In our study using wild-type mice, we found that the different SUS treatment regimes had no deleterious effect on neuronal function or morphology. In addition to this we made the interesting observation that repeated SUS treatments prevented reductions in the dendritic complexity and length of CA1 pyramidal neurons that occur in age-matched sham-treated wild-type mice over the course of three months, while a reduction in dendritic spine density was not halted. Taken together, these findings suggest that multiple SUS treatments ameliorate a reduction in the total number of dendritic spines per neuron. A more extensive follow-up study will determine, whether SUS treatments improves cognition in aging mice and what the underlying mechanism is of such an effect.

Age-associated reductions in the structure of neuronal dendritic trees have previously been reported in a range of brain areas and species. However, our understanding of changes in dendritic tree arborization in the hippocampus is less advanced, where both increases and decreases in CA1 pyramidal dendritic length and complexity have previously been reported. While a number of differences exist between these reports and the current work, perhaps the most important is the duration of ageing over which changes in dendritic tree structure was quantified (approximately 1.5 years versus 3 months in the current study). This is a limitation of the current study when evaluating changes in dendritic structure associated with ageing. Further experimentation will be required to assess changes in dendritic tree structure over longer time periods. Despite this, it is evident that multiple SUS treatments are able to prevent reductions in dendritic structure.

Also, the question of how SUS preserves dendritic structure remains to be determined. One possibility is that microglia may play a role, because SUS treatment has previously been reported to activate this cell-type in mouse models as well as in wild-type mice. Microglia constantly probe their local environment and secrete factors that alter neuronal signalling. During activation they can also modify synaptic connections, the key mediators of learning and memory, by increasing the expression of neurotrophins such as brain-derived neurotrophic factor (BDNF). In fact, a recent study has reported that microglia mediate synapse loss at an early time-point in Alzheimer's disease mouse models. One possible mechanism for the neurotrophic effect of SUS may therefore be the delivery of endogenously circulating neurotrophic factors from the blood to the brain. Furthermore, ultrasound waves by themselves, without the need for BBB opening, may also contribute to the observed preservation of dendritic structure, as increased BDNF expression has been reported following ultrasound application. Other neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) have also been linked to improve memory performance in rats following ultrasound treatment.

Researchers here present a potential way to slow the progression of heart failure. They have identified one of the proximate causes of pathology, a change in the gene expression of ANGPTL2 that accompanies aging or damage in heart tissue. Suppressing this signal improves function and slows the decline. This, like many of today's potential therapeutic approaches, is compensatory in nature. It doesn't address the underlying reasons for the identified change, but seeks to adjust the behavior of damaged tissues to be more youthful despite that damage. It cannot fix the problem, it can only slow down the inevitable; arguably other approaches that do address the root cause damage should have a higher priority.

Heart failure occurs when heart function is reduced making it no longer able to pump enough blood to body. Patients with severe heart failure have a very poor prognosis, with a five-year survival rate of 50-60% despite advances in modern medicine and medical technology. Researchers found that cardiac muscle cells that were from heart failure patients, were aged cells, or were under the stress of high blood pressure had increased production and secretion of the protein ANGPTL2. The research team previously reported that excessive secretion of the ANGPTL2 protein by aged or stressed cells causes chronic inflammation and promotes the development of lifestyle-related diseases such as atherosclerotic disease, obesity, diabetes, or cancer. ANGPTL2 is also related to heart failure. Excessive ANGPTL2 secretions by cardiac muscle cells impair important functions, such as intracellular calcium concentration regulation and energy production, that help maintain the contractile force of the heart. On the other hand, moderate exercise reduces the production of ANGPTL2 in cardiac muscle cells which helps keep the heart healthy.

"We found that ANGPLT2 is significantly involved in heart failure. Among knockout mice that could not produce the protein, the development of heart failure was suppressed in a manner similar to moderate exercise. Furthermore, we genetically engineered a non-pathogenic virus which was designed to infect cardiac muscle cells and reproduce a special RNA molecule that inhibited the production of the ANGPTL2 protein." This new gene therapy in the heart failure mouse model was successful in suppressing ANGPTL2 production in cardiac muscle cells thereby reducing the pathological progression of heart failure. Additionally, in cardiac muscle cells that were differentiated from human induced pluripotent stem cells, the suppression of ANGPYL2 promoted calcium concentration regulation and enhanced energy production. It is considered that the newly developed gene therapy may also be effective for human heart failure patients. Current treatment for heart failure is mainly symptomatic. The gene therapy developed here is expected to become a fundamental treatment that corrects the mechanism of reduced heart function itself.

Link: https://www.eurekalert.org/pub_releases/2016-10/ku-dag101116.php

Lifespan is length of life, while healthspan is length of healthy life. Are they strongly coupled? Is it possible to arrive at treatments that greatly alter one without much altering the other? A related concept is something that many researchers believe (or at least claim in public) that they are aiming for: compression of morbidity, in which healthspan is extended without lifespan being extended. It is hard to say how much of that is driven by the desire to avoid talking about life extension in the context of research, however, versus an earnest belief in the plausibility of the outcome. On the other side of that coin, it does seems plausible that the present bad strategy of trying to compensate for outcomes or ameliorate proximate causes of age-related disease - rather than address their root causes, the cell and tissue damage that causes aging - could be acting to marginally extend lifespan without extending healthspan. These are approaches that, at best, make suffering a chronic age-related condition a somewhat slower, somewhat less damaging process. It is a very expensive path to small gains, however. Keeping a damaged machine running without repairing that damage is a challenging undertaking, and far from the best approach to the problem.

Interventions that extend longevity in model laboratory organisms have proliferated. Traditionally, such interventions have been assumed to retard aging itself based on their ability to increase mean and maximum lifespan. The emphasis on longevity metrics alone made some sense in that longevity seemingly provides an unambiguous endpoint that has been assumed to be necessarily correlated with a general age-related physiological decline. While this may often be the case, it is not necessarily so. Indeed, human females live longer lives than males, but also suffer greater age-related morbidity by a number of measures. In laboratory species, long-lived worm genotypes are often outcompeted by shorter-lived genotypes and some evidence suggests that by a number of measures some long-lived worm genotypes are less healthy than the standard genotype even relatively early in life. As a major goal of basic aging research is to develop interventions that will enhance and prolong health in humans, it would be beneficial to the field to determine for all model organisms, which interventions extend health and which extend only life.

Because efforts to develop a cognate battery of tests to assess healthspan in mice and other model organisms have met with varying degrees of success we have taken a different approach. We feel that important indicators of health that can be commonly addressed in humans and in mice can be roughly categorized as those associated with age-related decreasing strength and mobility and those associated with decreasing cognitive capabilities. To this end, we present here an analysis of age-related change in commonly measured, noninvasive parameters associated with age-related changes in energetics, strength and mobility in the commonly used C57BL/6 mouse strain, and we determined to what extent these health parameters were associated with premature death. We measured age-related changes in healthspan in male and female mice assessed at 4 distinct ages (4 months, 20 months, 28 months and 32 months). Correlations between health parameters and age varied. Some parameters show consistent patterns with age across studies and in both sexes, others changed in one sex only and others showed no significant differences in mice of different ages. Few correlations existed among health assays, suggesting that physiological function in domains we assessed change independently in aging mice. With one exception, health parameters were not significantly associated with an increased probability of premature death. Our results show the need for more robust measures of murine health and suggest a potential disconnect between health and lifespan in mice.

Link: http://dx.doi.org/10.18632/aging.101059

Cell therapies involving transplantation from immune-matched donors go a long way back; think of the bone marrow transplants used in a variety of circumstances, for example. These were a way to ferry across stem cells before it was possible to extract and manage those stem cells in a clinical setting, and the approach is sufficiently advantageous and practiced to remain in use, even as cell based regenerative medicine is reaching the clinic. In the research I'll point out today, scientists take a little of that older world of patient matching to avoid immune rejection and a little of the new world of using small, easily obtained cell samples from a donor, such as blood or skin, to reprogram and culture a large number of cells of the desired type for transplantation. In this case they turn this mixed approach to heart regeneration, and demonstrate the ability to produce benefits following heart attack in monkeys.

The heart is not a very regenerative organ in mammals. Mammalian tissues span a range of willingness to heal, from the liver at one extreme, capable of regrowing lost sections, to the brain and the heart at the other, both of which exhibit little ability to recover from injury. Both ends of the range make for interesting targets for regenerative research: the liver because it seems like an easier starting point, and the brain and the heart because any improvement is significant given the present situation. Cell therapies for the heart have been underway within and outside the formal regulated system of trials for more than fifteen years, but at this point the effectiveness of the various strategies that have arisen is still something of a question mark. Better than nothing, but how much better? A wider range of approaches is available via medical tourism than has been rigorously tested, and the rigorous tests in trials and animal models have exhibited a sizable variation in outcomes. It seems clear that the methodology used is a very important determination of the outcome given the present state of the field: you can't just throw stem cells into a patient and hope for the best. That said, that strategy actually does seem to work fairly well when well-established and well-characterized cell types are used and the goal is reduction of chronic inflammation, which is why there is a high expectation of benefits to result from mesenchymal stem cell therapies for age-related joint pain and similar issues. Regenerative therapies for organs like the heart are a whole other ball game, however, and still a work in progress.

Stem cells regenerate damaged monkey heart

Cardiac muscle cells grown from the stem cells of one macaque monkey can be used to regenerate the hearts of other macaques. The transplanted cells improved the heart's ability to contract after an induced heart attack and integrated with no sign of rejection by the recipient's immune system. However, the recipient's heart did suffer from an irregular heart beat in the first four weeks after the transplant, but this passed and was non-lethal. Researchers used cardiac muscle cells derived from induced pluripotent stem cells (iPSC-CMs) from a donor instead of the patient's own cells. Donor cells are considerably easier to manufacture but increase the risk of being rejected by the recipient's immune systems. The scientists overcame this by matching a surface protein on the donor and recipient's cells that is used by the immune system to recognize foreign cells.

"We found that monkey iPSC-CMs or cardiac muscle cells derived from induced pluripotent stem cells survived in the damaged monkey heart and electrically coupled with the host heart. In addition, the heart's ability to contract was partially recovered by the transplantation. We had a hard time handling monkey iPS cells. Unlike human iPS cells, they are somewhat tricky. The condition of iPS cells are critical for generating high purity cardiac muscle cells. Also, it took a long time to get grafted cardiac muscle cells to survive in the recipients. In addition to daily treatments of immunosuppressant drugs, we made sure the surface protein major histocompatibility complex (MHC), which is used by the immune system to recognize foreign cells, was carefully matched on the donor and recipient's cells. Human embryonic stem cell-derived cardiac muscle cells have already been used in clinic as a new therapy for post myocardial infarction (MI) heart failure. But I think it will take at least a couple of years for this treatment to become more widely-used."

Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts

Induced pluripotent stem cells (iPSCs) constitute a potential source of autologous patient-specific cardiomyocytes for cardiac repair, providing a major benefit over other sources of cells in terms of immune rejection. However, autologous transplantation has substantial challenges related to manufacturing and regulation. Although major histocompatibility complex (MHC)-matched allogeneic transplantation is a promising alternative strategy, few immunological studies have been carried out with iPSCs. Here we describe an allogeneic transplantation model established using the cynomolgus monkey (Macaca fascicularis), the MHC structure of which is identical to that of humans. Fibroblast-derived iPSCs were generated from a MHC haplotype (HT4) homozygous animal and subsequently differentiated into cardiomyocytes (iPSC-CMs). Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intra-myocardial injection of iPSC-CMs.

The grafted cardiomyocytes survived for 12 weeks with no evidence of immune rejection in monkeys treated with clinically relevant doses of methylprednisolone and tacrolimus, and showed electrical coupling with host cardiomyocytes. Additionally, transplantation of the iPSC-CMs improved cardiac contractile function at 4 and 12 weeks after transplantation; however, the incidence of ventricular tachycardia was transiently, but significantly, increased when compared to controls. Collectively, our data demonstrate that allogeneic iPSC-CM transplantation is sufficient to regenerate the infarcted non-human primate heart; however, further research to control post-transplant arrhythmias is necessary.

A number of genes and proteins are turning out to be important in the processes of cell death that occur following a stroke or similar injury involving ischemia followed by reperfusion of tissue. It is the return of blood supply that leads directly to cell death, not the initial loss of blood supply. To pick one example from past research, absence of PHD1 has been shown to greatly reduce damage following stroke. Here, researchers investigate a similar functional role for macrophage migration inhibitory factor, MIF, representative of a range of other work along the same lines. These various genes and mechanisms are all windows onto the same core processes of programmed cell death in response to circumstances:

One particular protein is the final executioner of events that result in the death of brain cells during stroke, researchers report. This finding could ultimately lead to new ways to protect against brain damage. Researchers discovered that the protein, macrophage migration inhibitory factor (MIF), breaks the cell's DNA, resulting in brain cell death. The study outlines three possible ways to manipulate MIF to protect brain tissue during a stroke - and possibly in other brain-damaging conditions such as Alzheimer's, Parkinson's, and Huntington's diseases, although this study examined only stroke. Researchers screened thousands of human proteins to find 160 that could be the culprits behind stroke-induced cell death. Eventually, the researchers were able to narrow the field to just one - MIF, a protein long known for its roles in immunity and inflammation.

The MIF finding is the final piece in a puzzle that researchers have been carefully assembling for years to reveal the process by which brain cells die. Despite their very different causes and symptoms, brain injury, stroke, and Alzheimer's, Parkinson's, and Huntington's diseases have a shared mechanism involving a distinct form of "programmed" brain cell death called parthanatos, researchers said. The name comes from the personification of death in Greek mythology, and PARP, an enzyme involved in the cell death process. "I can't overemphasize what an important form of cell death it is; it plays a role in almost all forms of cellular injury." The researchers are working to identify chemical compounds that could block MIF's actions and possibly protect brain cells from damage.

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2016/oct/mif-wang.html

Researchers here claim that the high degree of overlap between Alzheimer's disease and vascular dementia could account for the difficulty in translating promising research results into successful clinical trials for Alzheimer's therapies. If patient cognitive decline is largely due to the vascular dementia in a sizable proportion of cases, that would be enough to tip the trial into failure when the benefits for Alzheimer's symptoms were modest. If large benefits could be produced, however, if the pathology of Alzheimer's could be cleared away, then it would be clear as to whether the therapy worked even if only half the patients saw a meaningful reduction in symptoms. Much of the difficulty in modern medicine exists precisely because most therapies for age-related disease are only producing small benefits, and thus trials results can be prone to misinterpretation due to any number of confounding factors.

Because Alzheimer's disease (AD) is the leading cause of dementia, many people use the two terms interchangeably. But inadequate blood flow to the brain due to microinfarcts, mini-strokes, or strokes is a hallmark of a disease called Vascular Cognitive Impairment and Dementia (VCID). VCID is the second most common cause of dementia, and the two are not mutually exclusive - researchers estimate that 40-60% of Alzheimer's disease patients also have VCID. A paper recently published reports that a certain form of immunotherapy targeted to Alzheimer's patients may be ineffective when that patient also has VCID. "These findings are important in that they provide a possible explanation for why clinical trials of anti-Aβ immunotherapy for Alzheimer's disease have been historically unsuccessful. If up to 40 percent of people with Alzheimer's also have VCID, treatment candidates that target only the AD physiology won't be effective in those patients. It's like treating only half the disease."

Most researchers agree that the formation of brain plaques containing amyloid β (Aβ) peptides is an initial step in the development of Alzheimer's disease, which has led to a race to identify and test treatments that reduce the levels of these plaques. Anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain, has been a leading approach. While these drugs showed promise in animal studies, clinical trials have failed to show similar benefits in human patients. Without a suitable animal model, testing the vascular dementia hypothesis would not have been possible. Fortunately, the research team had already developed an innovative model of combined AD and VCID. Using this mouse model, together with its parent model of AD without VCID, scientists evaluated the ability of an anti-Aβ antibody to enhance cognitive capabilities in both models. While Aβ levels were reduced in both groups, cognitive function was not improved in the groups with combined AD and VCID. "The failure of anti-Aβ immunotherapy in the mixed AD-VCID model suggests that both disease processes have to be treated to have a successful outcome. The missing link has been that our animal models usually possess the hallmarks of only one disease, which has led to failure of successful translation to clinic."

Link: http://uknow.uky.edu/content/sanders-brown-research-hints-underlying-cause-alzheimers-drug-trial-failures

Now that selectively clearing senescent cells from aged animals has been proven to produce benefits to health, tissue function, and life span, and its role in aging is well appreciated, there is a lot more interest in the research community in mapping out the biochemistry of these cells. Up until about five years ago, it was a real challenge to generate both this interest and the funding to sustain it, but better late than never. Below I'll point out a few recently published items in that theme, representative of much more work that is presently taking place. Researchers not actively working on methods of senescent cell destruction are looking for better definitions of what exactly constitutes cellular senescence, better biomarkers for these cells, and a better understanding of how exactly a comparatively small number of these cells can cause such harm to the rest of the tissue that contains them. This is all largely irrelevant to the first generation of senescent cell clearance therapies under development in companies like Oisin Biotechnologies and UNITY Biotechnology - the existing targets and methodologies are good enough for a first pass. When the second generation of therapies are under construction, however, the burning question will be the degree to which they are improvements over what already exists.

Cells become senescent in response to damage, the consequence of toxic and cancer-prone environments, or once they reach the Hayflick limit imposed on cell divisions for ordinary somatic cells. Senescent cells also transiently arise as a part of the wound healing process, and further are involved in shaping the body during embryonic development. Senescence predisposes a cell to self-destruction, and most destroy themselves via apoptosis. Those that do not self-destruct still remove themselves from the cell cycle of replication and begin to secrete a potent mix of molecules that spur inflammation, restructure the nearby extracellular matrix, and encourage surrounding cells to change their behaviors in a range of ways, few of them good in the long term. The immune system is attracted to these cells and destroys those that do not self-destruct, but nonetheless some senescent cells linger. That number grows with age, to the point at which a few percent of all the cells in a tissue or organ might be senescent. These cells collectively cause significant harm, by destroying functional structures in complex tissue, by secreting signals that alter and degrade function in healthy cells, and by producing enough chronic inflammation to meaningfully speed progression of age-related disease.

Given sufficiently comprehensive clearance of senescent cells, all of these contributions to the process of aging will go away, and we'll be healthier and longer-lived as a result. The first generation therapies are at present clearing as many as half of the identified senescent cells in a single treatment in laboratory mice. It remains to be seen how much that can be improved through longer treatment programs and tweaking the present treatment methods. It is interesting to ask whether the currently identified cells represent the full count of senescent cells, and whether or not they represent multiple different types of senescence, some better or worse for health than others. The answers to that will come in time, but the research and development community will still produce pretty good therapies in advance of those lines of further inquiry reaching their conclusions.

New method to detect ageing cells - and aid rejuvenation therapies - developed by researchers

Scientists have discovered a new way to look for ageing cells across a wide range of biological materials; the new method will boost understanding of cellular development and ageing as well as the causes of diverse diseases. Frustrated by the limitations of commercially available biomarkers the researchers have developed a universally applicable method to assess senescence across biomedicine, from cancer research to gerontology. Cellular senescence is a fundamental biological process involved in every day embryonic and adult life, both good - for normal human development - and, more importantly to researchers, dangerous by triggering disease conditions. Up to now available senescence detecting biomarkers have very limited and burdensome application. Therefore, a more effective, precise and easy-to-use biomarker would have considerable benefits for research and clinical practice. "The method we have developed provides unprecedented advantages over any other available senescence detection products - it is straight-forward, sensitive, specific and widely applicable, even by non-experienced users. In addition to helping researchers make significant new breakthroughs into the causes of diseases - including cancer - through more effective understanding of senescence in cells, the new process will also aid the impact of emerging cellular rejuvenation therapies. By the better identification - and subsequently elimination of - senescent cells, tissues can be rejuvenated and the health span extended."

Genes that control cellular senescence identified - Potential applications for cancer treatment and development of anti-aging products

The research group had previously discovered that cell senescence was effectively induced by using low concentrations of anticancer drugs on cancerous cells. In anticancer treatment, drugs are carried to the cancerous tissue via the bloodstream. The researchers predicted that differences in concentrations of the anticancer drugs would arise based on the distance of the cells from the blood vessels, and so even in the normal cancer treatment process senescent cells would emerge. Therefore, if we simultaneously administer a medicine that inhibits cell senescence during standard cancer treatment, there is the potential for a dramatic increase in treatment effectiveness. Previously the research group found that if cancerous cells are treated with a low concentration (10 μM) of the anticancer drug etoposide this induces cell senescence, and if they are treated with a high concentration of the drug (100 μM) this induces apoptosis. For this research, they treated cancerous cells under three different conditions: A) with no etoposide; B) with a low dose of etoposide (10 μM); and C) with a high dose of etoposide (100 μM). They then used DNA microarrays to identify the genes in which a rise in transcription levels could be observed.

They predicted that genes which showed increased expression in response to treatment B were mainly related to cell senescence, genes expressed in response to C were mainly those involved in apoptosis, and among the genes which specifically showed increased expression in B compared to C would be genes that play an important role in implementing cell senescence. There were 126 genes where three times as much expression was recorded under treatment B compared to A, and 25 genes that showed twice as much expression in B compared to C. These 25 genes are expected to express specifically in senescent cells since the other factors caused by DNA damage are removed, and researchers confirmed that the genes involved in causing cell senescence were among them. If we can develop a drug that targets and regulates the activity of the genes that control senescence identified in this research, by administering it together with conventional anticancer treatment we can limit the emergence of senescent cells and potentially increase the effectiveness of cancer treatment. Additionally, it has been reported that one of the causes of individual aging is the accumulation of senescent cells. This means that drugs which control cell senescence could have potentially large benefits for the development of anti-aging medication products.

CellAge Database of Cell Senescence Genes

Cell senescence can be defined as the irreversible cessation of cell division of normally proliferating cells. Human cells become senescent from progressive shortening of telomeres as cells divide, stress or oncogenes. Primarily an anti-tumour mechanism, senescent cells accumulate with age in tissues and have been associated with degeneration and ageing of whole organisms. Many proteins have been linked to cell senescence as biomarkers and as causal drivers. To facilitate studies focused on cell senescence, we developed CellAge, a database of genes associated with cell senescence. Our manually-curated data is based on gene manipulation experiments in different human cell types. A gene expression signature of cellular senescence will also be made available in due course. CellAge is in the beta phase of development and therefore still being improved and expanded. Collaborations and contributions are welcomed, please contact us if you wish to be involved.

Given the ability edit genes, why not also work on the ability to edit the epigenetic decorations such as DNA methylation, those that control the rate of gene expression, the production of proteins from the genetic blueprint? All cellular behavior is governed by the pace of production of specific proteins - these are the switches and dials of the cellular machine. So there are countless ways in which such an editing capability might prove useful. Perhaps the most interesting for this community is that efficient epigenetic editing should enable the production of compelling tests to disprove programmed aging theories that claim changes in gene expression to be the root cause of aging. Given that aging looks to be caused instead by accumulating molecular damage, with gene expression changes as a downstream reaction to that damage and its consequences, adjustments to gene expression should be of only marginal benefit, just like most of today's drug-based medicine for age-related disease. The ability to directly and precisely edit gene expression on a gene by gene basis without the use of a drug and its side-effects should make that very clear.

Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing.

Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.

Link: http://dx.doi.org/10.1016/j.cell.2016.08.056

Cognitive decline with aging is a complex process with many facets. Different classes of task suffer loss of function at different rates and vary between individuals. Researchers use these differences to map the brain and the neurodegeneration that accompanies aging. Here, researchers investigate speech processing:

Researchers have found clues to the causes of age-related hearing loss. The ability to track and understand speech in both quiet and noisy environments deteriorates due in part to speech processing declines in both the midbrain and cortex in older adults. Thirty-two native English-speaking volunteers with clinically normal hearing were assigned to two groups: younger adults (average age, 22) and older adults (average age, 65). The research team measured the volunteers' speech comprehension using the Quick Speech-in-Noise (QuickSIN) test. The researchers also gave the volunteers an electroencephalogram, which measured mid-brain activity, and a magnetocephalogram to measure cortical activity. For both groups, the researchers calculated the listeners' ability to comprehend speech in quiet settings and environments with more than one person talking. Background noise was delivered in four distinct signal-to-noise ratios (SNR), which measures signal strength (i.e., the primary talker) relative to background noise (i.e., the competing reader).

The researchers found that the older group had more trouble tracking speech than the younger group in both quiet and noisy environments across all SNRs. The older adults took more time to process several acoustic cues, such as accuracy of speech, and also scored lower on the QuickSIN test for speech comprehension in noise. Deficits from aging were also seen neurally, both in midbrain and cortex, according to the researchers. These results suggest that age-related problems with understanding speech are not only due to the inability to hear at certain volumes but also occur because the aging brain is not able to correctly interpret the meaning of sound signals.

The older adults gained significant benefit in focusing on and understanding speech if the background is spoken by a talker in a language that is not comprehensible to them (i.e. a foreign language). The results suggest that neural processing is strongly affected by the informational content of noise. Specifically, older listeners' cortical responses to the attended speech signal are less deteriorated when the competing speech signal is an incomprehensible language than when it is their native language. Conversely, temporal processing in the midbrain is affected by different backgrounds only during rapid changes in speech, and only in younger listeners. Additionally, cognitive decline is associated with an increase in cortical envelope tracking, suggesting an age-related over (or inefficient) use of cognitive resources that may explain difficulty in processing speech targets while trying to ignore interfering noise.

Link: http://www.the-aps.org/mm/hp/Audiences/Public-Press/2016/44.html

Epigenetics is the study of mechanisms that change the pace at which proteins are produced from the blueprints encoded in DNA, a process known as gene expression. The first step in gene expression is the generation of RNA, which is what is actually usually measured. Rates of production - and thus numbers of specific RNA and protein molecules in circulation - are the switches and dials that control cellular processes. These rates of production change constantly, as the various processes of production and activities of molecular machinery interact with one another in response to internal and external circumstances. Researchers have in recent years discovered that they can identify more stable patterns of changes in the noise, patterns that correspond to age. This is promising on many levels. On the practical front it is a path to biomarkers of aging that accurately reflect biological rather than chronological age, and thus can be used to greatly speed up the assessment and develoment of rejuvenation therapies. When it comes to fundamental research, patterns of epigenetic alterations to the production of biomolecules are another tool by which the course of aging and its mechanisms can be mapped.

It is fairly well established that most natural genetic variations are only important to health and mortality in later life, and even then only collectively. Individual genetic variants have tiny effects and very few are consistent across study populations. Young people see no measurable impact, but when old, with a high level of cell and tissue damage, many gene variants grant small, differing levels of protection or accommodation of damage. Obviously these are not large effects on the whole: the best of combinations raises the odds of living an extremely long life from minuscule to merely tiny, and beneficiaries are still frail and dependent at the end, crushed by high levels of damage in the biological machinery that sustains life.

If genetic variants are only really important in later life, then should we also expect the pace of change in epigenetic patterns and rates of gene expression to be much higher in later life? At the very high level, and even from simple metrics like activity, skin elasticity, and grip strength, we know that aging isn't a linear process. It is a downward spiral that proceeds ever faster as damage feeds on damage, and the final collapse into terminal ill health at the end of life is often a rapid thing after years of much slower decline. It would be surprising if measures that truly reflect the progression of mechanisms of aging turned out to show something different. In this paper, the researchers look at the RNA levels resulting from gene expression, and use statistical methods to mark the ages at which more significant changes start, going gene by gene to build the beginning of a picture. They find that most of the identifiable and robust changes occur in old age.

Blood RNA expression profiles undergo major changes during the seventh decade

Genome-wide alterations in RNA expression profiles are age-associated. Yet the rate and temporal pattern of those alterations are poorly understood. Most often, age-associated physiological and molecular alterations are extracted using linear regression models. Linear regression assumes a constant change over time and therefore might be appropriate for organisms that aged over a short period. In humans, however, adulthood spans from 50 to 80 years. It is very unlikely that the rate of age-associated changes progresses at a constant rate. The fitness of different regression models to describe age-associated physiological features demonstrated that a quadratic or a parabolic regression model are most suitable to describe age-associated changes. Quadratic models have fewer assumptions compared with a linear model. Moreover, a quadratic model could be employed to identify the age when major changes occur (named here age-position). Using cross-sectional transcriptome studies, it was suggested that most transcriptional alterations in brain frontal cortex occur around the age of 42, and in Vastus lateralis muscle major changes occur already in the fourth decade. In both studies, two linear regression models were applied to identify the age-positions. Applying a quadratic regression model we indeed confirmed that major expression profiles are changed first in the fourth decade in both brain frontal cortex and Vastus lateralis muscle.

Ideally, the pattern of aging-associated molecular changes could be extracted from population-based datasets. These datasets are cross-sectional, covering a broad age-range, and all subjects are included. Most population-based datasets are skewed in the old age, making a linear regression model unfit. Here we investigated age-associated molecular changes in whole blood from two population datasets. The Rotterdam Study (RS) cohort III and the SHIP-TREND cohort were independently generated using RNA microarrays. After correcting for the skewed sample distribution across age, we demonstrate that an age-associated pattern of molecular changes is highly similar between the two datasets. We show that in whole blood major molecular changes occur only at the seventh decade, predominantly affecting the translation and immune cellular machineries.

The RS dataset was split into two subsets with the age of 65 years being selected as a cut-off point. At 65 years the age-position was found in the two age-matched datasets. The younger group (less than 65 years) comprised 606 individuals, whilst the older group (greater than 65 years) included 156 individuals. In the younger group, only 128 probes were found to be significantly age-associated and those were not enriched in any functional group. Those probes were not found among the overlapping genes between RS and SHIP-TREND datasets. This suggests that molecular changes in blood prior to 65 years are neither robust nor consistent. In contrast, in the older age group 1319 probes were age-associated and those were mapped to the immune system, translation and the defense response functional groups. 65% of those genes overlapped with the significant probes from the SHIP-TREND. This indicates that major expression profile alterations in blood occur from the seventh decade onwards. This age-position is in agreement with a recent study showing that the number of immune cells and T-cell receptor reduces from the seventh decade onwards.

Whether or not the rate of molecular aging is similar between tissues is poorly understood. In whole blood, we identified only a single age-position during the seventh decade. A single age-position was found in kidney cortex, also during the seventh decade. However, in brain frontal cortex and in Vastus lateralis muscle two age-positions were identified, the first during the fifth decade and a second one during early eighth decade. This suggests that in humans the age at which major molecular changes occur differs between tissues. This conclusion in agreement with physiological studies suggesting that the rate of age-associated tissue deterioration differs between tissues. Moreover, the prominent aging-associated gene networks also differ between tissues: translation and the immune system gene networks from blood were not identified in brain cortex or skeletal muscles tissues. An age-position could indicate an aging-associated disease risk for tissue-specific disorders and could be a consideration for treatments and interventions during aging.

The research community has made considerable progress in regenerative medicine for bone since the turn of the century, and here is an example of the way in which work on scaffolding materials merges at the edges with tissue engineering. If scaffolds can be made from the same materials as bone, they can better guide regrowth and merge into the newly formed bone tissue. The focus at the present time is on repair of injuries or bone loss due to surgery, but it will be interesting to see whether or not any of these approaches can provide value in the treatment of age-related loss of bone strength. Any method that can spur greater bone deposition is probably worthy of a second look.

Researchers have created what they call "hyperelastic bone" that can be manufactured on demand and works almost as well as the real thing, at least in monkeys and rats. Though not ready to be implanted in humans, bioengineers are optimistic that the material could be a much-needed leap forward in quickly mending injuries ranging from bones wracked by cancer to broken skulls. The scaffold is simpler to make than others and it offers more benefits. Surgeons currently replace shattered or missing bones with a number of things. The most common option is an autograft, where a piece of bone is taken from a patient's own body, usually from a hip or a rib, and implanted where it's needed elsewhere in that same patient's skeleton. Surgeons prefer autografts because they're real bone complete with stem cells that give rise to cartilage and bone cells to provide extra support for the new graft. (Humans can't regrow entire skeletons from scratch with stem cells, but existing bone can signal stem cells where to grow and what to grow into.) What's more, because the new bone replacement comes from a patient's own body, there's no risk of immune rejection. But only so much of a person's skeleton is available for grafting, and doing so tacks on another painful surgery and recovery for the patient.

Another bone replacement option is creating a scaffold for bone to grow on. These scaffolds, made of both natural and synthetic materials, work like the framing of a building. When inserted into the body, stem cells latch onto the structure and differentiate into cells that start to build bone, much as construction workers assemble walls, floors, and glass around a skyscraper's steel girders. Or, at least, that's how it should work - unlike in an autograft, stem cells don't always turn into the needed bone or cartilage because of the scaffolds' material makeup. To make matters worse, the immune system occasionally sees these scaffolds as foreign and attacks them, preventing any bone growth at all. And if a scaffold is to be used to regenerate small bones, such as many of those found in the face, for example, doctors worry that it would take too much time and money to make them. The new hyperelastic bone is a type of scaffold made up of hydroxyapatite, a naturally occurring mineral that exists in our bones and teeth, and a biocompatible polymer called polycaprolactone, and a solvent. Hydroxyapatite provides strength and offers chemical cues to stem cells to create bone. The polycaprolactone polymer adds flexibility, and the solvent sticks the 3D-printed layers together as it evaporates during printing. The mixture is blended into an ink that is dispensed by the printer, layer by layer, into exact shapes matching the bone that needs to be replaced. The idea is, a patient would come in with a broken bone and instead of going through painful autograft surgeries or waiting for a custom scaffold to be manufactured, he or she could be x-rayed and a 3D-printed hyperelastic bone scaffold could be created that same day. Because the ink materials - that is, hydroxyapatite along with the polymer and solvent - are commonly used in biomedical engineering labs, hyperelastic bone would be cheap to print.

To test their material, the team first tested their 3D-printed scaffold as a material to fuse spinal vertebrae in rats. Their goal was to see whether their material could lock two adjacent vertebrae in place as well as other scaffolds commonly used to treat spinal injury patients. Eight weeks after the researchers implanted the hyperelastic bone, they found that new blood vessels had grown into their scaffold - a necessary step to keep bone-forming tissue alive - and calcified bone started to form from the rats' existing stem cells. The combination fused the vertebrae more efficiently than the controls that received either a bone graft from a donor or nothing at all. The researchers also used hyperelastic bone to repair a macaque monkey's damaged skull. After 4 weeks with a hyperelastic bone implant, the scaffold was infiltrated with blood vessels and some calcified bone. Equally important, the macaque didn't suffer from any adverse biological effects, such as inflammation or infection, that many synthetic implants can cause.

Link: http://www.sciencemag.org/news/2016/09/print-demand-bone-could-quickly-mend-major-injuries

While it is inarguable that exercise builds more and better muscle, and the outcomes are easily measured, it is much harder to determine the degree to which exercise improves bone. There is strong evidence to show that it does produce improvements to a degree that appears to taper with age, but present measurement technologies leave a lot of ambiguity and room for debate in that statement. Separately there is the question of the degree to which exercise slows the changes of aging, a related but quite different set of mechanisms. Both muscle and bone decline with age, so there is interest in the research community in exploring the biochemistry of reliable interventions, in search of ways to slow down that degeneration. This review paper is an introduction to present thinking on the effects of exercise on the quality and strength of bone tissue, and the challenges of measuring those outcomes:

In the United States, over 1.5 million osteoporotic fractures occur annually. The majority of these occur in the latter decades of life when rates of bone loss and microarchitectural deterioration are at their greatest. Exercise is a commonly recommended intervention for preventing bone fragility; however, human and animal studies suggest that the anabolic effect of exercise is much less potent in the mature and post-mature vs. the immature skeleton. These observations raised the question: is exercise a worthwhile strategy for promoting bone health in mature and elderly individuals? One author cites minuscule gains in bone density reported from exercise trials in adult populations and concludes that "exercise has little or no effect on bone strength." This conclusion, however, is based on studies that do not take into account recent advances in non-invasive technologies for measuring bone density and structure or new strategies to make exercise more potent, or osteogenic, in aging populations.

Human studies have demonstrated an age-related decline in the responsiveness of bone mineral density (BMD), as measured by dual-energy X-ray absorptiometry (DXA), to exercise interventions. Nevertheless, a recent meta-analysis in older adults revealed small but statistically significant increases in BMD at the lumbar spine and femoral neck. It is important to consider, however, the inherent limitations of DXA that may lead to underestimation of the mechanical benefits of exercise. Based on attenuation of photons by bone and soft tissue, DXA provides a precise estimate of the amount of bone located within an area; however, it does not reveal bone structure. Recent introduction of quantitative computed tomography (QCT), DXA-derived hip structural analysis (HSA), and magnetic resonance imaging (MRI) has afforded the ability to assess bone geometry, bone macro- and micro-structure, three-dimensional bone density, and estimates of bone strength using engineering analyses. A systematic review of studies using either peripheral QCT (pQCT) or HSA to measure exercise effects on bone strength across various age groups reported improvements of 1-8% in children and adolescents, with either no change or very modest improvements in middle-aged and older adults. Nevertheless, like DXA, HSA and pQCT have inherent limitations that make exercise studies difficult to interpret.

Multiple lines of evidence from human and animal studies indicate that the aging skeleton remains modestly responsive to exercise interventions. Animal and human studies demonstrate that mature and senescent bone retains the ability to respond to loading with osteogenesis. Clearly, further mechanistic research is needed to fully elucidate why bone becomes less sensitive to exercise with age. Innovative paradigms such as rest insertion and "non-customary" loading may be necessary to maximize the osteogenic potential of exercise. Further, studies suggest that the sympathetic nervous system may be an important mechanistic link between physical activity and bone health. This emerging evidence raises the possibility that pharmacological intervention may be able to augment the benefits of exercise on bone health in humans across the lifespan.

Link: http://dx.doi.org/10.3389/fphys.2016.00369

Correlations are everywhere, and not all of them are meaningful. Here I'll point out a short open access paper, in PDF format only at the moment, that outlines an interesting relationship between population altitude, mortality rate, and incidence of common age-related conditions. In short, people at higher altitudes have modestly better long term health and a few years of additional life expectancy when compared with those closer to sea level - a fairly interesting outcome, and one that might spur speculation. It has to be said that there are a number of fairly straightforward relationships between location and longevity. In many cases these are fairly obviously connected to wealth. If you look at wealthier regions, you find people who benefit from that wealth: greater access to medical technology and information about health, the education and will to use those resources, and all of the other matters of status, intelligence, and so forth that are linked with wealth in a web of correlations. If you look at smaller wealthier locations, you find selection and migration effects in which those already tending to greater longevity due to their greater wealth move there.

In the case of altitude, however, wealth isn't an obvious factor, one that might be used to explain greater health and longevity at higher elevations. The authors of this paper reach instead for greater levels of exercise as a likely factor, which is reasonable given the geography of the regions under study. Exercise and diet have two of the largest effects when it comes to natural variations in health and longevity, so thinking about how to use them to explain this sort of data is usually the best approach. As always, bear in mind that I point out papers of this nature because the subject is interesting, not because it is of any practical use whatsoever. Small variations of a few years up or down are unimportant, and the gains you can obtain from exercise and calorie restriction are only worth chasing because they cost nothing but time and the expected outcome is both reliable and backed by a large amount of scientific evidence, which is more than can be said for anything else you can do right now, this instant. The future of longevity for all of us is overwhelmingly determined by progress in medical science, the construction of rejuvenation therapies capable of repairing and reversing the causes of aging. The more of that taking place, the better off we are and the longer we live in good health. Even first generation therapies should extend human life to a much greater degree than just the few years of difference noted in this paper.

Lower mortality rates in those living at moderate altitude

Individuals living at moderate altitudes (up to about 2000m) were shown to have lower mortality from coronary artery disease (CAD) and stroke (-22% and -12% per 1000m) and an about 50% lower risk of dying from Alzheimer's disease compared with their counterparts living at lower altitudes. In contrast, reported altitude effects on cancer mortality are still conflicting. However, due to shared risk factors, e.g. obesity and diabetes, in cardiovascular disease and cancer a shared biology for both disease entities may be assumed. Therefore, it is hypothesized that mortality from certain cancers will decline with increasing altitude as demonstrated for CAD. Altitude-dependent mortality from CAD, male colorectal cancer and female breast cancer from 2003 to 2012 in Austria has been evaluated based on data from the Austrian Mortality Registries (Statistik Austria). Since the phenomenon of migration was most pronounced towards larger communities (a population of greater than 20,000) only communities with a population below 20,000 were included to avoid important confounding from migration.

The general life expectancy, e.g. in 2009, increased from low altitude (less than 251m) to higher altitudes (1001 to about 2000m) by about 2 years, in males from 76.7 to 79.1 years and in females from 82.1 to 84.1 years. From low to higher altitudes, mortality rate from CAD decreased by 28% in males and by 31% in females. Mortality rate from male colorectal cancer and female breast cancer decreased almost linearly from low to higher altitude by 45% and 38%. Independent of altitude, increasing agriculture employment was associated with a diminished mortality from ischemic heart disease by about 15% for males and females. In contrast, solely increasing altitude was related to the reduction in cancer mortality.

The lower mortality from CAD at moderate altitudes is in close agreement with that reported from Switzerland. Reduced oxygenation at higher altitudes and altitude-related climate changes, e.g. temperature, UV radiation, and/or air-pollution but also differences in dietary behaviour were considered as potentially protective factors. Similarly, a set of altitude-dependent environmental and life-style factors have been suggested to contribute to lower mortality from Alzheimer's disease at higher altitudes. The present data extend preventive effects of living at higher elevations on male colorectal and female breast cancer mortality. The observation that more rural conditions may not have affected cancer mortality will even heighten the importance of altitude-specific effects. The nearly linear mortality reduction with increasing altitude strongly indicates a dose-response relationship.

Unfortunately, to date only little and conflicting information is available on cancer mortality at altitude. Given the fact of shared risk factors in cardiovascular disease and cancer the beneficial effects of moderate hypoxia stimuli at altitudes up to 2500m on cardiovascular risk factors might also contribute to the lowering of cancer mortality. For instance, obesity and diabetes are such shared risk factors which have recently been reported to be lower in US individuals living at higher altitudes. These authors speculated that cold-induced thermogenesis, decreased appetite, unintentional increased physical activity, and hypoxia-related better glucose tolerance could represent potential mechanisms explaining the inverse relationship between the prevalence of obesity and/or diabetes and altitude. The author of an ecological study attributed lower cancer death rates at higher places to elevated natural background radiation (hormesis theory) but emphasized that causal inferences cannot be made.

Besides changing climate conditions with increasing altitude a potentially higher exercise capacity in the altitude population helps to explain lower mortality. Whereas high-altitude regions like Leadville in Colorado (US) or the Altiplano in South America are rather flat, in the Alps the amount of hilly terrain increases steeply with altitude likely contributing to a higher fitness level in the altitude population. In the Swiss study a similar amount of physical activity in the low and higher altitude populations has been suggested. However, since the hilly terrain is much more challenging than the plain terrain, e.g. when walking or cycling, a similar amount of physical outdoor activities can result in higher exercise capacity in the altitude population. In any case, the remarkable protective effects of living at moderate altitudes also on cancer mortality are fascinating and deserve further investigation.

Researchers here propose a mechanism by which gut bacteria might accelerate the accumulation of misfolded proteins in the brain, known to be at the very least associated with various forms of neurodegenerative condition. Beyond mere corrleation, there is good evidence for the accumulation of aggregates of these broken proteins to be actively harmful, an important part of the disease process. The participation of gut bacteria doesn't mean we should focus on them, however; the right approach is to develop ways to safely and periodically remove these aggregates, classifying their presence as a form of damage to be repaired before it rises to harmful levels.

Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are all characterized by clumped, misfolded proteins and inflammation in the brain. Researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid that have structural similarity to brain proteins leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS.

Alpha-synuclein is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Researchers hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. They also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain. The research involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of alpha-synuclein in the intestines and the brain and increased cerebral alpha-synuclein aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of alpha-synuclein aggregates, compared with nematodes not exposed to the bacterial amyloid. "These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer's disease, Parkinson's disease and ALS. This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut."

Link: https://www.eurekalert.org/pub_releases/2016-10/uol-sdr100516.php

Tissue engineers continue to forge ahead towards the use of smaller functional sections of tissue as a way to treat failing and damaged organs. The path to the construction of entire replacement organs will be an incremental one. Organovo recently announced their intent to turn their work on bioprinted liver tissue into an option for transplantation:

Organovo today announced its plan to develop 3D bioprinted human liver tissue for direct transplantation to patients. The company is announcing its program to develop this therapeutic tissue based on the achievement of strong results in preclinical studies in animal models showing engraftment, vascularization and sustained functionality of its bioprinted liver tissue, including stable detection of liver-specific proteins and metabolic enzymes. Organovo expects to pursue this opportunity with a formal preclinical development program. For patients in need of a liver transplant, no robust alternatives exist today. Approximately 17,000 patients are on the U.S. liver transplant waiting list, and only 6,000 liver transplants are performed each year. Organovo plans to develop clinical solutions in two initial areas. First, acute-on-chronic liver failure is a recognized and distinct orphan disease entity encompassing an acute deterioration of liver function in patients with liver disease, which affects 150,000 patients annually in the United States. Second, pediatric metabolic liver diseases represent another orphan disease indication where a bioprinted liver tissue patch may show therapeutic benefits.

"We're excited to introduce an implantable bioprinted liver tissue as the first preclinical candidate in our therapeutic tissue portfolio, and see the early results as extremely promising. The scientific and commercial progress we have already made with engineered human liver tissue in drug toxicity testing has given us a firm foundation upon which to build a larger tissue for transplant. Advancing our first therapeutic tissue into preclinical development is an important milestone for Organovo, and we believe that 3D bioprinted tissues have an opportunity to provide options for patients who suffer from liver disorders. Organovo's approach is designed to overcome many of the challenges that cell therapies and conventional tissue engineering have struggled to address, including limited engraftment and significant migration of cells away from the liver. In our preclinical studies, we deliver a patch of functional tissue directly to the liver, which integrates well, remains on the liver and maintains functionality. We believe our tissues have the potential to extend the lives of patients on liver transplant lists, or those who do not qualify for transplants due to other factors."

Link: http://ir.organovo.com/phoenix.zhtml?c=254194&p=irol-newsArticle&ID=2209393

A recently published analysis of the nature of limits to human life span under our present rapidly changing circumstances is receiving a lot of press attention today. The press being the press, you might skip the popular science articles in favor of the paper. Since it is not open access, you'll have to obtain it from the usual unofficial sources. It is an interesting read, and serves as a reminder that the research community actually knows very little about the demographics of aging at very advanced age. The data is so sparse past age 110 that the statistics of mortality, very reliable in earlier old age, rapidly turn into a sludge of uncertainty. It is possible at this point in time to argue either side of the position that there is or is not a limit to longevity under present circumstances, though most of us probably think that one or the other side is weak. On the one hand we can theorize that maximum human life span is increasing, in a way analogous to the fact that life expectancy at 60 is inching upward at a year every decade, but more slowly, and we might suggest the data for extreme old age is so bad that the ongoing change can't be identified. On the other hand we can instead theorize that there is some limiting process that hasn't changed at all over the course of recent human history, is not impacted meaningfully by modern medicine, plays a very large role in supercentenarians in comparison to younger old people, and renders mortality rates so very high at the extremes of human life spans as to form a limit.

This is actually a point worth making twice: when limits to lifespan are discussed, we're not talking about actual limits per se, but effective limits. A very large mortality rate, possibly coupled with rapid growth in mortality rate over time, looks a lot like a hard barrier to further progress in practice, but there is still the chance that someone could beat the odds. Where the data for supercentenarians is good enough to fill in tentative mortality rates with large error bars, up to age 115, that rate is around 50% annually. The mortality rate may increase greatly after that point, and that would be entirely expected given the absence of more than the one certified example making it past 120, but it is very unclear from the limited data. Mortality rates reflect actual physical processes, the accumulation of forms of cell and tissue damage that cause the suffering, death, and disease of old age. The damage is the same, but the proximate causes of death for supercentenarians are quite differently distributed from those of younger old people, prior to a century of age. The majority appear to be killed by transthyretin amyloidosis that clogs up the cardiovascular system, and that is becoming known to play a much lesser - but still significant role - in heart disease in earlier old age. Could this form of amyloidosis be the candidate for a process that is not all that affected by the past century of changes in medicine and lifestyle, and that becomes much more important in extreme old age than early old age? Possibly. The only way to know for sure is to build ways to clear this form of amyloid and see what happens.

The natural state of aging is a function of damage and how medicine addresses that damage - which is poorly and next to not at all at the present time. Almost all medicine for age-related conditions fails to address their root causes, the cell and tissue damage of aging, and takes the form of patching over that damage in some way or coaxing biological machinery to cope slightly better with running in a damaged environment. Predictably it is expensive and only marginally effective in comparison to true repair. As above in the comments on amyloidosis, find a way to repair that problem and life span will increase, as the machinery of biology will be less damaged and less worn down into high rates of failure. That is the point to take away from this discussion. It has to be said that the lead of the study, Jan Vijg, comes across as very pessimistic on aging in his comments here when considered in comparison to past remarks and collaborations with SENS folk that I've seen from him. That is the case even granting that he is in the camp of researchers who believe there is no alternative to a very slow and expensive reengineering of human metabolism in order make incremental gains in life span and slowing of the aging process.

What's the Longest Humans Can Live? 115 Years, New Study Says

On Aug. 4, 1997, Jeanne Calment passed away in a nursing home in France. The Reaper comes for us all, of course, but he was in no hurry for Mrs. Calment. She died at age 122, setting a record for human longevity. Jan Vijg doubts we will see the likes of her again. True, people have been living to greater ages over the past few decades. But now, he says, we have reached the upper limit of human longevity. "It seems highly likely we have reached our ceiling. From now on, this is it. Humans will never get older than 115." his is the latest volley in a long-running debate among scientists about whether there's a natural barrier to the human life span. "It all tells a very compelling story that there's some sort of limit," said S. Jay Olshansky, who has made a similar argument for over 25 years. James W. Vaupel has long rejected the suggestion that humans are approaching a life span limit. He called the new study a travesty. "It is disheartening how many times the same mistake can be made in science and published in respectable journals," he said. Dr. Vaupel bases his optimism on the trends in survival since 1900.

But when Dr. Vijg and his students looked closely at the data on survival and mortality,they saw something different. The scientists charted how many people of varying ages were alive in a given year. Then they compared the figures from year to year, in order to calculate how fast the population grew at each age. The fastest-growing portion of society has been old people, Dr. Vijg found. In France in the 1920s, for example, the fast-growing group of women was the 85-year-olds. As average life expectancy lengthened, this peak shifted as well. By the 1990s, the fast-growing group of Frenchwomen was the 102-year-olds. If that trend had continued, the fastest-growing group today might well be the 110-year-olds. Instead, the increases slowed down and appear to have stopped. When Dr. Vijg and his students looked at data from 40 countries, they found the same overall trend. The shift toward growth in ever-older populations started slowing in the 1980s; about a decade ago, it stalled. This might have occurred, Dr. Vijg and his colleagues said, because humans finally have hit an upper limit to their longevity.

Human lifespan may have maxed out

RG: Could you explain the research you did and the method you used in your analysis?

Vijg: We tested if human maximum life span is fixed or fluid and we found it to be fixed at around 115 years. We did this by looking at the maximum reported age at death in France, Japan, the United Kingdom and the United States. Firstly, we tested if improvement in survival also shifts to older age groups over time. We showed that improvement in survival in the oldest age group peaked in about 1980. This suggests - but does not prove - that we are reaching a maximum lifespan. Then we tested the maximum reported age at death since the 1960s. At first, this increased, but only up until the early 1990s. It then seemed to settle on a plateau, or even decline slowly, which is why we believe there is strong evidence that we have reached our ceiling.

RG: Why do you believe that humans have a natural age limit that is unlikely to be exceeded?

Vijg: Probably because the multiple longevity assurance systems humans have to prevent or fix damage and respond to stress are limited. This is also likely to be true for all animal species. A mouse lives much shorter than a human, possibly because it possesses inferior longevity assurance systems and can only get rid of damage and stress up until about three years.

Evidence for a limit to human lifespan

Driven by technological progress, human life expectancy has increased greatly since the nineteenth century. Demographic evidence has revealed an ongoing reduction in old-age mortality and a rise of the maximum age at death, which may gradually extend human longevity. Together with observations that lifespan in various animal species is flexible and can be increased by genetic or pharmaceutical intervention, these results have led to suggestions that longevity may not be subject to strict, species-specific genetic constraints. Here, by analysing global demographic data, we show that improvements in survival with age tend to decline after age 100, and that the age at death of the world's oldest person has not increased since the 1990s. Our results strongly suggest that the maximum lifespan of humans is fixed and subject to natural constraints.

The mainstream of aging research, at least in public, is characterized by a profound lack of ambition when it comes to treating aging as a medical condition. Researchers talk about slightly altering the trajectory of aging as though that is the absolute most that is possible, the summit of the mountain, and are in many cases ambivalent when it comes to advocating for even that minimal goal. It is this state of affairs that drove Aubrey de Grey and others into taking up advocacy and research, given that there are clear paths ahead to rejuvenation, not just a slight slowing of aging, but halting and reversing the causes of aging. Arguably embracing rejuvenation research programs would in addition cost less and take a much shorter span of time to produce results, since these programs are far more comprehensively mapped out than are efforts to produce drugs to alter the complex operations of metabolism so as to slightly slow the pace at which aging progresses. It is most frustrating to live in a world in which this possibility exists, yet is still a minority concern in the research community. This article is an example of the problem, in which an eminent researcher in the field takes a look at a few recently published books on aging research, and along the way reveals much about his own views on aging as an aspect of the human condition that needs little in the way of a solution. It is a terrible thing that people of this ilk are running the institutes and the funding bodies: this is a field crying out for disruption and revolution in the name of faster progress towards an end to aging.

How can we overcome our niggling suspicion that there is something dubious, if not outright wrong, about wanting to live longer, healthier lives? And how might we pursue longer lives without at the same time falling prey to quasiscientific hype announcing imminent breakthroughs? In order to understand why aging is changing, and what this means for our futures, we need to learn more about the aging process itself. As a biologist who specializes in aging, I have spent more than four decades on a quest to do exactly this. Not only have I asked why aging should occur at all (my answer is encapsulated in a concept called disposability theory), but I have also sought to understand the fastest-growing segment of the population - those aged 85 and above. The challenges inherent in understanding and tackling the many dimensions of aging are reflected in a clutch of new books on the topic. Are these books worth reading? Yes and no. They take on questions like: Can we expect increases in human longevity to continue? Can we speed them up? And, on the personal level, what can we do to make our own lives longer and healthier? If nothing else, these books and their varied approaches reveal how little we actually know.

To find out more about factors that can influence our individual health trajectories across ever-lengthening lives, my colleagues and I began, in 2006, the remarkable adventure of the still ongoing Newcastle 85+ Study, an extremely detailed investigation of the complex medical, biological, and social factors that can affect a person's journey into the outer reaches of longevity. For each individual, we determined whether they had any of 18 age-related conditions (e.g., arthritis, heart disease, and so on). Sadly, not one of our 85-year-olds was free of such illnesses. Indeed, three quarters of them had four or more diseases simultaneously. Yet, when asked to self-rate their health, an astonishing 78 percent - nearly four out of five - responded "good," "very good," or "excellent." This was not what we had expected. The fact that these individuals had so many age-related illnesses fit, of course, with the popular perception of the very old as sadly compromised. But the corollary to this perception - that in advanced old age life becomes a burden, both to the individuals themselves and to others - was completely overturned. Here were hundreds of old people, of all social classes and backgrounds, enjoying life to the fullest, and apparently not oppressed by their many ailments.

As for my stake in the enterprise, I began investigating aging when I was in my early 20s - well before I had any sense of my own body aging. Quite simply, I was curious. What is this mysterious process, and why does it occur? Everything else in biology seems to be about making things work as well as they can, so how is it that aging destroys us? Now that I am growing older myself, my research helps me understand my own body and reinforces the drive to live healthily - to eat lightly and take exercise - though not at the cost of eliminating life's pleasures. For all that I have learned about aging, my curiosity remains unabated. Indeed, it has grown stronger, partly because as science discovers more about the process, it reveals that there is ever more to learn, ever greater complexity to unravel, and partly because I am now my own subject: through new physical and psychological experiences in myself, I learn more about what older age is really like. I know all too well that the next phase of my life will bring unwelcome changes, and of course it must end badly. But the participants of the Newcastle 85+ Study have shown me that the journey will not be without interest.

Link: https://lareviewofbooks.org/article/want-live-longer-complicated-relationship-longevity/

Mitochondrially targeted antioxidants have been shown to modestly slow aging in a number of short-lived laboratory species, a smaller effect than that of calorie restriction. They have larger effects on inflammatory conditions, however, which is why the present thrust of clinical development is focused on a number of inflammatory eye conditions. This is in contrast to the sort of antioxidants you can buy in a supplement store, which do nothing useful, and at higher doses even appear to harm long-term health by interfering in signaling that mediates the beneficial response to exercise. Altered levels of mitochondrially generated oxidants show up in a range of methods that alter the pace of aging in animal species, mostly based on genetic engineering to alter mitochondrial operations. Here researchers are developing a drug-based approach along the same lines:

Go to any health food store and you're likely to see shelves crowded with antioxidants that promise to quell damage from free radicals, which are implicated in a myriad of human diseases and in the aging process itself. The problem is that antioxidants have failed to show benefits in several clinical trials and there is even some evidence they could be counterproductive. The current approaches to free radicals may fail because they apply a "sledgehammer" to a complex metabolic process that provides essential energy to our cells. Free radicals are produced in the mitochondria - the energy-converting organelles which are abundant in almost every type of human cell. Highly-reactive free radicals, which oxidize cell constituents (hence the use of antioxidants), are spun-off as a normal byproduct of cellular bioenergetics; it's a process that appears to go up when cells are stressed, something that can occur with aging and disease.

A chain of electron transporters within the mitochondria is involved in the production of both free radicals and the chemical energy essential for life. The challenge has been to stop the free radicals without shutting down the cell's ability to release energy. Researchers did that by painstakingly screening 635,000 small molecules to single out the few that blocked free radical production at a specific site thought to be a major source of free radicals in the electron transport chain. In this latest research, they demonstrated the potency and specificity of the successful molecules and tested their effects in cell culture, isolated hearts, and live models of disease. The compounds dramatically protected against reperfusion injury in a mouse heart model of ischemia. "Most of the lasting damage from heart attacks comes when blood flow is restored to the heart muscle. These compounds have great potential as therapeutic leads for drugs that could be given following a heart attack or after stents have been inserted to open blocked coronary blood vessels." In addition, the molecules diminished oxidative damage in brain cells cultured in low levels of oxygen; they also diminished stem cell hyperplasia in the intestines of fruit flies.

The study offers researchers a way to test the hypothesis that oxidative damage is specifically linked to disease. "For the first time we can test the effects of free radical damage in Alzheimer's, Parkinson's, cancer, type 2 diabetes, macular degeneration - you name it. It gives you a target, and a drug candidate to hit that target. We can start to answer questions that scientists have puzzled about for 50 years in terms of the specifics of oxidative damage. We now have a precise tool to find out if the theory is correct. We can go into a biological system, see specifically what free radicals do and take preliminary steps to stop it."

Link: http://buckinstitute.org/buck-news/future-therapeutics-drugs-stop-free-radicals-their-source

Lower levels of myostatin activity, achieved either through genetic engineering or blockade via antibodies, cause muscle growth. In the former case, where individuals lack functional myostatin throughout their lives, the result is lot of additional muscle growth; twice as much muscle tissue, or more. In the latter case the effects are smaller, but still significant. A short course of myostatin antibody treatment in mice added 20% extra muscle mass, and in humans a six month trial in elderly people added a measurable amount of additional muscle, while improving functional measures that typically decline dramatically in later age. There are a range of animal species in which it is possible to find established heavily muscled lineages with myostatin loss of function mutations of one sort or another: dogs, cows, and mice, the mutation either naturally occurring or created in the laboratory. There are even a few humans in the naturally occurring category.

Given the large numbers of myostatin-deficient animals, the extensive data on those animals, and results from human trials and the run up to those trials, it seems that manipulating one's own myostatin activity as an enhancement is something to look into for the near future. As in why don't we set out to try this today? Extra muscle with no effort is probably a nice to have for the younger folk in the audience, but the real application here is as a compensatory therapy to meaningfully delay the onset of physical frailty in older age. It doesn't solve any of the underlying issues that cause loss of muscle mass and strength with age, but it does appear to help a great deal more than other approaches are likely to at the present time, and is additive with those approaches. Young people can always substitute time and willpower for technology on the additional muscle front, but that option fades in effectiveness in later life - the returns on investment diminish greatly as age-related degeneration accelerates.

Viable myostatin or related follistatin and smad7 gene therapies for adults are a few years away yet, I think, pending a robust solution to tissue coverage. Methodologies must be developed to reliably ensure that therapies edit the genome in enough cells to be effective, but this is a challenge for everyone in the industry. It will not go unsolved for long now that CRISPR-based gene editing is a going concern. Still, a few years from now is not today. The antibody approach on the other hand is something that could be carried out today, if you had a reliable supply, dosage information, and the necessary materials to self-administer via injections. Give this list of ingredients, all of which are out there, I'm fairly certain that a range of individuals are already quietly doing exactly this. It will be the usual suspects, a mix of professional athletes and forward-thinking folk with laboratory experience and access. So why not forward-thinking older people as well?

The immediate raw materials to hand consist of research papers, study results, and suppliers of myostatin antibodies. From the research papers and study results one can obtain the particular brand of antibodies used and the dosages and treatment duration. There are a number of suppliers, such as Abcam, or take your pick of the dozens of others. Not all of which are providing a product that is appropriately useful in this context, of course. Not all suppliers sell to just anyone in this modern world of regulations and the drug war, either. Ideally you would pick the same antibody source as was used in one or more papers, and for preference the exact one used in a human trial. Human trials, however, have a way of being associated with specific companies, and they will probably be making their own, or exclusively licensing someone else's product. Regardless, there are choices, and a choice can be made. But most importantly, one has to verify that the supplier is actually delivering something that works.

At this point it would be prudent to obtain access to a laboratory and run tests. In our community there are a number of groups with the connections to kick that off. Let us say, for the sake of argument, a group buy organized by Longecity with additional fundraising to pay for the labs used by the Major Mouse Testing Program to validate that the product works in mice. There are three or four other organizations that could substitute in for either of those. The testing could even be structured to obtain useful scientific data in older mice, perhaps, which is something that seems a little less well exercised than the use of myostatin antibodies in younger mice. Overall that should not cost more than a few tens of thousands of dollars if picking a thrifty organization, and nor should it take more than a few months once the money is in hand.

There are matters other than the purely technical to be dealt with, however. Somewhere along the way the aforementioned prudent individual will engage a lawyer or two to figure out which part of buying the antibodies and injection kits and then self-administering is illegal or otherwise risky in the present jurisdiction. This will probably cost as much as the testing, which is a sad statement on the priorities of this fallen world of ours. This is the drug war age, and anything involving needles and biotechnology that falls outside the bounds of medical practice is at the least something that will raise the odds of attention from unwanted quarters. No purchase goes unmonitored for some types of apparatus, and injection kits are no doubt on that list. Further, everything involving medicine tends these days to operate on a forbidden unless explicitly allowed model, more is the pity. So all in all there is, as ever, a large difference between what one can do with little effort and what is prudent to do on one's own, without support or forethought.

Still, it seems to me that this is a viable project to explore further. The technology appears to have a good expectation of positive results given the human and extensive animal data to date, provided that the right tools are used, and there is a lot of data to establish dosages and the right products to use. The plausible worst outcome from an investigation of the legalities is likely to be along the lines of "contract the injecting to a clinic in Mexico or Canada." The whole exercise of research and validation outlined above is well within the capability of a motivated group of people pitching in a few thousand dollars each. The parts where it might cheerfully fall apart are in the cost of the desired antibodies, or in establishing a relationship with a supplier willing to go along with a group of people who are self-administering. That will no doubt make their legal teams nervous. It might be necessary to add an intermediary clinic or laboratory to the mix regardless of the formal legal status of the activities.

But you don't know unless you try.

Spermadine induces greater autophagy, the collection of cellular housekeeping processes that is associated with many of the methods demonstrated to modestly slow aging in laboratory species. Researchers here use dietary spermadine in flies to investigate one specific mechanism involved in age-related neurodegeneration. When it comes down to it, a great deal of fundamental life science research is a matter of finding or creating two similar situations and then using the small differences between them as a tool to probe the complexities of biology. Here one set of flies has a greater loss of memory, and that can be traced to specific functional changes in the synapses:

Neurons communicate by sending impulses, in the form of secretion of neurotransmitters, across small spaces called synapses. It is these synapses that undergo structural and functional changes during formation and retrieval of memories. Though alterations in synaptic performance are believed to accompany aging, the causal relationship between age-dependent memory impairment and synaptic changes remains largely unknown. Using the fly Drosophila melanogaster as a model, we found that feeding them spermidine - a polyamine compound - suppresses age-induced decline in olfactory memory, providing us with a tool to further decipher mechanisms associated with age-dependent memory impairment.

In this study, we investigated the relationship between synaptic changes and age-dependent memory impairment by studying the olfactory circuitry. We observed an age-related increase in the levels of the synaptic proteins Bruchpilot and Rim-binding protein, which caused an enlargement of the presynaptic active zone - the complex of proteins that mediate neurotransmitter release - and enhanced synaptic transmission. Interestingly, feeding of spermidine was sufficient to abolish these age-associated presynaptic changes, further emphasizing the relationship between presynaptic performance and age-dependent memory impairment. Furthermore, flies engineered to express an excess of the core active zone protein Bruchpilot showed a premature impairment in memory formation in young flies. Based on our data, aging plausibly steers the synapses towards the upper limit of their operational range, limiting synaptic plasticity and contributing to impairment of memory formation.

Link: http://dx.doi.org/10.1371/journal.pbio.1002563

Reduced levels of myostatin spur greater muscle growth, and there are animal lineages and even a few individual humans with myostatin loss of function mutations. The amount of evidence and experience in the scientific community working with this genetic alteration makes it a promising compensatory therapy for age-related loss of muscle mass and strength. Indeed, trials have already been held for the use of antibodies to reduce myostatin activity, and gene therapies are a possibility for the near future once tissue coverage issues have been solved. This study quantifies some of the differences between genetic loss of myostatin and antibody therapy for suppression of myostatin. As might be expected the results are similar in character but quite different at the detailed level, showing that genetic engineering for lifelong loss of myostatin produces superior results to an adult therapy. A further comparison with gene therapy carried out in adults remains to be conducted, but the outcomes will probably fall somewhere in the middle between these two examples.

Pharmacologic blockade of the myostatin (Mstn)/activin receptor pathway is being pursued as a potential therapy for several muscle wasting disorders. The functional benefits of blocking this pathway are under investigation, in particular given the findings that greater muscle hypertrophy results from Mstn deficiency arising from genetic ablation compared to post-developmental Mstn blockade. Using high-resolution mass spectrometry coupled with SILAC mouse technology, we quantitated the relative proteomic changes in gastrocnemius muscle from Mstn knockout (Mstn-/-) and mice treated for 2-weeks with REGN1033, an anti-Mstn antibody.

Relative to wild-type animals, Mstn-/- mice had a two-fold greater muscle mass and a greater than 1.5-fold change in expression of 12.0% of 1137 quantified muscle proteins. In contrast, mice treated with REGN1033 had minimal changes in muscle proteome (0.7% of 1510 proteins with more than a 1.5-fold change, similar to biological difference 0.5% of 1310) even though the treatment induced significant 20% muscle mass increase. Functional annotation of the altered proteins in Mstn-/- mice corroborates the mutiple physiological changes including slow-to-fast fiber type switch. Thus, the proteome-wide protein expression differs between Mstn-/- mice and mice subjected to specific Mstn blockade post-developmentally, providing molecular-level insights to inform mechanistic hypotheses to explain the observed functional differences.

Link: http://dx.doi.org/10.1002/pmic.201600006

As I mentioned not so long ago, and starting on November 1st, Fight Aging! will be doing something a little different in 2016 to support the end of year SENS rejuvenation research charitable fundraising efforts coordinated by the SENS Research Foundation staff. I would hope that I don't have to repeat to the audience here just how important this work is to the future - for ourselves, our descendants, for humanity as a whole. Aging is by far the greatest cause of suffering and death in the world, and we stand on the verge of being able to treat and prevent the causes of aging. Yet we live in a society of bread and circuses in which medical research is given little attention and little funding in comparison to the benefits it can bring. Medical research for aging receives but a tiny fraction of that pittance. Most of the important lines of work leading to human rejuvenation through repair of the cell and tissue damage that causes aging are still near-completely funded by philanthropy, through the foresight and generosity of communities like ours. If we can push things forward to the point at which they are picked up by established funding sources, that is a victory, one that leads to companies and products in development. We have achieved that for some types of rejuvenation therapy, but more must be accomplished yet.

So we in the grassroots have all been pitching in for years now, nearing a dozen fundraisers by my count, and this year we saw the big leap ahead represented by Michael Greve's $10 million pledge - a significant step forward. It was also a year in which we found smaller fundraisers more of a challenge than in the recent past. Donor fatigue is a real concern; the new crowdfunding platforms are an amazing tool, but reaching out several times a year produces diminishing returns. We've been taking things project by project and year by year in an ad-hoc manner, each its own effort, a new outreach. This is a long race of many years, however, not a series of sprints. The SENS Research Foundation's new Project|21 initiative should remind us of that, as their goalposts are explicitly set five years out, with a lot of implicit followup to continue on from there. Similarly for those of us who have invested in startups working on SENS technologies this year and last: a biotechnology startup is a project that comes to fruition in its own time, and that is likely five years or more in the average case. So perhaps we advocates banging the drum in the grassroots need to slow down a little and set up for the longer haul in our initiatives.

It is with this sort of thinking in mind that Josh Triplett, whom you may recall generously aided in setting up the 2015 matching fund, and I are each putting up $12,000 to encourage existing supporters and new arrivals to become SENS Patrons: to set up recurring monthly donations to the SENS Research Foundation. This will start when this year's SENS Research Foundation end of year initiative starts, on November 1st, and this Fight Aging! support will slot into that broader effort. Starting on November 1st, from the $24,000 fund Josh and I will match - dollar for dollar - a year of donations for anyone who becomes a SENS Patron by creating a new recurring donation. We think that this is a good way to help set up a solid of philanthropic grassroots support. Take a moment to look back at the history of the our community, all the way back to the launch of the Methuselah Foundation's 300, a group of people pledging monthly donations to the organization. The 300 initiative was instrumental in launching the Methuselah Foundation, and thus also instrumental in launching the first SENS research programs years before the SENS Research Foundation spun off into its own organization. The 300 remain an important part of the Methuselah Foundation's support today, providing a solid core of funding for a range of projects, including rejuvenation research. That is a good thing to emulate, we think.

$24,000 is a start, not the final word. We are looking for additional supporters willing to add their weight to this SENS Patrons matching fund. If you are interested please do contact me. The more people to put their shoulder to the wheel, the faster it turns. The way that organizations become attractive enough for high net worth donors to write seven figure checks is for there to be a large crowd at the gates, demonstrating their support. When it comes to philanthropy, wealth always follows the enthusiasm of the crowds, and it is the role of advocates and early donors to help draw in those crowds, to persuade ordinary folk just like you and I that this business of rejuvenation biotechnology is serious, plausible, and, given the funding, imminent. Bootstrapping a movement is always hard, but in this case the payoff is truly enormous. We are entering the era in which money can buy additional years of healthy life, which today means paying for progress in the right lines of medical research, and we can help to make it happen.

Heat shock proteins are involved in cellular quality control mechanisms that ensure correct functioning of proteins and the removal of damaged protein machinery. Research has demonstrated that more heat shock protein activity is a good thing. More quality control means less damage, and less damage means fewer secondary effects of that damage and, ultimately, a longer life. This is the way it works out in the numerous methods of modestly slowing aging in laboratory animals in which greater cellular repair and maintenance occurs as a result of the intervention. Calorie restriction is perhaps the most studied, but there are many others these days. There has been some interest in the research community in harnessing aspects of cellular quality control processes for therapeutic use, but little progress towards clinical applications. In that context, the research here is a perhaps surprisingly direct application of the principle to show benefits:

Molecular chaperone Heat Shock Protein 70 (Hsp70) plays an important protective role in various neurodegenerative disorders often associated with aging, but its activity and availability in neuronal tissue decrease with age. The compromised ability of neurons to express Hsp70 correlates with aging-related neurodegeneration. Here we explored the effects of intranasal administration of exogenous recombinant human Hsp70 (eHsp70) on lifespan and neurological parameters in middle-aged and old mice. Long-term administration of eHsp70 significantly enhanced the lifespan of animals of different age groups. Behavioral assessment after 5 and 9 mo of chronic eHsp70 administration demonstrated improved learning and memory in old mice. Likewise, the investigation of locomotor and exploratory activities after eHsp70 treatment demonstrated a significant therapeutic effect of this chaperone. Measurements of synaptophysin show that eHsp70 treatment in old mice resulted in larger synaptophysin-immunopositive areas and higher neuron density compared with control animals. Furthermore, eHsp70 treatment decreased accumulation of lipofuscin, an aging-related marker, in the brain and enhanced proteasome activity.

In summary, Hsp70 treatment extended mean and maximum lifespan, improved learning and memory in old animals, increased curiosity, decreased anxiety, and helped maintain synaptic structures that degrade with age. These results provide evidence that intranasal administration of Hsp70 could have significant therapeutic potential in preserving brain tissue and memory for middle-age and old individuals and could be applied either as unique self-contained treatment or in combination with other pharmacological therapies.

Link: http://dx.doi.org/10.1073/pnas.1516131112

Researchers here make some progress in understanding how stem cell therapies can reduce scarring in a damaged cornea. While focused on injuries rather than age-related damage, this should hopefully still speed progress towards better therapies for a range of conditions that cause blindness through opaque corneal scarring. That the mechanism is keyed to inflammation may also explain why some other approaches known to reduce levels of inflammation, such as those involving mitochondrially targeted antioxidants, are effective.

In cases of severe ocular trauma involving the cornea, wound healing occurs following intervention, but at the cost of opaque scar tissue formation and damaged vision. Recent research has shown that mesenchymal stem cells (MSCs) are capable of returning clarity to scarred corneas; however, the mechanisms by which this happens remained a mystery. Researchers have now identified hepatocyte growth factor (HGF), secreted by MSCs, as the key factor responsible for promoting wound healing and reducing inflammation in preclinical models of corneal injury. Their findings suggest that HGF-based treatments may be effective in restoring vision in patients with severely scarred corneas. "Our results show that mesenchymal stem cells, in an inflamed environment, secrete high levels of HGF, which inhibit scar formation and restore corneal transparency. But if you silence the HGF expression, the stem cells lose their capacity to inhibit scar formation."

Trauma to the eye is the leading cause of corneal opacity, leading to 25 million cases of blindness annually. While injury is not a major cause of blindness, it is one of the most common causes of monocular blindness. Current treatments for corneal scarring vary from topical steroids to corneal transplantation. However, there are limitations to these treatments, including increased risk of infection and rejection of transplants. With the goal of better understanding why MSCs are capable of restoring clarity to scarred corneas, researchers used an animal model of ocular injury. They observed secretion of high levels of HGF from stem cells at the site of injury. Furthermore, the researchers showed that HGF is solely responsible for the restoration of corneal transparency - an observation that holds promise for developing HGF-based therapy for patients.

Link: http://www.masseyeandear.org/news/press-releases/2016/09/researchers-shed-light-on-repair-mechanism-for-severe-corneal-injuries