Fight Aging!

Alzheimer's disease research is perhaps the largest single theme in the aging research community, with the majority of National Institute on Aging funding going towards Alzheimer's programs. The most advanced of efforts in Alzheimer's research are those that seek to clear the accumulation of amyloid-β in the brain through the use of immunotherapies, enlisting the immune system to break down and remove the unwanted amyloid. To date, however, this has proven to be a road of great expense characterized by disappointment and slow progress, to the point at which it was possible to question whether amyloid was the right target. Other theories and lines of research have begun to prosper due to the lack of tangible human results for anti-amyloid immunotherapies, in particular that neurofibrillary tangles of misfolded tau protein are just as much a target for clearance as is amyloid-β, and that perhaps it is time to focus on the decline of known clearance mechanisms rather than the amyloid itself.

Still, over the past couple of years, one of the latest entries to the class of anti-amyloid immunotherapies has lived up to some of the promise first seen in animal studies of amyloid clearance. It may well be that the light at the end of the tunnel is in sight. In a human trial that has now lasted a year, this new immunotherapy cleared near all detectable amyloid-β from patients, and the patients showed improvement in the sense that their decline appeared to slow significantly. The caveat here is that a year is not long enough to declare a slowing of the condition in certainty given the number of people treated in the trial, 165 individuals. Certainty will arrive given time and more patients. Regardless, simply through the demonstrated clearance of amyloid in human patients this is a big step forward for the field. If this holds up over the next few years of larger trials it should become very clear as to the degree to which amyloid-β is or is not in fact the primary cause of pathology in Alzheimer's disease.

I have long said that the best way to answer these questions of cause and contribution is to remove the mechanism in question and see what happens. As an approach that is much, much faster - and thus more cost-effective - than trying to infer the answer by analyzing the enormously complex workings of cellular biochemistry. It is an important point when arguing for more funding for SENS rejuvenation therapies: fix the damage, and see whether it works, because that is cheap and fast in comparison to all of the other options. This principle is well demonstrated here in the matter of amyloid, I think, given the past decade of theorizing on the degree to which the harm of Alzheimer's is due to amyloid, tau, or other causes, and the lack of progress on that front from theorizing alone. As soon as a treatment can reliably and safely remove the amyloid from a sizable number of Alzheimer's patients, we will have the answer.

Antibody reduces harmful brain amyloid plaques in Alzheimer's patients

Although the causes of Alzheimer's disease are still unknown, it is clear that the disease commences with progressive amyloid deposition in the brains of affected persons between ten and fifteen years before the emergence of initial clinical symptoms such as memory loss. Researchers have now been able to show that Aducanumab, a human monoclonal antibody, selectively binds brain amyloid plaques, thus enabling microglial cells to remove the plaques. A one-year treatment with the antibody, as part of a phase Ib study, resulted in almost complete clearance of the brain amyloid plaques in the study group patients. "The results of this clinical study make us optimistic that we can potentially make a great step forward in treating Alzheimer's disease. The effect of the antibody is very impressive. And the outcome is dependent on the dosage and length of treatment."

The antibody was developed with the help of a technology platform from Neurimmune. Using blood collected from elderly persons aged up to one hundred and demonstrating no cognitive impairment, the researchers isolated precisely those immune cells whose antibodies are able to identify toxic beta-amyloid plaques but not the amyloid precursor protein that is present throughout the human body and that presumably plays an important role in the growth of nerve cells. The good safety profile of Aducanumab in patients may well be attributed to the antibody's specific capacity to bond with the abnormally folded beta-amyloid protein fragment as well as the fact that the antibody is of human origin.

165 patients with early-stage Alzheimer's disease were treated in the phase 1b clinical trial. Although not initially planned as a primary study objective, the good results encouraged researchers to additionally investigate how the treatment affected the symptoms of disease. This was evaluated via standardized questionnaires to assess the cognitive abilities and everyday activities of the patients. "Aducanumab also showed positive effects on clinical symptoms. While patients in the placebo group exhibited significant cognitive decline, cognitive ability remained distinctly more stable in patients receiving the antibody."

Alzheimer's treatment appears to alleviate memory loss in small trial

The trial mainly tested the safety of the drug in people, and so the final word on whether aducanumab works to ameliorate the memory and cognitive losses associated with Alzheimer's will have to wait until the completion of two larger phase III trials. They are now in progress, and planned to run until at least 2020. Patients in the groups that got the drug were given one of four different doses of aducanumab. Individuals who received the highest doses also saw the highest reductions in plaques. And a group of 91 patients treated for 54 weeks saw slower cognitive declines than did those who received placebo infusions. Scientists have debated for years whether the build-up of amyloid-β causes the memory loss and other symptoms of Alzheimer's. This trial is a point in favour of the "amyloid hypothesis", which suggests that elimination of the protein itself might alleviate the disease's symptoms. Still, the trial is too small to prove that the drug actually works. Numerous other Alzheimer's drugs have looked promising in early-stage trials, yet ended in failure.

The antibody aducanumab reduces Aβ plaques in Alzheimer's disease

Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

This study is a good example of the degree to which the choice to remain active in later life makes a difference. That implies a range of other choices over the decades in order to raise the odds that you can in fact choose to remain active when older, such as avoiding weight gain.

Moderate physical activity is associated with a greater than 50% reduction in cardiovascular death in over-65s. The 12 year study in nearly 2500 adults aged 65 to 74 years found that moderate physical activity reduced the risk of an acute cardiovascular event by more than 30%. High levels of physical activity led to greater risk reductions. The present study assessed the association between leisure time physical activity and cardiovascular disease (CVD) risk and mortality in 2456 men and women aged 65 to 74 years who were enrolled into the National FINRISK Study between 1997 and 2007. Baseline data collection included self-administered questionnaires on physical activity and other health related behaviour, clinical measurements (blood pressure, weight and height), and laboratory measurements including serum cholesterol. Participants were followed up until the end of 2013. Deaths were recorded from the National Causes of Death Register and incident CVD events (coronary heart disease and stroke) were collected from the National Hospital Discharge register.

During a median follow-up of 11.8 years, 197 participants died from CVD and 416 had a first CVD event. When the researchers assessed the link between physical activity and outcome they adjusted for other cardiovascular risk factors (blood pressure, smoking and cholesterol) and social factors (marital status and education). To minimise reverse causality, where worse health leads to less physical activity, patients with coronary heart disease, heart failure, cancer, or prior stroke at baseline were excluded from the analysis. The investigators found that moderate and high leisure time physical activity were associated with a 31% and 45% reduced risk of an acute CVD event, respectively. Moderate and high leisure time physical activity were associated with a 54% and 66% reduction in CVD mortality. "Our study provides further evidence that older adults who are physically active have a lower risk of coronary heart disease, stroke, and death from cardiovascular disease. The protective effect of leisure time physical activity is dose dependent - in other words, the more you do, the better. Activity is protective even if you have other risk factors for cardiovascular disease such as high cholesterol."

Link: http://www.eurekalert.org/pub_releases/2016-08/esoc-mpa082616.php

Researchers here identify AMP-activated protein kinase (AMPK) as important in the loss of muscle that occurs in cancer patients, a wasting syndrome known as cachexia. They manage to reduce cachexia in mice. AMPK shows up in many considerations of metabolism and aging; to pick just a few, it can be used to extend life in flies, and appears to be involved in the mechanisms by which exercise improves health. Its role in these matters may be related to mitochondrial activity and cellular quality control, but like so many of these proteins it is involved in a large number of processes. An open question as a result of this research is the degree to which altered activity of AMPK might be involved in the loss of muscle mass and strength that occurs with aging, known as sarcopenia, or in other wasting conditions.

Healthy fat tissue is essential for extended survival in the event of tumor-induced wasting syndrome (cachexia). Cancer often results in weight loss due to unwanted metabolic complications. This so-called cancer cachexia is accompanied by a poor prognosis with regard to disease progression, quality of life, and mortality. After sepsis, cachexia is the most frequent cause of death in cancer patients. It is not entirely clear which biochemical mechanisms play a role. To date there have also not been any pharmacological possibilities for selectively influencing tumor-associated wasting syndrome.

Researchers have identified the AMP-activated protein kinase (AMPK) as the central enzyme in cancer cachexia. AMPK is normally responsible for protecting cells from energy deficiency. In the case of cancer cachexia, however, AMPK activity is inhibited due to the illness, resulting in a pointless waste of the body's own energy store. Selective AMPK reactivation was successfully carried out in tumor models. The therapeutic manipulation took place through a specific peptide which prevents the interaction between AMPK and the lipid droplet-associated protein Cidea, and which consequently can stop the increased fat breakdown (lipolysis) found in tumor diseases. "Our data suggest that the preservation of "healthy" adipose tissue can promote not only the quality of life, but also the response to treatment and the survival of cancer patients. The interaction between AMPK and Cidea can be taken as a starting point for developing new lipolysis inhibitors which could then prevent the breakdown of energy stores in the fat of tumor patients."

Link: http://www.helmholtz-muenchen.de/en/news/latest-news/press-information-news/article/35754/index.html

In the research linked here, publicity materials and open access paper (PDF only, alas), the authors report on the generation of liver organoids that spur the growth of functional liver tissue when implanted into mice. The degree of functional gain is small, but this is one step upon a longer road. This is very much the age of organoids, a period of tissue engineering in which researchers are successfully establishing the methodologies needed to grow functional organ tissue, but are still very limited by the inability to reliably generate blood vessel networks. Thus the created tissues largely work as they are intended to, but are tiny in size: any bigger and the inner cells could not be supplied with sufficient oxygen and nutrients.

Organoids are useful in research, as a much more cost effective way of performing drug assessments, for example, or a way to generate dysfunctional tissues that mimic disease processes more accurately than animal models. The utility doesn't stop there, however. For those organs that operate largely as filters or chemical factories, and where the present large-scale structure and shape is not strictly necessary for correct function, it is a very plausible near-term goal to grow organoids from the patient's own cells and implant them inside or alongside the existing organ. Either the implanted organoids contribute to organ function, helping to rescue the patient from organ damage, or in the best of scenarios they will encourage regrowth and regeneration as well - a sort of hybrid half-way point between a cell therapy and an organ transplant. I predict that we'll be seeing ever more of this sort of use of organoids, and that usage will accelerate as the blood vessel challenge continues to go unsolved.

The liver is the most regenerative of organs in mammals. Even we humans are capable of regrowing lost sections of liver under favorable circumstances. Further, many of the liver's activities are independent of its location and shape - a selection of biochemical and cellular factory processes such as detoxification that only require access to the bloodstream. These points make the liver an excellent place to start building regenerative therapies, given the present state of biotechnology. There is certainly a need for these therapies: at the present time comparatively little can be done to compensate for the loss of the liver's activities as the organ fails with age.

Functional Human Tissue-Engineered Liver Generated from Stem and Progenitor Cells

Liver transplantation is the only effective treatment for end-stage liver disease, but scarcity of available organs and the need for lifelong immunosuppressive medication make this treatment challenging. Alternate approaches that have been investigated include significant limitations. For example, conventional liver cell transplantation requires scarce donor liver and a perfusion protocol that wastes many cells. This type of cell transplant typically lasts less than one year, with most patients ultimately requiring a liver transplant. Human-induced pluripotent stem (iPS) cells are another possibility but, so far, iPS cells have remained immature rather than developing into functional and proliferative liver cells, called hepatocytes. There continues to be a need for a durable treatment, particularly one that could eliminate the need for immunosuppression.

"Based on the success in my lab generating tissue-engineered intestine and other cell types, we hypothesized that by modifying the protocol used to generate intestine, we would be able to develop liver organoid units that could generate functional tissue-engineered liver when transplanted." The research team generated liver organoid units (LOU) from human and mouse liver and implanted both varieties of LOU into murine models. Tissue-engineered liver developed from the human and mouse LOU, with key cell types required for hepatic function including bile ducts and blood vessels, hepatocytes, stellate cells and endothelial cells. However, the cellular organization differed from native liver tissue. Human albumin, the main type of protein in the blood, was detected in the host mouse serum, indicating in vivo secretory function from the human-derived tissue-engineered liver. In a mouse model of liver failure, tissue-engineered liver was able to provide some hepatic function. In addition, the hepatocytes proliferated in the tissue-engineered liver.

Functional Human and Murine Tissue-Engineered Liver is Generated from Adult Stem/Progenitor Cells

Liver disease affects large numbers of patients, yet there are limited treatments available to replace absent or ineffective cellular function of this crucial organ. Donor scarcity and the necessity for immunosuppression limit one effective therapy, orthotopic liver transplantation. But in some conditions such as inborn errors of metabolism or transient states of liver insufficiency, patients may be salvaged by providing partial quantities of functional liver tissue. After transplanting multicellular liver organoid units composed of a heterogeneous cellular population that includes adult stem and progenitor cells, both mouse and human tissue-engineered liver (TELi) form in vivo.

TELi contains normal liver components such as hepatocytes with albumin expression, CK19-expressing bile ducts and vascular structures with α-smooth muscle actin expression, desmin-expressing stellate cells, and CD31-expressing endothelial cells. At 4 weeks, TELi contains proliferating albumin-expressing cells and identification of β2-microglobulin-expressing cells demonstrates that the majority of human TELi is composed of transplanted human cells. Human albumin is detected in the host mouse serum, indicating in vivo secretory function. Analysis of mouse serum after debrisoquine administration is followed by a significant increase in the level of the human metabolite, 4-OH-debrisoquine, which supports the metabolic and xenobiotic capability of human TELi in vivo. Thus implanted TELi grew in a mouse model of inducible liver failure.

Researchers have uncovered another way in which growing amounts of amyloid, aggregates of a misfolded protein, can cause dysfunctional cellular behavior in the brain. As presented, this is actually a good example of the way in which research to explore exactly how a disease state progresses tends to focus on the novel mechanisms rather than the known root causes, to the detriment of building better therapies. The right approach is to tackle the root causes, and with greater support for that approach provided by the new knowledge as to why those root causes are in fact damaging. Instead research institutions chase after ways to manipulate newly discovered secondary effects because they are novel and therefore open to patent protection or other forms of ownership:

Vesicles, fluid-filled sacs that brain cells make to trap amyloid, a hallmark of Alzheimer's, appear to also contribute to the disease. Reducing the production of these vesicles, called exosomes, could help reduce the amount of amyloid and lipid that accumulates, slow disease progression and help protect cognition. When confronted with amyloid, astrocytes, plentiful brain cells that support neurons, start making exosomes, to capture and neutralize it. Not unlike a landfill, the real problems begin when the biological sacs get piled too high. In such volume and close proximity to neurons, exosomes begin to interfere with communication and nutrition, neurons stop functioning well and eventually begin to die, a scenario that fits with disease progression.

Scientists followed the process in an animal model with several genetic mutations found in types of Alzheimer's that tend to run in families and make brain plaques early in life. One mouse group also was genetically programmed to make a nonfunctional form of the enzyme neutral sphingomyelinase-2. Amyloid also activates this enzyme, which converts another lipid, called sphingomyelin, into ceramide, a component of the brain cell membrane known to be significantly elevated in Alzheimer's. In fact, with disease, the brain has two to three times more of the lipid. The scientists found exosomes made by astrocytes accelerated the formation of beta amyloid and blocked its clearance in their animal model of Alzheimer's. Male mice, which were also sphingomyelinase-deficient, developed fewer plaques and exosomes, produced less ceramide and performed better in cognitive testing. For reasons that are unclear, female mice did not reap similar benefits; Alzheimer's tends to be more aggressive in women. Earlier work has shown that female mice have higher levels of antibodies in response to the elevated ceramide levels that further contribute to the disease.

The new work is the first evidence that mice whose brain cells don't make as many exosomes are somewhat protected from the excessive plaque accumulation that is the hallmark of Alzheimer's. It is also an indicator that drugs that inhibit exosome secretion may be an effective Alzheimer's therapy. The team is already testing different drugs given to patients for reasons other than Alzheimer's that may also inhibit sphingomyelinase and ultimately ceramide and exosome production.

Link: http://jagwire.augusta.edu/archives/36646

Immunosenescence is the name given to the decline of immune system effectiveness with aging, a large component of the frailty that arises in later life. This decline is partially a result of a failing supply of new immune cells, and partially a result of a growing misconfiguration of the immune system as a whole, driven by life-long exposure to infections. On this second front, persistent infection by herpesviruses such as cytomegalovirus appears to be particularly problematic, the cause of large fractions of the immune cell population in an old individual becoming specialized and unable to react to new threats. This open access paper considers the potential role for cell therapies in reversing immunosenescence, with possibilities that go beyond merely generating and delivering new immune cells to the patient on a regular basis:

Human life expectancy has increased from 40 to 80 years of age just over the past 2 centuries largely due to medical advances. However, it is likely that the human immune system did not evolve to protect the host over such an extended lifespan. Immunosenescence is a term that describes the changes in the immune system that are seen in the aging population. The hallmarks of immunosenescence include a reduced capability to respond to new antigens, increased memory responses, and a lingering level of low-grade inflammation that has been termed "inflamm-aging." Decline of the immune system is associated with increased incidence of infection, immune disease, and cancer in the elderly. While immunosenescence is often described as a decline in the number and function of immune cells, myeloid cells have been shown to increase in the aged population and some secreted peptides are also expressed in greater amounts. Therefore, it is important to keep in mind that immunosenescence is more appropriately conceptualized as a change in the actions of the immune system, rather than an overall decline of all functions and constituents.

The immune system is generated and maintained by asymmetric division of multipotent haematopoietic stem cells (HSCs) in the bone marrow. The immune system has 2 arms, the innate and the adaptive systems, which work together to eliminate pathogens and neoplastic cells, respond to vaccination, and regulate processes such as tissue turn over and wound healing. Increasing evidence shows that HSCs themselves undergo age-related changes and have a limited replicative lifespan. HSC aging was demonstrated by serial transplantation of whole bone marrow, which only supported 4-6 rounds of transplantation, suggesting the possibility of stem cell exhaustion or replicative senescence. In addition, accumulation of DNA damage has a profound impact on HSCs, leading to loss of proliferation, diminished self-renewal, increased apoptosis, and subsequent exhaustion. Differentiation of the HSCs is also affected by aging, where HSCs committed to the myeloid lineage outnumber lymphoid cells in both mice and men.

Rejuvenating the HSCs might improve some of the dysfunction of both macrophages and T-cells, as well as many other cell types, observed in aging. Bone marrow transplantation from a young donor to an elderly patient could be used to rejuvenate the exhausted, aged progenitor pool. However, imperfect tissue matches often lead to rejection and even graft-vs.-host disease, a major hurdle to overcome in many fields of study. Induced pluripotent stem cells (iPSCs) could theoretically be used to generate HSCs from a patient's own cells, thereby eliminating donor-recipient mismatch. Techniques to differentiate HSCs from iPS cells exist, but efficiency and safety are major hurdles that this technology must yet overcome. In addition, genetic reprogramming will likely need to take place ex vivo to prevent collapse of organ function in the intermediate, undifferentiated cell state, so repopulation of tissue resident macrophages and lymphocytes will take several weeks or months from a single bone marrow transplantation. Also, effectiveness of rejuvenated HSCs would be limited by thymic output for T-cells and would likely not replace tissue resident macrophages, which are self-sustaining. However, repopulating the bone marrow with autologous iPSC-derived HSCs is a promising approach to rejuvenating the majority of immune system, especially the innate effector response.

The thymus begins to significantly deteriorate around 10 years of age in humans, and likely plays a role in the decline of the immune system, especially the diversity of the T-cell repertoire, during aging. Rejuvenating or somehow regulating thymic output is an intriguing approach to combat age-related decline of T-cells. Approaches to replacing or regenerating the thymus include tissue and cell transplantation. Transplantation of cultured thymic tissue from human cadavers into the kidney capsule of patients with DiGeorge syndrome successfully restored immune function for up to 10 years. However there are limitations to this approach for treating the aging population due to lack of donated tissue, invasive surgery, and tissue rejection. Regenerative medicine, including tissue engineering and cell and gene therapy, offer alternative approaches to replacing the thymus. Many groups have identified multipotent progenitors, termed thymic epithelial cells (TEC), that can grow into a 3-dimensional thymus and support normal T-cell development when transplanted into the kidney capsule. Human TECs have yet to be isolated in sufficient numbers, however protocols to push human embryonic stem cells toward TEC lineage are becoming consistently more efficient.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879890/

Modern advocacy for longevity science, and indeed the entire longevity science community, is comparatively young and comparatively small when viewed in the grand scheme of things. Some single sports teams have a larger footprint in the world, measured in people and dollars. The importance of work on longevity science for the future of humanity is enormous, and enormously underappreciated, but that importance must be realized through growth. It is near all a potential yet to be realized. As of now our community includes many quite small organizations and initiatives which, while doing something valuable, are very vulnerable to happenstance and accident because of their small size. Many of the advocacy efforts that have arisen from the community, like Fight Aging!, have a bus factor of 1. If anything happened to me, that would be the end of Fight Aging! Not everyone is in that boat, of course. If you survey some of the organizations that are running research programs relevant to the medical control of aging rather than just talking about research and longevity, you'll find that their bus factors are in a more respectable range for their size of 2 to 4. That represents an organization far less likely to be rendered unable to continue through a normal rate of attrition of essential personnel.

Still, these are low numbers when considered against the bigger picture. They are a outcome of small organizations, areas of cutting edge research without a large number of experts, and the fact that the community of longevity science supporters is not large. If you look at larger institutions, those further from rejuvenation biotechnology but still within the field of aging research and interested in intervention, you might see that losing four people from, say, the Buck Institute - ten times the size of the SENS Research Foundation - would be unfortunate, but the organization would continue much as it is today without missing a step. On the other hand losing four people from the very select group of scientists who carry out research into glucosepane cross-links would probably set back that line of research for years - there are only a couple of labs with good experience, and little funding for the very important goal of clearing these cross-links from old tissues. Senescent cell clearance doesn't have this problem, given the growth in interest and the greater breadth of knowledge to start with: half of the researchers could decide tomorrow to take up a different line of work, and there would still be plenty of hands left to get the job done. Most of the lines of research relevant to the SENS vision for human rejuvenation fall somewhere between these two extremes.

Advocacy for research is a job for small groups of people - it is hard to justify spending enormous amounts on education and outreach when early stage research costs so very little. The biotechnology revolution has completely changed the economic calculus for near all of the life sciences. Fortunately writing doesn't take much effort, and one of the points of the exercise is to encourage more people to do exactly the same thing. In theory, the sooner you make yourself obsolete the better the job you are doing. So it shouldn't much matter than any one initiative has a low bus factor, because all initiatives have their start and their end, and it is the broader tapestry that is the important thing. One shouldn't lose sight of the forest for the trees. With that in mind, it has been encouraging to see more people trying their hand at this advocacy for longevity science business in the past few years. A number of quite promising attempts have come and gone, some of which are still in the sidebar links on the Fight Aging! home page, but I think it noteworthy that we're starting to see initiatives with a bus factor that is higher than 1. I might point out the Longevity Reporter, for example, that has good number of people involved.

Whether talking about advocacy or the actual work of making progress in rejuvenation biotechnology, growth in the community and the funding solves all concerns about the fragility of organizations and initiatives. The ideal world is one in which there are so many contributors and so much funding that the failure of a company or a laboratory group is not going to cause any significant delay in the pace of progress. The stem cell or cancer research fields are examples to aspire to in this regard. Longevity science is a way removed from that level of funding and participation, but I think it only a matter of time. There is no danger that treating aging as a medical condition will find itself in the same place that the cryonics industry has occupied for the past four decades, struggling to grow both support and funding. The dynamics are very different: I find it hard to envisage a scenario in which a working prototype of a narrowly focused rejuvenation therapy is ignored for decades. Approaches to rejuvenation that are demonstrated to work will be adopted by the biotechnology and medical industry, and after the first couple of these therapies the major players of that industry will stop waiting to be handed the technologies and start in on early stage development of the remainder themselves. It is all a matter of bootstrapping, as always. Just how long it will take is the big question mark, and the number we hope to influence through our actions.

I would hope it to be a matter of great irrelevance as to whether Fight Aging! itself is still around ten years from now or next year or tomorrow. I would be more comfortable saying that with a few more organizations working at advocacy in much the same way, and a five to tenfold growth in the size of this community, however.

Researchers here demonstrate that mice with a larger number of mitochondrial deletion mutations exhibit a greater age-related loss of muscle fibers, a study that you might compare with past results showing reduced life span resulting from increased mitochondrial mutations. Mitochondria are the power plants of the cell, responsible for generating chemical energy store molecules, descended from symbiotic bacteria, and still bearing the leftover remnant of their original DNA. Mitochondrial dysfunction is implicated in the progression of aging and age-related disease, both from fairly high level measures of age-related changes in mitochondrial function and dynamics in specific tissues, and from an examination of mitochondrial DNA damage and its consequences. Further, differences in the composition of mitochondria correlate strongly with species life span across many types of organism: the more resistant mitochondria are to oxidative damage, the longer the life span.

The evidence to date makes a compelling argument for work on mitochondrial repair of one sort or another as the basis for a rejuvenation therapy, a way to remove this contribution to the aging process. The favored approach for the SENS Research Foundation is to insert suitably edited copies of mitochondrial genes into the cell nucleus as a form of backup, something that is, gene by gene, slowly advancing into commercial development. Deletions in mitochondrial DNA cause problems because they prevent the creation of necessary proteins required for correct function, but if the proteins are also created and supplied from the nucleus, then the expected outcome is that no harm will come from mitochondrial DNA damage.

With age, somatically derived mitochondrial DNA (mtDNA) deletion mutations arise in many tissues and species. In skeletal muscle, deletion mutations clonally accumulate along the length of individual fibers. At high intrafiber abundances, these mutations disrupt individual cell respiration - the electron transport chain (ETC) mechanisms - and are linked to the activation of apoptosis, intrafiber atrophy, breakage, and necrosis, contributing to fiber loss. This sequence of molecular and cellular events suggests a putative mechanism for the permanent loss of muscle fibers with age.

To test whether mtDNA deletion mutation accumulation is a significant contributor to the fiber loss observed in aging muscle, we pharmacologically induced deletion mutation accumulation. Beta-guanidinopropionic acid (GPA), a creatine analogue, induces mitochondrial biogenesis primarily in skeletal muscle. Previous experiments demonstrated that a 7 weeks GPA treatment of 27-month-old rats resulted in an increased incidence (3.7-fold) of ETC abnormal fibers, but did not result in measureable fiber loss. Clonally expanded mtDNA deletion mutations first appear as ETC abnormal fibers at approximately 28 months of age in the hybrid rat. We hypothesized that inducing mitochondrial biogenesis at older ages, when deletion mutation frequency is higher, would explicitly test the role of these mutations in muscle fiber loss. Four months of GPA treatment in 30-month-old rats resulted in a 12-fold increase in ETC abnormal fibers, accelerating cell death, fiber loss and fibrosis, leading to a 22% loss of muscle mass.

In muscle aging, activation of apoptosis and necrosis predominantly occurs in ETC abnormal muscle fibers. The ETC abnormality results from the focal accumulation of mtDNA deletion mutations. As GPA treatment promotes sarcopenic changes through an increase in ETC abnormal fiber abundance, treatment should also accelerate the mitochondrial genotypic changes observed with muscle aging. To test this relationship, we quantitated mtDNA deletion mutation abundances in both muscle tissue homogenates and single muscle fibers. The mtDNA deletion frequency (20%) in tissue homogenates mirrored the increased abundance of ETC abnormal fibers. Similarly, in single fibers, GPA treatment resulted in deletion mutation abundances that exceed the 90% phenotypic threshold for presentation of a respiration deficiency. These data strengthen the causal link between mtDNA deletion mutation and fiber loss and underscore the significance of latent mtDNA deletion mutations.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12520/full

The author quoted here has written a number of interesting posts on aspects of philosophical thinking pertinent to rejuvenation biotechnology and the goal of bringing an end to the pain and suffering caused by aging. While from my position I see that no more justification is needed for working to greatly lengthen healthy life spans than the fact that some of us want to do it, and that it will make the world a better place for all if successful, there are always those who want more of a story than that. There is of course a small mountain of literature that does indeed go far beyond my brief motivations, but I suspect that this is the case because writing and thinking is easy. Building new technology is much harder, and so, inevitably, there is far more discussion than action for rejuvenation research, just as is the case for every challenging form of human endeavor.

A friend recently recommended a paper by Davide Sisto entitled "Moral Evil or Sculptor of the Living? Death and the Identity of the Subject". Unfortunately I was slightly underwhelmed. While it does contain an interesting metaphor - namely: that we should view death as a valuable 'sculptor' of our identities - it presents this metaphor in a way that bothers me. It presents it as part of critique of the contemporary (transhumanist) view of death as a biological problem that can be solved with the right the technological fix. Indeed, it tries to suggest that those who favour radical life extension are beholden to an absurd metaphysics of death. Now, to the extent that certain transhumanists believe we can achieve a genuine immortality - i.e. an existence free from all prospect of death - I might be inclined to agree that there is something absurd in their views. But I'm not convinced that this fairly represents the views of anti-ageing gurus like Aubrey de Grey. I think they have a much more modest, and I would suggest sensible, view: that human life can be prolonged far beyond the current limits without thereby causing us to lose something of tremendous value to our sense of self.

Ostensibly, Sisto's paper attempts to contrast two views of death. The first view of death is the one that has now started to dominate in the secular, medicalised world. It is the view of death as something that is part of the current natural order. When Christianity dominated the western world, death was viewed as a consequence of original sin. As the Christian view slowly receded into the background, it was replaced by a biological and medical view of death. Death was a consequence of the current natural order - an unfortunate result of biological decay. Our cells slowly degrade and denature themselves. The degradation eventually reaches a critical point at which our metabolically maintained homeostasis breaks down. This results in our deaths (though the precise markers of biological death are somewhat disputed - 'brain death' is the currently preferred view). This naturalised view of death is very different from the old Christian ideal, closely joined to something that the bioethicist Daniel Callahan calls 'technological monism', the belief that everything in the world is, in principle if not in fact, within the reach of our technology. Technological monism suggests that death is not a fixed and immutable feature of our existence. It is something we can - with the right kind of intervention - prevent. We can slow down and reverse our biological ageing. We can preserve our identities for longer than we previously hoped. This 'technologised' view of the world lends support to the belief that death is a moral evil: it is something within our power to fix, and hence we are, morally speaking, on the hook for allowing it to continue.

There is much more in Sisto's discussion of the 'death as moral evil' view, but I think the preceding summary captures the gist. The main argumentative thrust of Sisto's paper comes from the contrast he draws between this view and his own preferred view of 'death as a sculptor'. The essence of this view is that death is not separable from life contrary to what the technological monists want to believe. They want to have a life without death. But this is not possible. Death is a necessary part of life as a whole. It is what gives shape, direction and, above all else, a sense of identity to life. Sisto explains this symbolic idea by reference to the biological process of apoptosis, or programmed cell death. This is a highly regulated biological process whereby cells within an organisms body will kill themselves off when they are no longer necessary for some particular tissue. Sisto makes this example do a lot of work. He argues that the apoptotic process is essential to biological life; that it is what gives the organism its unique identity. He believes that this supports his contention that life and death are inseparable. Death is built into the biological process of being alive. Once you die, your life becomes characterised by the path you took through the space of possible choices. This path contains all your accomplishments and failures, all your loves and losses, all your aspirations and fears. It effectively constitutes your identity. Without death, this lifeline would lose its unique identity. If you had infinite time to play around in, you could travel back down some other paths; take routes through life that you hadn't taken before. Death - the end of choice-making - is what sculpts you from the void of possibilities. I find this metaphor to be very evocative. It really does give you an interesting perspective on the nature of death. But I don't think it is as interesting and useful as Sisto supposes.

Link: http://philosophicaldisquisitions.blogspot.ca/2016/07/is-death-sculptor-of-life-or-evil-to-be.html

Researchers have recently demonstrated that raised levels of neuroregulin-1 in parts of the brain can reduce the build up of amyloid plaque and improve measures of memory in a mouse lineage engineered to reproduce the features of Alzheimer's disease. This is one of a range of methods that have shown improvements of one kind or another in a mouse model of Alzheimer's disease, and so far most have not exhibited useful results in human studies, or otherwise failed to make it much further along the path to the clinic. The degree to which particular models steer research in a useful direction is a legitimate question: Alzheimer's research is a field in which a great deal of debate, theorizing, and second guessing takes place precisely because meaningful results have yet to emerge from many years of large-scale investment. Given the history it is entirely appropriate to take a wait and see approach to this sort of thing. The reason I point out this research rather than any other is because it involves neuregulin-1.

If you wander the literature, or even just look back in the Fight Aging! archives, you'll find neuregulin-1 showing up in all sorts of interesting lines of research. Levels of neuregulin-1 are high in long-lived naked mole-rats and appear to vary by longevity in various rodent species. Increased neuregulin-1 in the heart has been shown to spur usually active regeneration, and bear in mind that the heart is an organ that normally regenerates poorly following damage in mammalian species. There are clinical trials at various stages for the use of neuregulin in heart failure patients. Higher levels of neuregulin-1 appear to slow kidney damage and might help with nerve repair as well. There are also lines of research that connect neuregulin-1 with exercise levels, making it yet another candidate for one of the myriad ways in which exercise produces health benefits, and others that link neuregulin-1 and related proteins with the exceptional regenerative capacity of species like salamanders and zebrafish. All in all this protein is something of a nexus for numerous distinct areas of research into regeneration and the effects of aging. That said, given all the other information, it is still perhaps a little surprising from an outside observer's perspective to find it reducing levels of amyloid - it doesn't quite follow the theme established above.

Elevating brain protein allays symptoms of Alzheimer's and improves memory

Boosting levels of a specific protein in the brain alleviates hallmark features of Alzheimer's disease in a mouse model of the disorder. The protein, called neuregulin-1, has many forms and functions across the brain and is already a potential target for brain disorders such as Parkinson's disease, amyotrophic lateral sclerosis and schizophrenia. Previously, researchers have shown that treating cells with neuregulin-1, for example, dampens levels of amyloid precursor protein, a molecule that generates amyloid beta, which aggregate and form plaques in the brains of Alzheimer's patients. Other studies suggest that neuregulin-1 could protect neurons from damage caused by blockage of blood flow.

In the new study, researchers tested this idea in a mouse model of Alzheimer's disease by raising the levels of one of two forms of neuregulin-1 in the hippocampus, an area of the brain responsible for learning and memory. Both forms of the protein seemed to improve performance on a test of spatial memory in the models. What's more, the levels of cellular markers of disease - including the levels of amyloid beta and plaques - were noticeably lower in mice with more neuregulin-1 compared to controls. The group's experiments suggest that neuregulin-1 breaks up plaques by raising levels of an enzyme called neprilysin, shown to degrade amyloid-beta. But that is probably not the only route through which neuregulin-1 confers its benefits, and the group is exploring other possible mechanisms - such as whether the protein improves signaling between neurons, which is impaired in Alzheimer's.

A neuregulin-1 treatment is not available on the market, though it is being explored in clinical trials as a potential treatment for chronic heart failure and Parkinson's disease. One advantage of neuregulin-1 as a potential drug is that it can cross the blood brain barrier, which means that it could be administered relatively noninvasively even though the efficiency is not clear. On the other hand, other research suggests too much of the protein impairs brain function. The team has come up with a small molecule that can raise levels of existing neuregulin-1 (rather than administering it directly) and are testing it in cells. This alternative therapy could be a better way to prevent plaques from forming because small molecules more readily cross the blood brain barrier.

Neuregulin 1 improves cognitive deficits and neuropathology in an Alzheimer's disease model

Several lines of evidence suggest that neuregulin 1 (NRG1) signaling may influence cognitive function and neuropathology in Alzheimer's disease (AD). To test this possibility, full-length type I or type III NRG1 was overexpressed via lentiviral vectors in the hippocampus of line 41 AD mouse. Both type I and type III NRG1 improves deficits in the Morris water-maze behavioral task. Neuropathology was also significantly ameliorated. Decreased expression of the neuronal marker MAP2 and synaptic markers PSD95 and synaptophysin in AD mice was significantly reversed. Levels of Aβ peptides and plaques were markedly reduced. Furthermore, we showed that soluble ectodomains of both type I and type III NRG1 significantly increased expression of Aβ-degrading enzyme neprilysin (NEP) in primary neuronal cultures. Consistent with this finding, immunoreactivity of NEP was increased in the hippocampus of AD mice. These results suggest that NRG1 provides beneficial effects in candidate neuropathologic substrates of AD and, therefore, is a potential target for the treatment of AD.

As illustrated by this study, most people don't think about their own future aging, and when they do they are unaware that we stand on the verge of new medical technologies that will greatly extend healthy life spans. We humans have evolved a masterful ability to avoid thinking about the future when it looks likely to be unpleasant. That is a useful trait when the unpleasant future is inevitable and unavoidable, as was the case for aging and age-related disease for the entirety of human history. Now, however, when it has become possible and plausible to produce effective rejuvenation therapies in the decades ahead, this ability to put the future out of sight and out of mind works against us. It is hard to get people to commit to planning and support of rejuvenation research in the matter of adjusting the course of their own future aging, even when the adjustment is entirely beneficial: everything they have been taught when young, formally and informally, has led them to put away considerations of later life as an ugly thing that they don't want to think about. Yet in reality, and as a further confounding outcome, people are happier when older, up to the point at which the decline into ill health becomes very evident and a real struggle. That effect is probably a measure of just how much value we place on financial security and a higher position in the hierarchy of society; from the perspective of contentment, these aspects of later life can outweigh the decline of health and function for a large fraction of a life span. This, again, may well be another reason why it is hard to obtain support to bring an end to aging.

Why do some people want to live a very long time, while others would prefer to die relatively young? A team of researchers investigated how long young and middle-aged adults in the United States say they want to live in relation to a number of personal characteristics. The results showed that more than one out of six people would prefer to die younger than age 80, before reaching average life expectancy. There was no indication that the relationship between preferring a life shorter or longer than average life expectancy depended on age, gender or education. The study is one of the first to investigate how younger adults perceive and anticipate their own aging. Using data from a telephone survey of over 1600 adults aged 18 to 64 years, the authors also found that one-third would prefer a life expectancy in the eighties, or about equal to average life expectancy, and approximately one-quarter would prefer to live into their nineties, somewhat longer than average life expectancy. The remaining participants said they hope to live to 100 or more years. Participants were on average 42 years old, half were women and 33 per cent were university graduates.

"We were particularly interested in whether how long people want to live would be related to their expectations about what their life in old age will be like." The results, which were controlled for overall happiness, confirmed that having fewer positive old age expectations was associated with the preference to die before reaching average life expectancy. On the contrary, having fewer negative old expectations was associated with the preference to live either somewhat longer or much longer than average life expectancy. "Having rather bleak expectations of what life will be like in old age seems to undermine the desire to live up to and beyond current levels of average life expectancy. People who embrace the 'better to die young' attitude may underestimate their ability to cope with negative age-related life experiences as well as to find new sources of well-being in old age."

Link: http://www.eurekalert.org/pub_releases/2016-08/cums-hld082416.php

There is great potential in the destruction and recreation of the immune system: the removal of all immune cells and replacement with new cells. This is an approach capable of curing autoimmune conditions, but perhaps more importantly it might also be used to clear out much of the dysfunction of the aged immune system. Immune system decline is an important component of the frailty of aging, and it speeds other aspects of the aging process through inflammation and a growing failure to monitor and destroy potentially harmful cells, such as those that become senescent. Just recently researchers made real progress on the immune system destruction front, finding a way to achieve that goal without harmful chemotherapy, and to match that advance, here is news of a potential method to improve the restoration phase of the process:

New research has shown how a cell surface molecule, Lymphotoxin β receptor, controls entry of T-cells into the thymus; and as such presents an opportunity to understanding why cancer patients who undergo bone-marrow transplant are slow to recover their immune system. The thymus, which sits in front of the heart and behind the sternum, imports T-cell precursors from the bone marrow and supports their development into mature T-cells that fight off dangerous diseases. T-cells are often the last cells to recover in cancer patients receiving bone marrow transplants. Though the cancer is cured, patients are often left with an impaired immune system that can take years to recover. Researchers found that Lymphotoxin β receptor was required to allow the entry of T-cell progenitors to the thymus both in a healthy state, and during immune recovery following bone-marrow transplantation.

Significantly, the team also found that antibody-mediated stimulation of Lymphotoxin β receptor in mouse models enhanced initial thymus recovery and boosted the number of transplant derived T-cells. "Post-transplantation, T-cell progenitors derived from the bone marrow transplant can struggle to enter the thymus, as if the doorway to the thymus is closed. Identifying molecular regulators that can 'prop open' the door and allow these cells to enter and mature, could well be a means to help reboot the immune system. This is just one piece of the puzzle. It may be that there are adverse effects to opening the door to the thymus, but identifying a pathway that regulates this process is a significant step." Following these positive findings the team aim to move towards in-vitro samples of human thymus to examine the role that Lymphotoxin b receptor might play in regulation of thymus function in humans.

Link: http://www.birmingham.ac.uk/news/latest/2016/08/Researchers-identify-possible-pathway-to-reboot-immune-system-after-bone-marrow-transplants.aspx

Today I'll point out a recent selection of studies on lifestyle choices and life expectancy: the costs of bad choices and the benefits of good choices. The numbers are not particular new, but it is good to be occasionally reminded of the bounds of the possible when it comes to choice versus technology. It is impossible to reliably live to 100 through the use of exercise, diet, and other good lifestyle choices. The best you can do is to change your odds from being low to being slightly less low. Lifestyle choices are not the primary driver of your future longevity. According to the actuarial community, the chance of living to 100 is 10-15% for people in the middle of life now, as opposed to 1% or so for people born a century ago. This difference is due to the progress in every area of medical technology that has produced 150 years of a gentle upward slope in adult life expectancy. If projecting that trend outwards for the rest of our lives at the same steady pace one arrives at these odds. This is the primary business of actuaries, to provide these conservative models of the future.

It is highly unlikely that this trend will in fact continue at the same pace, however, and actuaries have increasingly hedged their pronouncements for more than a decade now. Everything accomplished to date in the extension of human life expectancy has been an incidental byproduct, a side-effect of initiatives that did not deliberately target or address the root causes of aging. Aging is a consequence of cell and tissue damage and we are in the midst of a transition towards research and therapies that can slow or repair this damage; treating aging as a medical condition and working deliberately to bring it under control, in other words. The different between the past and the future of aging will be the difference between a problem left to run untended and a problem that people are actively trying to fix. The trend in life expectancy will leap to the upside in decades ahead.

The evidence suggests that the range in human life expectancy that is under our control through common lifestyle choices is somewhere in the vicinity of fifteen to twenty years. An exemplary set of choices might add five to ten years to life expectancy, and a truly terrible set of choices loses five to ten years from the baseline average. Why does this matter, beyond the obvious? It matters because we live in an age of revolutionary, rapid progress in biotechnology, through the present state of regulation ensures that what happens in the laboratory is only slowly making it to the clinic. Despite the regulatory ball and chain, a few years of life might one day make the difference between being able to benefit from a new rejuvenation therapy, and thus gaining health and additional years, or dying too soon. Ahead of us is the upward curve of technology versus the downward curve of individual mortality. Some people will reach the point at which medical technology keeps them alive and in good health for long enough to reach the era of agelessness, when aging can be completely controlled through comprehensive periodic repair of molecular damage. This is the primary reason as to why it is worth living a better lifestyle rather than a worse lifestyle - quite aside from the other benefits, such as a longer life, better health, lower lifetime medical expenditure, and so on.

Diet and exercise can reduce protein build-ups linked to Alzheimer's

In the study, 44 adults ranging in age from 40 to 85 (mean age: 62.6) with mild memory changes but no dementia underwent an experimental type of PET scan to measure the level of plaque and tangles in the brain. Researchers also collected information on participants' body mass index, levels of physical activity, diet and other lifestyle factors. Plaque, deposits of a toxic protein called beta-amyloid in the spaces between nerve cells in the brain; and tangles, knotted threads of the tau protein found within brain cells, are considered the key indicators of Alzheimer's. The study found that each one of several lifestyle factors - a healthy body mass index, physical activity and a Mediterranean diet - were linked to lower levels of plaques and tangles on the brain scans. Earlier studies have linked a healthy lifestyle to delays in the onset of Alzheimer's. However, the new study is the first to demonstrate how lifestyle factors directly influence abnormal proteins in people with subtle memory loss who have not yet been diagnosed with dementia. Healthy lifestyle factors also have been shown to be related to reduced shrinking of the brain and lower rates of atrophy in people with Alzheimer's.

Diet, Exercise, Both: All Work Equally to Protect Heart Health

Researchers divided 52 overweight, middle-aged men and women into three groups - those who dieted, exercised or did both - and charged them with losing about 7 percent of their body weight during a 12-14 week period. Those who exclusively dieted or exercised were told to decrease their food intake by 20 percent or increase their activity levels by 20 percent. Those who did both were told to eat 10 percent less and move 10 percent more. The researchers analyzed how the changes affected indicators of cardiovascular health, such as blood pressure, heart rate and other markers for heart disease and stroke, like high "bad" cholesterol levels. They found the three strategies were equally effective in improving cardiovascular health, and were expected to reduce a person's lifetime risk of developing cardiovascular disease 10 percent - from 46 percent to 36 percent.

"Because our previous research and that of others indicates that exercise and diet each provide their own unique health benefits beyond those that were evaluated in the current study, it is important to recognize that both diet and exercise are important for health and longevity. While our study did not find additive benefits of calorie restriction and exercise on traditional risk factors for cardiovascular disease, much of the actual risk of developing cardiovascular disease cannot be accounted for by traditional risk factors. Therefore, our findings don't preclude the possibility that dieting and exercise have additive effects for reducing the likelihood of developing cardiovascular disease. Furthermore, an inactive lifestyle itself is a risk factor for cardiovascular disease, although the physiologic mechanisms for this effect are unknown."

Lifestyle Modifications Versus Antihypertensive Medications in Reducing Cardiovascular Events in an Aging Society: A Success Rate-oriented Simulation

It is difficult to compare directly the practical effects of lifestyle modifications and antihypertensive medications on reducing cardiovascular disease (CVD). The purpose of this study was to compare the hypothetical potential of lifestyle modifications with that of antihypertensive medications in reducing CVD in an aging society using a success rate-oriented simulation. We constructed a simulation model for virtual Japanese subpopulations according to sex and age at 10-year intervals from 40 years of age as an example of an aging society. The fractional incidence rate of CVD was calculated as the product of the incidence rate at each systolic blood pressure (SBP) level and the proportion of the SBP frequency distribution in the fractional subpopulations of each SBP. If we consider the effects of lifestyle modifications on metabolic factors and transfer them onto SBP, the reductions in the total incidence rate of CVD were competitive between lifestyle modifications and antihypertensive medications in realistic scenarios. In middle-aged women, the preventive effects of both approaches were limited due to a low incidence rate. In middle-aged men and extremely elderly subjects whose adherence to antihypertensive medications is predicted to be low, lifestyle modifications could be an alternative choice.

Unhealthy habits cost Canadians 6 years of life

Unhealthy habits are costing Canadians an estimated six years of life. Researchers found that smoking, poor diet, physical inactivity, and unhealthy alcohol consumption contribute to about 50 percent of deaths in Canada. The study found: 26 per cent of all deaths are attributable to smoking; 24 per cent of all deaths are attributable to physical inactivity; 12 per cent of all deaths are attributable to poor diet; 0.4 per cent of all deaths are attributable to unhealthy alcohol consumption. For men, smoking was the top risk factor, representing a loss of 3.1 years. For women it was lack of physical activity, representing a loss of 3 years. The researchers also found that Canadians who followed recommended healthy behaviours had a life expectancy 17.9 years greater than individuals with the unhealthiest behaviours.

Accumulation of transthyretin amyloid is one of the root causes of aging. This is a form of protein misfolding that products harmful deposits, amyloids, in tissues. In recent years this type of amyloid has been identified as the major cause of death in supercentenarians, but it was not until very recently understood to also be a significant cause of heart failure in the earlier stages of old age. Researchers here demonstrate a scanning methodology to detect transthyretin amyloid in heart tissue, which should hopefully lead to more resources directed towards finalizing the development of an existing therapeutic approach to breaking down and clearing this amyloid. That approach has been trialed successfully in a few patients, but is currently languishing in the endless regulatory pipeline somewhere prior to clinical availability. It is madness that so little funding and urgency is given to this sort of development, especially given the existence of an approach that appears to work: transthryretin amyloid clearance should be undertaken every few years by pretty much every adult over the age of 40, and the outcome would be significantly less heart disease.

A type of heart failure caused by a build-up of amyloid can be accurately diagnosed and prognosticated with an imaging technique, eliminating the need for a biopsy. The technique may also detect the condition - called transthyretin-related cardiac amyloidosis (ATTR-CA) - before it progresses to advanced heart failure. "This is a huge advance for patients with ATTR-CA, which is under recognized and often misdiagnosed. This test will spare certain patients from having to undergo a biopsy in order to get a definitive diagnosis. Many people with ATTR-CA are frail and elderly, so being able to avoid a biopsy, even when it can be done with a less-invasive catheter-based procedure, is a significant step forward."

ATTR-CA is one of many types of amyloidosis, a condition in which a protein breaks down and forms fibrils that deposit in organs and tissues, eventually causing the organs to fail. In ATTR-CA, the transthyretin protein breaks down and forms amyloid fibrils, which mainly accumulate in the heart, disrupting its function. Different types of amyloidosis require different treatments, so obtaining an accurate diagnosis is critical. ATTR-CA was once thought to be rare, but it's now known that ATTR-CA resulting from a normal variant of the transthyretin protein has a prevalence of about 32 percent in patients with heart failure over age 75 years at autopsy. The prevalence in hospitalized patients with heart failure is about 13 percent.

The diagnostic tool evaluated in the study is derived from bone scintigraphy, a form of single-photon emission computed tomography, or SPECT, that is conventionally used to detect bone cancer. In bone scintigraphy, patients are injected with a radioactive isotope with a particular affinity for bone that has remodeled due to bone cancer. Early on, researchers noticed that the isotope, technetium 99m pyrophosphate (Tc 99m PYP), also gravitates to amyloid deposits in the heart, a defining characteristic of ATTR-CA. In this study, the researchers examined the diagnostic accuracy of the Tc 99m PYP test for ATTR-CA in a retrospective study of 179 amyloidosis patients (121 with ATTR and 50 with other types). The researchers found that the imaging test was able to correctly identify ATTR in 91 percent of those diagnosed with the disease, and was able to rule out ATTR-CA in 92 percent of those with other forms of amyloidosis or no amyloidosis.

Link: http://newsroom.cumc.columbia.edu/blog/2016/08/24/amyloid-related-heart-failure-now-detectable-with-imaging-test/

The use of animals in the study of aging has always meant striking a balance between species life span and distance from humans in the evolutionary tree of life. Very short-lived species such as worms and flies allow for much cheaper, faster studies, but the biochemistry of these species is more distant from ours, meaning fewer of the results are relevant to human medicine. Fortunately many of the fundamental processes of aging are near universal in animal life, all the way down to yeast colonies, so it is possible to perform useful exploratory research at a reasonable price. Still, researchers are ever in search of a better class of animal, one that has a much greater similarity to humans without the very lengthy life span. Even using short-lived mammals such as mice, that live for a few years, results in studies that are expensive and long-running when considered as a fraction of the length of a career, or placed against the size of most grants. Further, even mice have sometimes meaningful differences when compared with humans, such as their telomere dynamics. If large amounts of time and money are to be spent, then researchers would ideally want to run studies of aging in primates, and this has happened for decades-long studies of calorie restriction in rhesus macaques. Such studies are highly unlikely to happen again in the foreseeable future, however, given a broad dissatisfaction with the planning and outcomes of these examples. Researchers have started to look at the small selection of comparatively short-lived primates instead, and currently there is a faction advocating the use of marmosets:

Great leaps forward in our understanding of the basic biology of aging, including interventions that extend longevity, have come about from using common laboratory animal models. As we now strive to apply these findings for human benefit, a serious concern arises in how much of this research will directly translate to normal, largely healthy, and genetically varied populations of people. Laboratory animals, including rodents, are only distantly related to humans and have undergone different evolutionary pressures that likely have driven species-specific idiosyncrasies of aging. Due to our long lifespans, any outcomes of longevity interventions in human studies are unlikely to be discovered even during the research careers of current graduate students. There is then strong rationale for testing whether the interventions discovered that slow aging in laboratory rodents, such as dietary restriction, mTOR (mechanistic target of rapamycin) inhibition, or acarbose, will also extend the lifespan of species more closely related to humans. In this context, the calorie restriction studies utilizing non-human primates are prime examples of this approach. However, the rhesus macaques used in these studies also have relatively long lifespans which required time commitment in the order of decades to accomplish the recently published final results.

Most non-human primates that can be kept in healthy laboratory populations have relatively long lifespans, but the small South American common marmoset (Callithrix jacchus) may offer a number of advantages over other non-human primate species, particularly for researchers interested in aging. The normal lifespan of the common marmoset is the shortest of any anthropoid primate, with an average lifespan in captivity of approximately 7-8 years and maximum lifespans reported between 16 and 21 years. While much longer-lived than rodents, the average age of marmosets is more manageable for a designed longevity study than the 25-year average lifespan of rhesus macaques or the 70-plus average lifespan of humans. In addition, marmosets in a closed colony have a natural adult mortality that drives a decline in their cumulative survival rate from about 85 to 35% that occurs between 5 and 10 years of age. In other words, a carefully designed intervention study could occur over the time course of a single NIH RO1 granting period using this non-human primate.

Similar to other non-human primates, the sequenced marmoset genome has high homology (more than 93%) with that of humans. Many of the common molecular biology tools, including antibodies, have relatively good cross-species recognition. Marmosets have a growing track record as a non-human primate model used for a number of diseases and pathologies that are generally considered as age-related, including Parkinson's disease, respiratory diseases, and infectious diseases. Moreover, marmosets display age-related changes in pathologies associated with diabetes, cardiac disease, cancer, and renal disease similar to those seen in humans. Marmosets thus represent a complement to the existing non-human primate models used to study aging and, in particular, a model in which effects on longevity might be assessed in a relatively timely manner. Despite this promising outlook, there are some potential challenges to using the common marmoset as a non-human primate model to study aging. Like other non-human primates, there is much less genetic tractability in this species relative to the mouse, which must be taken into account when designing studies on the biology of aging. However, transgenic marmosets have been previously generated and new technologies including CRISPR/Cas systems may lead the way in developing new, genetically modified marmoset models for the study of age-related diseases or the basic biology of aging.

Link: http://dx.doi.org/10.3402/pba.v6.32758

Today I'll point out an open access critique of programmed aging theories by the originator of the disposable soma theory of aging, one of the modern views of aging as accumulated damage rather than programming. The question of how and why we age is wrapped in a lot of competing theory, but of great practical importance. Our biochemistry is enormously complex and incompletely mapped, and thus the processes of aging, which is to how exactly our biochemistry changes over time, and all of the relationships that drive that change, are also enormously complex and incompletely mapped. Nonetheless, there are shortcuts that can be taken in the face of ignorance: the fundamental differences between young and old tissue are in fact well cataloged, and thus we can attempt to reverse aging by treating these changes as damage and repairing them. If you've read through the SENS rejuvenation research proposals, well, that is the list. The research community may not yet be able to explain and model how exactly this damage progresses, interacts, and spreads from moment to moment, but that effort isn't necessary to build repair therapies capable of rejuvenation. You don't need to build a full model of the way in which paint cracks and peels in order to scrub down and repaint a wall, and building that model is a lot most costly than just forging ahead with the painting equipment.

The engineering point of view described above, simply getting on with the job when there is a good expectation of success, is somewhat antithetical to the ethos and culture of the sciences, which instead guides researchers to the primary goal of obtaining full understanding of the systems they study. In practice, of course, every practical application of the life sciences is created in a state of partial ignorance, but the majority of research groups are nonetheless oriented towards improving the grand map of the biochemistry of metabolism and aging rather than doing what can be done today to create rejuvenation therapies. Knowledge over action. If we had all the time in the world this would be a fine and golden ideal. Unfortunately we do not, which places somewhat more weight on making material progress towards the effective treatment of aging as a medical condition - ideally by repairing its causes.

But what are the causes of aging? The majority view in the research community is that aging is a process of damage accumulation. The normal operation of metabolism produces forms of molecular damage in cells and tissues, a sort of biological wear and tear - though of course the concept of wear and tear is somewhat more nuanced and complex in a self-repairing system. This damage includes such things as resilient cross-links that alter the structural properties of the extracellular matrix and toxic metabolic waste that clutters and harms long-lived cells. As damage accumulates, our cells respond in ways that are a mix of helpful and harmful, secondary and later changes that grow into a long chain of consequences and a dysfunctional metabolism that is a long way removed from the well-cataloged fundamental differences between old and young tissues. An old body is a complicated mess of interacting downstream problems. In recent years, however, a growing minority have suggested and theorized that aging is not caused by damage, but is rather a programmed phenomenon - that some portion of the what I just described as the chain of consequences, in particular epigenetic changes, are in fact the root cause of aging. In the programmed view of aging, epigenetic change causes dysfunction and damage, not the other way around. That these two entirely opposite views can exist is only possible because there is no good map of the detailed progression of aging - only disconnected snapshots and puzzle pieces. There is a lot of room to arrange the pieces in any way that can't be immediately refuted on the basis of well-known past studies.

There are two ways to settle the debate of aging as damage versus aging as evolved program. The first is to produce that grand map of metabolism and aging, something that I suspect is at the least decades and major advances in life science automation removed from where we stand now. The other is to build therapies that produce large degrees of rejuvenation, enough of a difference to put it far beyond argument that the approach taken is the right one. That is not so far away, I believe, as the first SENS rejuvenation therapies are presently in the early stages of commercial development. I think that, even with the comparative lack of funding for this line of development, ten to twenty years from now the question will be settled beyond reasonable doubt. Meanwhile, the programmed aging faction has become large enough and their positions coherent enough that the mainstream is beginning to respond substantially to their positions; I expect that this sort of debate will continue all the way up to and well past the advent of the first meaningful rejuvenation therapies, which at this point look to be some form of senescent cell clearance.

Can aging be programmed? A critical literature review

Many people, coming new to the question of why and how aging occurs, are attracted naturally to the idea of a genetic programme. Aging is necessary, it is suggested, either as a means to prevent overcrowding of the species' environment or to promote evolutionary change by accelerating the turnover of generations. Instead of programmed aging, however, the explanation for why aging occurs is thought to be found among three ideas all based on the principle that within iteroparous species (those that reproduce repeatedly, as opposed to semelparous species, where reproduction occurs in a single bout soon followed by death), the force of natural selection declines throughout the adult lifespan. This decline occurs because at progressively older ages, the fraction of the total expected reproductive output that remains in future, on which selection can act to discriminate between fitter and less-fit genotypes, becomes progressively smaller. Natural selection generally favours the elimination of deleterious genes, but if its force is weakened by age, and because fresh mutations are continuously generated, a mutation-selection balance results. The antagonistic pleiotropy theory suggests that a gene that has a benefit early in life, but is detrimental at later stages of the lifespan, can overall have a net positive effect and will be actively selected. The disposable soma theory is concerned with optimizing the allocation of resources between maintenance on the one hand and other processes such as growth and reproduction on the other hand. An organism that invests a larger fraction of its energy budget in preventing accumulation of damage to its proteins, cells and organs will have a slower rate of aging, but it will also have fewer resources available for growth and reproduction, and vice versa. Mathematical models of this concept show that the optimal investment in maintenance (which maximizes fitness) is always below the fraction that is necessary to prevent aging.

In recent years, there have been a number of publications claiming that the aging process is a genetically programmed trait that has some form of benefit in its own right. If this view were correct, it would be possible experimentally to identify the responsible genes and inhibit or block their action. This idea is, however, diametrically opposed to the mainstream view that aging has no benefit by its own and is therefore not genetically programmed. Because experimental strategies to understand and manipulate the aging process are strongly influenced by which of the two opinions is correct, we have undertaken here a comprehensive analysis of the specific proposals of programmed aging. On the principle that any challenge to the current orthodoxy should be taken seriously, our intention has been to see just how far the various hypotheses could go in building a convincing case for programmed aging.

This debate is not only of theoretical interest but has practical implications for the types of experiments that are performed to examine the mechanistic basis of aging. If there is a genetic programme for aging, there would be genes with the specific function to impair the functioning of the organism, that is to make it old. Under those circumstances, experiments could be designed to identify and inhibit these genes, and hence to modify or even abolish the aging process. However, if aging is nonprogrammed, the situation would be different; the search for genes that actively cause aging would be a waste of effort and it would be too easy to misinterpret the changes in gene expression that occur with aging as primary drivers of the senescent phenotype rather than secondary responses (e.g. responses to molecular and cellular defects). It is evident, of course, that genes influence longevity, but the nature of the relevant genes will be very different according to whether aging is itself programmed or not.

For various programmed theories of aging, we re-implemented computational models, developed new computational models, and analysed mathematical equations. The results fall into three classes. Either the ideas did not work because they are mathematically or conceptually wrong, or programmed death did evolve in the models but only because it granted individuals the ability to move, or programmed death did evolve because it shortened the generation time and thus accelerated the spread of beneficial mutations. The last case is the most interesting, but it is, nevertheless, flawed. It only works if an unrealistically fast-changing environment or an unrealistically high number of beneficial mutations are assumed. Furthermore and most importantly, it only works for an asexual mode of reproduction. If sexual reproduction is introduced into the models, the idea that programmed aging speeds up the spread of advantageous mutations by shortening the generation time does not work at all. The reason is that sexual reproduction enables the generation of offspring that combine the nonaging genotype of one parent with the beneficial mutation(s) found in the other parent. The presence of such 'cheater' offspring does not allow the evolution of agents with programmed aging.

In summary, all of the studied proposals for the evolution of programmed aging are flawed. Indeed, an even stronger objection to the idea that aging is driven by a genetic programme is the empirical fact that among the many thousands of individual animals that have been subjected to mutational screens in the search for genes that confer increased lifespan, none has yet been found that abolishes aging altogether. If such aging genes existed as would be implied by programmed aging, they would be susceptible to inactivation by mutation. This strengthens the case to put the emphasis firmly on the logically valid explanations for the evolution of aging based on the declining force of natural selection with chronological age, as recognized more than 60 years ago. The three nonprogrammed theories that are based on this insight (mutation accumulation, antagonistic pleiotropy, and disposable soma) are not mutually exclusive. There is much yet to be understood about the details of why and how the diverse life histories of extant species have evolved, and there are plenty of theoretical and experimental challenges to be met. As we observed earlier, there is a natural attraction to the idea that aging is programmed, because developmental programming underpins so much else in life. Yet aging truly is different from development, even though developmental factors can influence the trajectory of events that play out during the aging process. To interpret the full complexity of the molecular regulation of aging via the nonprogrammed theories of its evolution may be difficult, but to do it using demonstrably flawed concepts of programmed aging will be impossible.

Given that the author here has in the past been among those who dismissed the SENS initiative as an approach to treating aging by repairing damage, it is perhaps a little amusing to see him putting forward points such as this one: "despite the cogent arguments that aging is not programmed, efforts continue to be made to establish the case for programmed aging, with apparent backing from quantitative models. It is important to take such claims seriously, because challenge to the existing orthodoxy is the path by which science often makes progress." Where was this version of the fellow ten years ago?

Ghrelin is related to the hunger response, but has a very broad range of influences on many tissues and systems, including immune system activities. Inflammaging is the name given to the inflammation-focused view of the characteristic decline and dysfunction of the immune system with aging. While increased levels of inflammation occur for everyone due to immune system aging, those people who allow themselves to become overweight suffer a greater level of chronic inflammation, driven by the way in which metabolically active visceral fat tissue provokes immune activation. The research here joins all of these dots, and the scientists involved demonstrate that removing the ghrelin receptor in mice can suppress the influence of fat tissue on chronic inflammation:

"To date, ghrelin is the only known appetite-stimulating hormone. The pharmaceutical industry has been calling ghrelin 'the key to obesity' since its discovery. We investigated the impact of ghrelin signaling on adipose tissue macrophages, in order to understand the role of ghrelin signaling in obesity." Hunger stimulates ghrelin in the gut, which activates brain regions where the ghrelin receptor, growth hormone secretagogue receptor, or GHS-R, is highly expressed, triggering the hunger sensation. Ghrelin enhances appetite and increases weight gain, promoting obesity and consequent insulin resistance.

Obesity, in essence, is a condition characterized by low-grade chronic inflammation in adipose tissues. Adipose tissue serves as a major endocrine organ, secreting various hormones and cytokines which play crucial roles in normal metabolism and obesity-associated dysfunctions. Adipose tissue macrophages, or ATMs, are a major mediator of inflammation in adipose tissues, which are closely linked to insulin resistance. Macrophages are a type of white blood cells that surround and digest microbes, pathogens and other foreign substances. "Macrophages are a major mediator of inflammation in the body. Increased macrophage infiltration in adipose tissues has been shown to positively correlate with age-associated metabolic complications, neurodegenerative diseases and cardiovascular diseases."

ATMs consist of two subsets - pro-inflammatory M1 and anti-inflammatory M2. M1-like macrophages are associated with an obese and insulin-resistant state, while M2-like macrophages are associated with a lean and insulin-sensitive state. M1-like macrophages release pro-inflammatory cytokines to inhibit insulin action in the tissues. On the other hand, M2-like macrophages release anti-inflammatory cytokines. "We have found that the GHS-R functions as a key regulator of age-associated adipose tissue inflammation. The removal of GHS-R shifts macrophages toward an anti-inflammatory state." Aging is commonly accompanied by increased fat mass and chronic low-grade inflammation, so concurrences of obesity and insulin resistance become significantly greater as people get older.

GHS-R global null mice - with the GHS-R removed in all cell types - showed a macrophage profile shifted toward the anti-inflammatory M2, exhibiting a healthier lean and insulin-sensitive phenotype. "Old mice with GHS-R deletion showed a reduction in macrophage infiltration, M1/M2 ratio and pro-inflammatory cytokine production in adipose tissues." The new findings suggest suppressing the ghrelin receptor may serve as a new therapeutic strategy for inflammation and obesity in aging. The study indicates the ghrelin receptor plays an important role in macrophages, which can have profound implications on obesity and insulin resistance. Current research using global null mice cannot determine whether the phenotype is resulted in by the effect of GHS-R in macrophages alone, however. Scientists must determine the macrophage-specific effects of GHS-R, and understand precisely how ghrelin signaling works, in order to avoid unintended side effects. The researchers are now developing new mouse models which would enable them to delete GHS-R selectively in macrophages.

Link: http://today.agrilife.org/2016/08/22/agrilife-researcher-takes-close-look-inflamm-aging/

Rapamycin, an immunosuppressant and MTOR inhibitor, is known to slow aging in mice - though it has been debated whether this extension of life span is actually a slowing of aging versus a lower rate of cancer. Researchers here try a variety of different treatment regimens and find that a comparatively short period of rapamycin treatment in mouse middle age produces better effects than the longer term dosage that has been standard in studies. The publicity materials emphasize the high points and the outliers in the mouse data; I'd recommend reading the paper for a more responsible and overall view of the outcomes.

Even with improved results and possibly a new longevity record for this mouse species, I don't think the improved outcomes much alter the overall picture for trying to slow the processes of aging in this way, by altering metabolism towards the sort of changes known to occur in response to calorie restriction. It is, however, interesting to consider what must be going on in mouse biochemistry to allow a shorter intervention to have a larger effect than a longer intervention. One possibility is that the longer intervention does in fact have all of the beneficial effects, but that the unpleasant side-effects of rapamycin begin to outweigh those benefits greatly as the mice get older. Regardless, keep in mind that mice have very plastic life spans - interventions such as calorie restriction and growth hormone receptor knockout that extend life in mice by 40-70% are known not to have large effects on longevity in humans, and we should expect that to be the case for the beneficial side of rapamycin as well.

Rapamycin, approved by the FDA for certain organ transplant recipients, is already known to extend life in mice and delay some age-related problems in rodents and humans. Still, many questions prevail about when, how much and how long to administer rapamycin, what its mechanisms of action are in promoting healthy aging, and ways to avoid serious side effects. Researchers showed that a transient dose of rapamycin in middle age was enough to increase life expectancy and improve measures of healthy aging. The scientists treated mice with rapamycin for 90 days starting at 20 months of age, approximately the mouse equivalent of a 60 year old person. The control and rapamycin-treated mice were maintained identically both before and after the treatment period. Remarkably, the rapamycin treated mice lived up to 60 percent longer after the treatment was stopped, compared to the animals that received a mock control treatment.

This, the researchers said, seems to be the biggest increase in life expectancy ever reported in normal mice from a medication. "It's quite striking that short-term rapamycin treatment had such a lasting impact on health and survival after the treatment was stopped." The reasons behind this outcome aren't completely clear, according to the researchers, but one interpretation might be that the animals were, to some degree, rejuvenated by the treatment and became biologically younger than their actual age. The most-senior mouse in the study was Ike, the namesake of a relative of one of the researchers. The mouse Ike lived 1400 days. For a person, that would be like hailing a 140th year birthday. "To our amazement, considering the relatively small size of the group of mice we studied, Ike might have been one of the longest lived mice of his kind." Ike was a wild-type C57BL/6, a designation for the one of the most common sub-strains of mice.

On the other hand, some of the side effects observed during the study were less than celebratory. The cautionary findings, the researchers noted, illustrate the need to better understanding the relationship between the dose of rapamycin and its beneficial as well as detrimental effects. The researchers saw a gender difference when higher doses of rapamycin were given: males outlived the females. At lower doses, both male and female mice had longer lives, compared to untreated mice. Higher doses can make female mice more susceptible to aggressive cancers of blood-forming cells and tissue. At the same time, middle-aged female mice receiving high-doses of rapamycin were less likely to develop other types of cancer. The transient rapamycin treatment also changed the composition of the microbiome - the collection of bacteria and other microbes - in the guts of the mice. They had more segmented, filamentous bacteria of a type not usually present in high numbers in aged mice. While these bacteria are not invasive, they adhere tightly to the cells of the intestinal wall and may encourage the formation of immune cells in the mouse. Otherwise, the influence of this gut microbiome change from rapamycin on the health of an animal, for good or bad, and whether the same thing happens in humans, has not been determined.

Link: http://hsnewsbeat.uw.edu/story/brief-rapamycin-therapy-middle-aged-mice-extends-lives

As I mentioned last week, earlier this year Fight Aging! invested a modest amount in the Ichor Therapeutics initiative to develop a treatment for macular degeneration, joining a number of other amateur and professional investors in helping to get this venture started. The approach taken here is based on the results of research carried out at the Methuselah Foundation and SENS Research Foundation over much of the past decade, funded by philanthropists and the support of our community of longevity science enthusiasts. This is how we succeed in building the future: medical science in the laboratory leads to medical development in startup companies, each new stage bringing treatments capable of repairing specific forms of age-related molecular damage that much closer to the clinic.

Ichor Therapeutics is one of a growing number of success stories to emerge from the SENS rejuvenation research community. Young scientists, advocates, and donors involved in earlier projects - years ago now - have gone on to build their own ventures, while retaining an interest in stepping up to do something meaningful to help bring an end to aging. Back in 2010, Kelsey Moody worked on the LysoSENS project to find ways to break down damaging metabolic waste in old tissues; fast-forward six years, and he is the now the CEO of a successful small biotechnology company with a great team, taking that very same technology and putting it to good use. I recently had the chance to ask Kelsey a few questions about the future of SENS rejuvenation research, as well as how the Ichor scientists intend to construct a new class of therapy for macular degeneration, one based on removing one of the root causes of the condition.

Who are the people behind Ichor Therapeutics? How did you meet and decide that this was the thing to do? Why macular degeneration as a target?

People have always been the focus of Ichor. Since day one we have worked to create a positive environment that cultivates a product-oriented research focus and emphasizes autonomy and personal accountability for work. As a result, ambitious self-starters tend to find their way to Ichor and remain here. However, we recognized early on that just filling a lab with a bunch of blue-eyed bushy tailed young up-and-comers is not sufficient to develop a robust, mature, translational pipeline. We have augmented our team with a number of critical staff members who are seasoned pharma operators, including our Quality Assurance Director and General Counsel.

Age-related macular degeneration (AMD) was chosen as a target because we believe it is the closest SENS therapy to the clinic. While we obviously have an interest in providing cures for the patients suffering from AMD and are attracted to the large market opportunities such a treatment could bring, our broader interest is in validating the entire SENS paradigm. We believe that Aubrey de Grey continues to receive excessive criticism because nothing spun out of SENS has ever made it into a legitimate pre-clinical pipeline, much less to the bedside. However, this does not mean he is wrong. Our goal is to be the first group to bring a SENS inspired therapy into the clinic and in doing so, silence critics and generate new energy and capital for this cause.

I understand there's a lengthy origin story for the approach you are taking to treat AMD; it'd be great to hear some of it.

Our approach to treating AMD is based on the hypothesis that cellular junk that accumulates over the lifespan significantly contributes to the onset and progression of AMD. Our goal is to periodically reduce the burden of the junk so it never accumulates to levels sufficient to induce pathology. The strategy to accomplish this calls for the identification of enzymes that can break down the junk in a physiological setting, and the engineering of these enzymes such that they can break down the target in the correct organelle of the correct cell without appreciable collateral damage to healthy cells or tissue.

Methuselah Foundation and SENS Research Foundation did excellent work in establishing this program nearly a decade ago. They successfully identified a number of candidate enzymes that could break down the molecular junk, but reported that the targeting systems evaluated failed to deliver these enzymes to the appropriate organelles and cells. My group reevaluated these findings, and discovered that these findings were flawed. The delivery failure could be entirely attributed to a subtle, yet highly significant difference between how the target cells behave outside of the body as compared to inside the body. It turned out that the approach was in fact valid, it was the cell based assay that had been used that was flawed. This discovery was striking enough that SENS Research Foundation provided Ichor with funding and a material and technology transfer agreement to reassess the technology, and over $700,000 in directed program investments and grants have been received in the last year or two.

You recently completed a round of funding for the AMD work; what is the plan for the next year or so?

The new funds will allow us to develop a portfolio of enzyme therapy candidates to treat AMD. We will obtain critical data necessary to secure follow-on investment including in vitro studies (cell culture studies to confirm mechanism of action and cytotoxicity) and pivotal proof-of-concept in vivo studies, such as toxicity, PK/PD (how long the enzyme stays in the body and where), and efficacy. We will also be restructuring the company (reincorporating an IP holding company in Delaware, ensuring all contracts are up to date and audited) and ensuring our IP position is on solid footing (licensing in several related patents from existing collaborators, and filing several provisional patents from our intramural work). Collectively, we believe these efforts will position us to obtain series A for investigational new drug (IND) enabling pre-clinical studies.

You've been involved in the rejuvenation research community for quite some time now. What is your take on the bigger picture of SENS and the goal of ending aging?

This is a loaded question. What I can say is that the medical establishment has made great progress in the treatment of infectious disease through the development of antibiotics, vaccines, and hygiene programs. However, similar progress has not been realized for the diseases of old age, despite exorbitant expenditures. I have chosen to work in this space because I think a different approach is necessary, and it is here that I believe my companies and I can be the most impactful. I think SENS provides a good framework within which to ask and answer questions.

What do you see as the best approach to getting nascent SENS technologies like this one out of the laboratory and into the clinic?

We need more people who fully understand, in a highly detailed way, what a real translational path looks like. To take on projects like this, being a good scientist is not enough. We need people who can speak business, science, medicine, and legal, and apply these diverse disciplines to a well articulated, focused product or problem. There is no shortage of people who partially understand some of these, but the details are not somewhat important - they are all that matter for success in this space.

Another area is for investors. Some of the projects that come across my desk for review are truly abysmal, yet I have seen projects that are clearly elaborate hoaxes or outright scams (to anyone who has stepped foot in a laboratory) get funded to the tune of hundreds of thousands of dollars or more. While it is perfectly reasonable for high net worth individuals to gamble on moon shots in the anti-aging space (and I am ever grateful for the investors who have taken such a gamble on us) even aggressive development strategies should have some basis in reality. This is especially true as more and more high tech and internet investors move into the space.

If this works stupendously well, what comes next for Ichor Therapeutics?

I really want to get back into stem cell research, but I basically need a blank check and a strong knowledge of the regulatory path to clinic before I feel comfortable moving into the space. A successful AMD exit would accomplish both of these goals, and position us to pivot to cell-based therapies.

It is known that cells can transfer mitochondria from one to another under some circumstances, and here researchers demonstrate that they can transfer lysosomes as well. The lysosomes in a cell play the role of recycling units, breaking down damaged structures and waste proteins. Unfortunately there are some forms of waste that our biochemistry cannot manage, and these compounds accumulate over time into a harmful mix called lipofuscin. In old tissues, long-lived cells have clogged and malfunctioning lysosomes, unable to perform the task of recycling waste. This spirals downwards into a garbage catastrophe and the cells either die or become highly dysfunctional themselves. This process of resilient waste accumulation in lysosomes is one of the root causes of aging and age-related disease.

The research here focuses on just one form of damaged protein and one class of conditions caused by the accumulation of that protein, but the transfer of lysosomes noted by the researchers has broad implications for the more general process of lysosomal dsyfunction in aging. If cells are transferring lysosomes in all tissues then this will act to dilute damage for the worst affected cells at the cost of spreading the damage more widely within important cell populations - it will be an important determinant of the way in which damage and decline progresses. That said, this is of interest but not importance given a class of therapy that can break down the waste that makes up lipofuscin. With such a tool, capable of delivering suitable enzymes to the lysosome, it doesn't matter how the waste material spreads. The SENS Research Foundation has been working on this for a while now, mining the bacterial world for suitable enzymes. Some of these have been licensed to Human Rejuvenation Technologies, and others to Ichor Therapeutics for further development for specific therapies.

Synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, are characterized by the pathological deposition of aggregates of the misfolded α-synuclein protein into inclusions throughout the central and peripheral nervous system. Intercellular propagation (from one neuron to the next) of α-synuclein aggregates contributes to the progression of the neuropathology, but little was known about the mechanism by which spread occurs. In this study researchers used fluorescence microscopy to demonstrate that pathogenic α-synuclein fibrils travel between neurons in culture, inside lysosomal vesicles through tunneling nanotubes (TNTs), a new mechanism of intercellular communication.

After being transferred via TNTs, α-synuclein fibrils are able to recruit and induce aggregation of the soluble α-synuclein protein in the cytosol of cells receiving the fibrils, thus explaining the propagation of the disease. The scientists propose that cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. However, this results in the disease being spread to naive neurons. This study demonstrates that TNTs play a significant part in the intercellular transfer of α-synuclein fibrils and reveals the specific role of lysosomes in this process. This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies. These compelling findings, together with previous reports from the same team, point to the general role of TNTs in the propagation of prion-like proteins in neurodegenerative diseases and identify TNTs as a new therapeutic target to combat the progression of these incurable diseases.

Link: http://www.pasteur.fr/en/institut-pasteur/news-institut-pasteur/tunneling-nanotubes-between-neurons-enable-spread-parkinson-s-disease-lysosomes

Researchers here demonstrate a method of improving the effectiveness of a stem cell therapy targeted to brain tissues, enabling the treatment to repair more of the damage caused by a stroke:

A team of researchers has developed a therapeutic technique that dramatically increases the production of nerve cells in mice with stroke-induced brain damage. The therapy relies on the combination of two methods that show promise as treatments for stroke-induced neurological injury. The first consists of surgically grafting human neural stem cells into the damaged area, where they mature into neurons and other brain cells. The second involves administering a compound called 3K3A-APC, which the scientists have shown helps neural stem cells grown in a petri dish develop into neurons. However, it was unclear what effect the molecule, derived from a human protein called activated protein-C (APC), would have in live animals.

A month after their strokes, mice that had received both the stem cells and 3K3A-APC performed significantly better on tests of motor and sensory functions compared to mice that received neither or only one of the treatments. In addition, many more of the stem cells survived and matured into neurons in the mice given 3K3A-APC. "This animal study could pave the way for a potential breakthrough in how we treat people who have experienced a stroke. If the therapy works in humans, it could markedly accelerate the recovery of these patients."

To confirm that the stem cells were responsible for the animals' improved function, the researchers used a targeted toxin to kill the neurons that had developed from them in another group of mice given the combination therapy. These mice showed the same improved performance on the tests of sensory and motor functions prior to being given the toxin but lost these gains afterwards, suggesting that the neurons that grew from the implanted cells were necessary for the improvements. In a separate experiment, the team examined the connections between the neurons that developed from the stem cells in the damaged brain region and nerve cells in a nearby region called the primary motor cortex. The mice given the stem cells and 3K3A-APC had many more neuronal connections, called synapses, linking these areas than mice given the placebo. In addition, when the team stimulated the mice's paws with a mechanical vibration, the neurons that grew from the stem cells responded much more strongly in the treated animals. "That means the transplanted cells are being functionally integrated into the host's brain after treatment with 3K3A-APC. No one in the stroke field has ever shown this, so I believe this is going to be the gold standard for future studies."

Link: https://www.nih.gov/news-events/news-releases/stem-cell-therapy-heals-injured-mouse-brain

Researchers have of late been mapping the activities and relationships of Forkhead box protein N1 (Foxn1) in the thymus, and the paper I'll point out today outlines some of the most recent findings. Sadly it isn't open access, but I'm sure that won't stop the determined reader in this day and age. This work is of interest to our community of longevity science supporters because increased levels of Foxn1 have been shown to restore a more youthful level of thymic activity in older animals and human cell lines, and have been used to regrow thymic tissue when used in conjunction with cell therapies.

Why is thymic activity important? To simplify greatly, the thymus is where new T cells of the adaptive immune system mature after they are created. Its comparatively low level of activity in adults is one of the gating factors limiting the supply of new immune cells across most of the life span. Children have a very active thymus, and as a result a comparatively large supply of new immune cells, but the organ atrophies quite early in adulthood in a process known as thymic involution. Fat tissue replaces most of the structures that once nurtured immune cells and going forward an adult must get by with far fewer new immune cells. This low level of supply is one of the factors that effectively limits the size of the immune cell population in adults, and the fact that this population is limited eventually gives rise to a form of harmful resource misallocation. After a lifetime of exposure to pathogens, by the time old age arrives too many immune cells become focused on threats that cannot be cleared from the body, such as cytomegalovirus. When a large fraction of the limited population of cells become uselessly specialized in that way, too few cells are left to perform all of the other needed tasks: destroying cancerous and senescent cells, tackling unfamiliar pathogens, and so on.

The decline of the immune system is an important component of the frailty of aging, but this isn't just because old people become very vulnerable to infection. A failing immune system accelerates many of the other causes of aging. It produces greater chronic inflammation, as it is more active even as it is less able to do its job, contributing to a faster progression of near all of the common age-related diseases. The immune system is responsible for destroying senescent cells, which in larger numbers cause harm through the creation of inflammation and destruction of tissue structures. Fewer of these cells destroyed means more left to produce damage and dysfunction. Then there are potentially and actually cancerous cells, which have a greater chance of survival as the immune system becomes ever less effective. This is not to mention that the immune system plays a role in wound healing, as well as many other important processes. Given all of this, the goal of a restored immune system is a very important one, and even partially restoration should produce clear benefits.

One approach to this problem is to destroy the unwanted cells that are taking up space. Another approach is to deliver a much larger supply of new immune cells, such as directly via regular cell therapies, or alternatively through restoration of the thymus. There are a few different possible ways to restore the thymus. Transplantation has been shown to work in mice, producing improved immune function and extension of life, but that isn't going to work in human medicine since we'd want everyone to get a new thymus in old age. Tissue engineering is a strong possibility: researchers have made promising inroads towards the creation of thymic tissue. Then there is the use of Foxn1 to spur regrowth of the thymus, and this can even be mixed in with forms of cell therapy to grow thymic tissue within the patient rather than build outside the body and then transplant. Given the demonstrated importance of Foxn1, it is worth paying attention to research such the results noted here.

Study suggests routes to improved immunity in older people

Humans, like all higher animals, use T cells as part of the immune system, to fight off infections and cancer. T cells are generated in an organ called the thymus, where they closely interact with thymic epithelial cells (TEC) as they mature. People without TEC cannot generate T cells, severely compromising the immune system and consequently increasing the risk for life threatening infections and cancer. More than 20 years ago the transcription factor Foxn1 was identified as an essential molecule for the normal development of TEC. However, the genes directly controlled by Foxn1 - and thus responsible for the various TEC functions - have remained unidentified.

The researchers used new experimental models and analytical tools to investigate which genes were regulated by Foxn1 and how it affected them. Transcription factors bind to particular sections of our DNA and the team is the first to identify the DNA sequence bound by Foxn1. From there, they identified the hundreds of genes whose expression is regulated by this master regulator. These include genes that are essential to attract precursor cells in the blood, which are destined to become T-cells, to the thymus, genes that commit these precursor cells to become T cells and genes that provide the molecular machinery which allows the selection of those T cells that best serve an individual. Experiments in which Foxn1 expression by TEC was inhibited, confirmed that the transcription factor needs to be continuously present for TEC to function normally.

"The thymus is the organ in humans that first displays an age-dependent, physiological decline in function. It grows until puberty and then shrinks throughout the rest of our lives. This is thought to contribute to the decline in immunity in older people, which makes them more susceptible to opportunistic infections and cancers. The findings from these studies therefore provide important insight into the genetic control of regular TEC function and identify new potential strategies to preserve thymus function for longer, raising the prospect of a healthier old age."

Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells

Thymic epithelial cell differentiation, growth and function depend on the expression of the transcription factor Foxn1; however, its target genes have never been physically identified. Using static and inducible genetic model systems and chromatin studies, we developed a genome-wide map of direct Foxn1 target genes for the postnatal thymic epithelium and defined the Foxn1 binding motif. We determined the function of Foxn1 in these cells and found that, in addition to the transcriptional control of genes involved in the attraction and lineage commitment of T cell precursors, Foxn1 regulates the expression of genes involved in antigen processing and thymocyte selection. Thus, critical events in thymic lympho-stromal cross-talk and T cell selection are indispensably choreographed by Foxn1.

In this open access paper, results are presented for an animal study of an approach to increasing the pace of remyelination in the brain. Myelin acts as sheathing for the axons that connect nerve cells; when it is degraded, insufficiently maintained, or damaged, the result is dysfunction in the nervous system. A range of demyelinating diseases result from the loss of myelin in specific locations, many of which are life-threatening. To a lesser degree, loss of myelin occurs over the course of aging for all of us. It is unclear as to the degree that this process contributes to age-related decline in cognitive and physical function, but given what is known from the observation of demyelinating diseases it is unlikely that the losses are harmless. Thus it is well worth paying attention to progress towards therapies that can increase the rate of remyelination, as it is likely that a robust and effective approach would be useful for all older individuals:

Microglia play critical but incompletely understood roles in propagation and resolution of central nervous system (CNS) injuries. These cells modulate neuroinflammation, produce factors that regulate activities of astrocytes, oligodendrocytes, and neurons, and clear debris to provide an environment for oligodendrocytes to begin to remyelinate neurons. Separately, limited information is available concerning the role of human blood monocytes in the dynamics of repair of brain injury. Circulating human monocytes include subpopulations that differ in their ability to migrate to tissues, proliferate, and form inflammatory or reparative macrophages at sites of injury. Based on experiments in rodents, several groups have proposed that cell products composed of human monocytes could be considered as candidates for the treatment of injury-induced CNS demyelination. CD14+ monocytes present in human umbilical cord blood (CB) are among these candidates.

We have recently developed DUOC-01, a cell therapy product composed of cells with characteristics of macrophages and microglia that is intended for use in the treatment of demyelinating CNS diseases. DUOC-01 is manufactured by culturing banked CB-derived mononuclear cells (MNCs). The studies described in this report were designed to provide proof of concept for the use of DUOC-01 in treatment of demyelinating diseases that do not arise from enzyme deficiency. To accomplish this, we assessed the ability of DUOC-01 to promote remyelination of mouse brain after cuprizone-induced (CPZ-induced) demyelination, a model that has been widely used to study the mechanisms and cellular dynamics of remyelination in the corpus callosum (CC) region, and also to test the effects of various interventions, including cell therapy agents.

We showed, to the best of our knowledge for the first time, that CPZ feeding in immunodeficient mice results in reversible demyelination in the CC with a time course similar to the process in immune-competent mouse strains, and that this model can be used to assess the activity of human cell therapy products in promoting brain remyelination. Using this model, we demonstrate that the DUOC-01 cell product accelerates brain remyelination following CPZ feeding. We also show that uncultured CD14+ CB cells that give rise to DUOC-01 also accelerate remyelination, but significantly less actively than DUOC-01 cells. A comparison of whole-genome expression arrays of CB CD14+ monocytes and DUOC-01 revealed large differences in gene expression, and helped identify candidate molecules that may participate in remyelination. We subsequently confirmed that cells in the DUOC-01 product express and secrete several factors that promote myelination by several mechanisms.

Link: http://insight.jci.org/articles/view/86667

The lacrimal gland provides moisture for the eyes, and like all parts of our physiology is prone to decline and failure in old age. Dry eye conditions, some of which are painful and debilitating, are common in old people. Researchers here demonstrate a cell therapy to spur regeneration of the lacrimal gland in an animal study, a step along the road to achieving the same thing in humans:

The eye's lacrimal gland is small but mighty. This gland produces moisture needed to heal eye injuries and clear out harmful dust, bacteria and other invaders. If the lacrimal gland is injured or damaged by aging, pollution or even certain pharmaceutical drugs, a person can experience a debilitating condition called aqueous deficiency dry eye (ADDE) - sometimes called "painful blindness." If injured, a healthy lacrimal gland naturally regenerates itself in about seven days. When diseased and chronically inflamed, however, regeneration stops - and scientists are not sure why.

Researchers looked at whether they could kick start regeneration by injecting progenitor cells into the lobes that make up the lacrimal gland. Progenitor cells are similar to stem cells in their ability to differentiate into different kinds of tissue. In this study, the researchers used progenitor cells that were poised to become epithelial tissue, a key component of the lacrimal gland. The researchers knew they faced a major challenge: sorting and separating "sticky" epithelial cell progenitors without destroying them. "We had to figure out how to dissociate the tissue into single cells without completely obliterating everything." The researchers solved this problem by developing markers to label the cells of interest and then testing different enzymes and other reagents to draw them out of tissues.

With these cells in hand, the researchers injected them into the lacrimal glands of mouse models of Sjogren's syndrome, an autoimmune disease that results in ADDE, dry mouth and other symptoms. The team used only older, female mice because ADDE most commonly strikes that demographic in humans. The treated mice showed a significant increase in tear production, indicating - for the first time - that epithelial cell progenitors could repair the lacrimal gland. Further tests suggested that epithelial cell progenitors helped by restoring the connection between cells called myoepithelial contractile cells and the lacrimal gland's secretory cells, which produce tears. The next step in this research will be to study how long the improvement in the lacrimal gland lasts after progenitor cell injections.

Link: https://www.sciencedaily.com/releases/2016/08/160818090048.htm

Across the last twenty years or so two very important, slow-moving battles over ideas and strategy have been fought within and around the aging research community. The first was to gain acknowledgement that the treatment of aging as a medical condition is a viable goal, and thus obtain the necessary support to make progress towards that goal. Even as recently as fifteen years ago ago, after years of extending the lifespan of laboratory animals in various ways, treating aging was still more or less a forbidden topic in the research community. Thankfully we have a long way since then in the matter of ideas, and it was a tough and long-running uphill process of advocacy and persuasion - a great deal of work was required to create change. Today we can say that this first battle is near done and finished, with only the mopping up remaining to be accomplished within the scientific community. Those who a decade ago dismissed the goal of treating aging or simply remained silent are now ready to talk in public and provide support. The public at large is unfortunately still behind the times, much less informed or convinced on the matter of aging, but that will change too.

It is the second battle within the scientific community that is now more of a concern for advocates - certainly more of a concern for this advocate. That battle is to shape the research strategies that are funded and pursued: in short whether to try to modestly slow aging or to aim to build rejuvenation therapies capable of reversing aging. When it comes to the future of our health and longevity, this is just as important as the efforts needed to move the research community to support the treatment of aging at all, and at this point has much further to go to a satisfactory conclusion. Sadly we live in a world in which, for various historical and regulatory reasons, the research community is almost entirely set on trying to modestly slow aging. Research groups follow the traditional approach of drug development, searching for compounds that can alter the operation of metabolism so as to slow down some of the changes that accompany aging. This is enormously expensive and has a low rate of success - you can look at the failed efforts to produce calorie restriction mimetics, for example, such as the hundreds of millions of dollars and a decade put into sirtuin research with nothing to show for it at the end. Current efforts to repurpose the drug metformin are likely to end up in the same place: enormous sums and a great deal of effort are spent chasing effects that are tiny.

Aging is all about damage accumulation. Slowing aging means a slower pace at which damage accrues. Reversing aging means repairing that damage - and thus there are ways to do much better than merely tinkering metabolism to somewhat slow down the arrival of new damage. Since the research community has a very good catalog of the damage that causes aging, researchers are in a position to build treatments to repair it, therapies that can in principle produce rejuvenation. Those treatments have been planned and visualized in great detail for years now, and in a sparse few cases are under early clinical development in startups. Yet repairing the damage of aging to produce rejuvenation is a minority concern in the broader field, with little support despite its far greater potential. This, then, is the battle fought now, to direct the research community to the far better option rather than continuing in their status quo of working towards the far worse option.

The Geroscience Network is an example of what has come from victory in the first battle of ideas, to generate much greater support for treating aging within the research community. In the past few years things have blossomed to the point at which many influential figures openly advocate for the goal of treating aging, the root cause of all age-related disease, rather than treating age-related diseases one by one. The Geroscience Network was established among those US research groups and institutions whose principals have the greatest interest in treating aging as a medical condition. To quote the pertinent part of their brief:

We hypothesize that by targeting fundamental mechanisms of aging, clinical interventions can be envisaged that could delay or prevent age-related diseases and disabilities as a group, rather than one at a time. By planning and working in a coordinated way through the Geroscience Network, we intend to accelerate development and translation of effective treatments to delay or prevent age-related disabilities and diseases.

Some of the Geroscience Network researchers recently published a selection of open access position papers in the Journals of Gerontology. The papers frame their determination to treat aging, and are focused on aspects of the strategy: how to move forward within the regulatory system, how to undertake clinical translation of potential therapies, how to build clinical trials for this new world of treating aging rather than age-related disease. Notably where specific technologies are mentioned there is little of anything that SENS rejuvenation research supporters would recognize as an effective approach to treat aging, however. The Geroscience Network is the product of researchers who have a slightly overlapping but overall quite different view of aging, which you can find described in the noted Hallmarks of Aging paper, or the later pillars of aging materials. Much of what is seen in those publications as a cause of aging, such as epigenetic changes, looks to my eyes to be a later consequence of the forms of molecular damage described in the SENS proposals. The overlapping areas where the Hallmarks of Aging and SENS agree, such as senescent cell clearance, are to be welcomed where they lead to efforts like UNITY Biotechnology, but it is still the case that more representative examples of Geroscience Network participant projects include the clinical trial of metformin and efforts to develop calorie restriction mimetic drugs, such as the failed sirtuin projects. So while on the one hand it is great to see that the treatment of aging is now well supported as a goal for the research community, it remains unfortunate that the chosen approaches are so very marginal.

Still, there is a clear path ahead for the spread of SENS technologies into the mainstream. That is to demonstrate effectiveness, the old story of bootstrapping enough success on a shoestring budget to obtain greater support from those who were originally skeptical or had their own favored but less effective approach. Senescent cell clearance is the pioneering example here: advocated in the SENS vision for fifteen years, but ignored by the vast majority of researchers. Only in the last five years, since a 2011 demonstration of effectiveness, has more of the research community started to work in this area - and now two startups are working on bringing therapies to the clinic. This example puts the future of SENS rejuvenation therapies squarely on us, the donors, the philanthropists, the supporters. We determine the degree to which SENS succeeds in spreading to the mainstream by our efforts to pull in enough funding and attention to get the research done and the prototypes built. So look at the message of the Geroscience Network researchers with some optimism: yes it is frustrating that they are headed down the wrong road, but they will adopt SENS approaches just as soon as those approaches can be proven in animal studies. Yes, it will be a hard work all the way to the finish line, but when was anything in life easy? In any case, take a look at the papers and see what you think.

Moving Geroscience Into Uncharted Waters

Research into the basic biology of aging has undergone a seismic shift in the last 10-20 years, moving rapidly from the very descriptive approach focused on the aged that was the predominant focus by the end of the last century, to a more mechanistic (and primarily genetics-driven) phase, focused less on describing the aging phenotype in different models, and more on a definition of the molecular and cellular drivers of the process. This progression was accompanied by an evolution in the concepts and ideas that have dominated the field in the past, namely free radicals, cell senescence, and caloric restriction, each of which became the seed upon which the modern foci of research now stands. Progress in a variety of research areas has crystallized into the beginnings of a conceptualization of the process, including seminal publications that described the major hallmarks or pillars of aging.

Aging research is not simply an academic pursuit, it actually holds more promise in terms of helping mankind than most or all other biomedical fields. In terms of health and human suffering, it is well known that four out of five older Americans suffer from at least one chronic disease, and more than half suffer from multiple comorbidities. Aging being the major risk factor for all those diseases, it follows that research into aging could be pivotal in our efforts to reduce the suffering associated with the ravages of old age. In addition to the direct health issues, it has been calculated that care for the elderly currently accounts for 43% of the total health care spending in the United States. By delaying aging even by a lesser degree than currently achieved in animal models, there will be significant gains both in terms of health and wealth. The enormous advances in basic aging research, coupled with the promises described in the previous paragraphs, led to the concept of geroscience, a field that aims to understand the molecular and cellular mechanisms responsible for aging being the major risk factor and driver of common chronic conditions and diseases of the elderly. Of course, there is considerable work to be done in order to bring the field forward and move aging biology towards translation. Major areas in need of further development include, in the preclinical space, the development of better, reliable, and predictive biomarkers, as well as development of metrics for health, including resilience.

Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms

An effective preclinical pipeline for developing interventions that target fundamental aging processes could one day transform medicine. However, at the Geroscience Network retreat, it was evident that the best potential strategies for drug discovery and development were not perceived as uniform among those working in the field. In some sense this is not surprising, as researchers have yet to define what is needed to develop a mechanism-based aging therapeutic with clinical utility. Still, the discordance among leaders in the field was enlightening-revealing many unanswered questions and unmet challenges in the discovery and preclinical development of drugs that target mechanisms of aging.

Recent, fundamental advances in our understanding of aging biology have brought the prospects of therapeutic interventions to extend health span and treat age-related diseases and disabilities as a group closer to reality. Despite the growing numbers of promising genetic and pharmaceutical interventions, significant work and financial investment are still needed in order to translate these basic science discoveries into the clinic. To this end, clinical trial strategies relevant to human frailty and resilience must first be established in validated invertebrate and vertebrate models. In addition, standardized preclinical drug development pathways are desperately needed. Some barriers to the clinical translation of therapies that target fundamental aging processes can be overcome by developing new preclinical testing approaches and clinical trials strategies, as well as and funding impediments unique to aging interventions. Together, we must engage in dialog and establish a framework to facilitate the translation of candidate compounds into effective drugs that promote health span and target age-related disorders in humans.

Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes

The successful translation of therapies that target fundamental aging processes into routine clinical interventions could transform the practice of medicine and human health. A number of candidate drugs (many already FDA-approved for other indications) have shown promise in preclinical studies. This Geroscience Network retreat developed ideas for proof-of-concept clinical trials that could be the next step in translating interventions that target fundamental aging processes into clinical practice. We described three frameworks for proof-of-concept trials, targeted at age-related diseases, geriatric syndromes, and resilience to acute stressors. Some aspects of clinical trial design are common to all three, whereas some require unique consideration in each framework. Importantly, proof-of-concept clinical trials would serve to test and advance the "geroscience hypothesis" that targeting the fundamental biology of aging will affect a range of age-related outcomes. Trial outcomes would be multidimensional and include outcomes related to the mechanism of action of the intervention; specific to the disease, syndrome, or stress under study; related to off-target effects of the intervention; and broadly relevant to the mechanisms and physiology of aging. Finally, several concrete steps could greatly accelerate the progress of clinical trials of interventions that target basic aging processes, including the development of standardized templates for trial design, toolkits for standardized outcome measurements, the establishment of a national geroscience biobank, and the development of specialist trial and training centers in the Geroscience Network.

Strategies and Challenges in Clinical Trials Targeting Human Aging

Clinical trials that target fundamental aging processes in humans are a novel concept that presents unique challenges and enormous opportunities. Challenges include selection of appropriate study populations, study designs, interventions, and outcomes. We presented two models that conceptualize trial designs for interventions that target fundamental aging processes in long-term and acute settings, defined by extension of health span and resilience to acute stressors, respectively. However, in order to gain the full support of federal and private sectors for development of therapeutics that target aging in humans, it is important to have "aging" or aging-associated outcomes such as frailty, functional decline, and multimorbidity designated as conditions eligible for registration by the FDA. Evidence from human studies is emerging that indicates certain interventions can target multiple age-related conditions simultaneously, potentially by interfering with the aging process itself. With the aging population projected to grow exponentially in the near future, clinical studies that can demonstrate the protective effect of these therapeutics during acute and chronic perturbations in aging humans are more timely than ever. Thus, delaying or preventing the disabilities that occur as a consequence of the aging process would result not only in tremendous cost savings for the healthcare system but also in gains for society on the whole from the increase in productive contributions from older members of society.

Resilience in Aging Mice

Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance healthspan and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects.

At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context. The preliminary set of tests ranked by the participants is discussed here, recognizing that this is a first attempt.

Heat shock proteins such as the Hsp70 family are involved in the housekeeping processes that keep cells functioning well by destroying damaged proteins. They become active in response to stresses that cause a higher rate of damage to the protein machinery within cells, such as toxicity or heat - and hence the name. Many of the genetic alterations and other interventions shown to modestly slow aging in short-lived laboratory animals involve increased cellular maintenance in one way or another, so there is some interest in the research community in building therapies to artificially increase such maintenance activities. So far this hasn't resulted in useful approaches, however, and thus the only reliable way to improve these matters in your own life is still to exercise and practice calorie restriction - increased cellular maintenance is one of the ways in which these lifestyle choices make a difference to long-term health. There is no doubt value in going beyond this to seek much greater increases in cellular maintenance through medical science, but the large sunk costs and lack of results so far suggests that other, more direct means of repairing important forms of cell and tissue damage will be cheaper and more effective. Here I'm thinking of the SENS research proposals; the present state of natural repair processes would be sufficient given the existence of rejuvenation therapies capable of as-needed damage repair of the more critical issues.

One hallmark of aging is the accumulation of protein aggregates, promoted by the unfolding of oxidized proteins. Unraveling the mechanism by which oxidized proteins are degraded may provide a basis to delay the early onset of features, such as protein aggregate formation, that contribute to the aging phenotype. Members of the 70 kDa-heat shock protein (Hsp70) family are, in their function as molecular chaperones, involved in folding of newly synthesized proteins and refolding of damaged or misfolded proteins, as well as in assembly and disassembly of protein complexes. The role of Hsp70 in protection against oxidative stress-related damage has been widely accepted. However, to our knowledge, a possible function of Hsp70 in promoting the removal of oxidized proteins has not been investigated. In the current study, we are able to demonstrate not only the involvement of Hsp70 in protection against the oxidative stress-related accumulation of oxidized proteins, but also in their proteasomal degradation.

Hsp70 knockdown and prevention of Hsp70 induction during stress resulted in significantly increased levels of protein carbonyls after hydrogen peroxide treatment. Although heat shock proteins can refold mildly disordered proteins, it is clear that heat shock proteins are not able to repair covalently-modified oxidized proteins nor to reverse oxidative protein modifications. Thus, we suggested that Hsp70 must somehow be implicated in the removal of oxidized proteins. Moreover, Hsc70 deficiency did not lead to changes in protein carbonyl levels and, therefore, Hsc70 seems not to have a major role in this process. Albeit, Hsp70 and Hsc70 have a quite similar structure, it appears that their participation in (oxidative)-stress induced protein degradation is different. It is postulated that both proteins differ in their C-terminal regions, which may result in different cellular functions. Hsc70 is an important housekeeping protein, mostly responsible for the folding of newly synthesized proteins and involved in maintaining protein homeostasis in non-stressed conditions. In contrast, Hsp70 is mainly responsible for a rapidly inducible cell protection following stress situations. Relating to this, we have shown that Hsc70 expression is not affected by oxidative stress, while Hsp70 expression is induced about two-fold in our cellular model, which is comparable to results obtained in other cell lines. Since oxidative damage to proteins leads to their unfolding, the 'heat shock response' is activated and the expression of molecular chaperones is increased.

We demonstrated the ability of Hsp70 to bind oxidized proteins in vitro, as well as in our cell model and in vivo. Interestingly, these oxidized proteins bound to Hsp70 did not show a higher polyubiquitination, which further supports the widely accepted assumption that oxidized proteins are degraded by the 20S proteasome in an ubiquitin-independent way. It has been demonstrated that oxidized proteins are not preferentially ubiquitinated and that an intact ubiquitination system is not required for their degradation. Using various techniques, we demonstrated that Hsp70 interacts additionally with the 20S proteasome, confirming our hypothesis that Hsp70 seems to mediate the interaction between oxidized proteins and the 20S proteasome.

Taken together, the results presented in our current study demonstrate the involvement of the stress-inducible molecular chaperone Hsp70 in the 20S proteasomal degradation of oxidized proteins. We suggest that in the early phase after oxidative stress, Hsp70 binds to partially unfolded oxidized proteins and keeps them in a soluble, degradable form. Oxidized proteins bound to Hsp70 can then migrate to 20S proteasomes where they can be efficiently degraded. Thus, besides the direct recognition of oxidized protein substrates by the 20S proteasome, there seems to be another, Hsp70-mediated, way to catalyze the efficient degradation of oxidized proteins. Future studies should investigate the involvement of co-chaperones/interacting proteins and co-factors which may be involved in this process and which modulate the ability of Hsp70 to mediate shuttling of oxidized proteins to the 20S proteasome. Moreover possible interaction sites of Hsp70 on 20S proteasome subunits remain to be identified. Furthermore, there is increasing evidence that the stress-related inducibility of Hsp70 expression declines in aged cell models and organisms and that the chaperones are overloaded in aged cells due to increasing formation and accumulation of oxidized proteins and. Thus, modulating Hsp70 levels may be a possible pharmaceutical goal to maintain protein homeostasis and prevent the formation of toxic protein aggregates that can disrupt cellular function.

Link: http://dx.doi.org/10.1016/j.freeradbiomed.2016.08.002

Researchers here report on an interesting finding emerging from epidemiological data on twins, in that twins exhibit modestly lower mortality rates than the rest of the population. The paper focuses on the support and relationship angle, referencing the marriage effect on life expectancy, but I think that one could just as well field arguments based on effects in the womb, statistical differences in physical robustness, or a number of other items linked to longevity in human or animal studies that have shown up in the literature over the past few decades. Ultimately this is all interesting but irrelevant to the future of human longevity: small natural differences will be overwhelmed by the results of progress in medicine if things go well. A few years either way won't much matter when rejuvenation therapies can add decades of healthy life, something that may well happen within our lifetime if enough support goes to the right lines of research.

While studies of extreme longevity clustered within human families have indicated at least some genetic role in determining lifespan at very advanced ages, twin studies, which offer the opportunity to disentangle the genetic and environmental factors for a given trait, indicate genetic factors are responsible for only a modest amount of the variation (20-30%) in human lifespan and that the role of genetic factors is minimal before age 60, but increases thereafter. Although twin studies that focus on the correlation in age-at-death have yielded important insights into the role of genetics in human lifespan, the determinants of human survival patterns are immensely complex and change with age - i.e. while genetic factors play an increasingly larger role at advanced ages, environmental, social, and behavioral factors influence survival patterns much more heavily at younger ages. Perhaps owing to this complexity and the traditional structure of twin survival studies, less is known about differences in survival across age by zygosity, the underlying mortality processes that produce these differences, or the role of zygosity itself in shaping age patterns of survival.

Using data from the Danish Twin Registry and the Human Mortality Database, we show that monozygotic (MZ) twins have greater cumulative survival proportions at nearly every age compared to dizygotic (DZ) twins and the Danish general population. We examine this survival advantage by fitting these data with a two-process mortality model that partitions survivorship patterns into extrinsic and intrinsic mortality processes roughly corresponding to acute, environmental and chronic, biological origins. Overall, we find a survival advantage for MZ twins over DZ twins of both sexes at nearly every age and of DZ twins over the general population, but that different processes confer these advantages at different ages. For females, the survival advantage at all ages can be attributed to lower extrinsic mortality rates. Among males, extrinsic advantages account for the survival advantage up to about age 65 where the overall survival advantage begins to narrow and MZ males show better intrinsic survival than DZ males and DZ males show better intrinsic survival compared to the general population.

This research has documented a 'twin protection effect' akin to a marriage protection effect where a socially close relationship contributes to better survival outcomes throughout most of life. Notably, while we find evidence for a health protection effect arising from zygosity, the use of twin data allows us to avoid the confounding issue of self-selection that studies of marriage and health often encounter. Research on marriage protection effects as well as the findings presented in this paper are part of a larger body of literature that documents the importance of social support and cohesion for mortality and longevity outcomes. In this case greater survival for MZ twins over DZ twins and DZ twins over the general population is driven by lower extrinsic mortality at most ages, which is a likely consequence of the social bond between twins buffering against risky behaviors, providing emotional or material assistance during times of stress exposure, and promoting health-enhancing behaviors.

Link: http://dx.doi.org/10.1371/journal.pone.0154774

Today I'll direct your attention to a couple of videos, thematically linked by the presence of Aubrey de Grey, cofounder of the SENS Research Foundation and tireless advocate for progress towards working rejuvenation therapies. For the first of the videos, de Grey recently took part in a panel discussion involving representatives of the biotechnology industry, the research establishment, and venture capital community, with the topic being the coming development of a new industry that will develop therapies to extend healthy life and turn back aging. That industry has barely started to form its earliest and smallest stage today, as the first lines of rejuvenation research reach the point of commercial viability. There are a few startups and a lot of deep pockets yet to be convinced that this is going somewhere - though the commentary in the panel is encouraged, considering those involved.

The recent Rejuvenation Biotechnology 2016 conference hosted by the SENS Research Foundation was more along the same lines, focused on creating a foundation for the near future industry that will build and provide rejuvenation therapies. The purpose of the conference series is to help smooth the way for these treatments to move rapidly from the laboratory to the clinic, to build the necessary relationships, manage expectations, and pull in the additional support needed to make best possible progress. The conference was livestreamed over the past couple of days, and at one point Aubrey de Grey announced the just-then-and-there acceptance of the first scientific publication for the MitoSENS team at the SENS Research Foundation. They are presently in the lead, at the cutting edge, among the few groups working on the project of copying mitochondrial genes into the cell nucleus to protect them from the damage of aging. Ultimately, copying all thirteen genes should completely remove the contribution of mitochondrial damage to degenerative aging, as mitochondria will no longer become dysfunctional as their local DNA is damaged. They will get the proteins they need from the cell nucleus instead. It is a worthy project, and it is always welcome to see progress on this front.

Launching Longevity: Funding the Fountain of Youth

Can technology make human longevity a reality? As the pace of discovery accelerates, scientists and entrepreneurs are closing in on the Fountain of Youth. Disrupting the aging process by hacking the code of life, promises better health and longer maximum lifespans. With many layers of complexity from science to ethics, there are still skeptics placing odds against human longevity. Venture capitalists are betting on success; putting big money on the table to fund longevity startups. Google/Alphabet and drugmaker AbbVie have invested $1.5 billion on Calico, while Human Longevity Inc. recently raised $220 million from their Series B funding round. Complementing traditional venture investment, VCs like Peter Thiel and Joon Yun have established foundations and prizes to accelerate the end of aging. Why are VCs suddenly investing heavily in longevity startups? Will extended lifespan be a privilege of the wealthy or will the benefits be accessible to all? How long before these well-funded startups bring viable products to market?

Aubrey de Grey Announces Progress in MitoSENS

Ok everybody, before I introduce the next session I just wanted to make a very small, brief, but very welcome announcement. Literally half an hour ago we received some extremely good scientific news. Those of you who have been following SENS research since before the SENS Research Foundation itself even existed will know that, about a decade ago, the very first project, the very first research program that we were able to initiate - with the help of, especially, the initial donation of Peter Thiel - was to make mitochondrial mutations harmless by essentially putting backup copies of the mitochondrial DNA into the nuclear genome, modified in such way of course that the encoded proteins would be colocated back into the mitochondria to do their job. This is an idea that was first put forward more than 30 years ago, but it is an idea that despite quite a bit of initial effort, nobody was able to make work. When I first came across this concept, in fact I'd thought of it myself, it's a pretty obvious idea really, I came to the conclusion that a lot of the despair and despondency and pessimism about this approach was premature, and that it was worth having another go, and so that was the very first project we decided to fund.

Suffice to say that it has not been quite as easy as I was hoping to make progress in that space, but progress has now been made, step by step, over the past several years, with the help especially of the absolutely amazing team we have at the research center, who work on this, headed by Matthew O'Connor. Amutha Boominathan is the number two on the team, and is absolutely indispensable, I've no idea where we'd be without her. So, what's happened half an hour ago is that for the very first time in the entire history of this project, we have got far enough to have a paper accepted in a very nice journal, Nucleic Acids Research, which reports on our progress in this area. The headline result in this paper is that we are the first team ever to get two of the proteins encoded by genes in the mitochondrial DNA simultaneously functioning in the same cell line, and of course - two is equivalent to infinity for mathematicians, you know that, right? - this is extremely heartening news, and I just wanted to let you all know, thank you.

In recent years a growing number of researchers have investigated the effects of putting old tissue into a young supporting environment. Typically this involves parabiosis: joining the circulatory systems of an old mouse and a young mouse. Given a knowledge what exactly is different between old and young environments, work also be carried out in cell cultures, however. Researchers have been using these methodologies to search for and evaluate potentially important signaling changes that occur with aging. Of particular interest are changes that impact stem cell populations, causing them to become less active, as the decline in stem cell activity with age is an important contribution to frailty and loss of function. In the research noted here, scientists are focused on cerebrospinal fluid and neural tissues rather than blood and the cardiovascular system, but find similar signs of an ability to spur greater stem cell activity in old tissue:

Researchers have discovered that the choroid plexus, a largely ignored structure in the brain that produces the cerebrospinal fluid, is an important regulator of adult neural stem cells. The study also shows that signals secreted by the choroid plexus dynamically change during aging which affects aged stem cell behavior. Stem cells are non-specialized cells found in different organs. They have the capacity to generate specialized cells in the body. In the adult brain, neural stem cells give rise to neurons throughout life. The stem cells reside in unique micro-environments, so-called niches which provide key signals that regulate stem cell self-renewal and differentiation. Stem cells in the adult brain contact the ventricles, cavities filled with cerebrospinal fluid (CSF) that bathes and protects the brain. The research team has now shown that the choroid plexus is a key component of the stem cell niche, whose properties change throughout life and affect stem cell behavior.

The researchers uncovered that the choroid plexus secretes a wide variety of important signaling factors in the CSF, which are important for stem cell regulation throughout life. During aging, the levels of stem cell division and formation of new neurons decrease. The research team showed that although stem cells are still present in the aged brain, and have the capacity to divide, they do so less. "One reason is that signals in the old choroid plexus are different. As a consequence stem cells receive different messages and are less capable to form new neurons during aging. In other words, compromising the fitness of stem cells in this brain region. But what is really amazing is that when you cultivate old stem cells with signals from young fluid, they can still be stimulated to divide - behaving like the young stem cells. We can imagine the choroid plexus as a watering can that provides signals to the stem cells. Our investigations also open a new route for understanding how different physiological states of the body influence stem cells in the brain during health and disease, and opens new ways for thinking about therapy."

Link: https://www.unibas.ch/en/News-Events/News/Uni-Research/Cerebrospinal-fluid-signals-control-the-behavior-of-stem-cells-in-the-brain-.html

It is by now well known that the ApoE4 variant of Apolipoprotein E is associated with a higher risk of Alzheimer's disease in many populations. This is thought to be the case because this variant is less effective in roles that influence the breakdown of amyloid-β, a form of metabolic waste that accumulates in Alzheimer's patients. Researchers here provide evidence that ApoE4 is also relevant to the harmful accumulation of damaged tau protein, another form of waste that is associated with Alzheimer's disease. This should probably be taken as an indication that greater attention should be given to the development of ways to clear tau aggregates as well as amyloid aggregates:

For decades, scientists have known that people with two copies of a gene called apolipoprotein E4 (ApoE4) are much more likely to have Alzheimer's disease at age 65 than the rest of the population. Now, researchers have identified a new connection between ApoE4 and protein build-up associated with Alzheimer's that provides a possible biochemical explanation for how extra ApoE4 causes the disease. Apolipoprotein E comes in three versions, or variants, called ApoE2, ApoE3 and ApoE4. All the ApoE proteins have the same normal function: carrying fats, cholesterols and vitamins throughout the body, including into the brain. While ApoE2 is protective and ApoE3 appears to have no effect, a mutation in ApoE4 is a well-established genetic risk factor for late-onset Alzheimer's disease. Previous reports have suggested that ApoE4 may affect how the brain clears out amyloid-β, but what was happening at the molecular level wasn't clear.

Scientists had previously uncovered hints that ApoE4 might degrade differently than the other variants, but the protein that carried out this breakdown of ApoE4 was unknown. To find the protein responsible for degrading ApoE4, researchers screened tissues for potential suspects and homed in on one enzyme called high-temperature requirement serine peptidase A1 (HtrA1). When they compared how HtrA1 degraded ApoE4 with ApoE3, they found that the enzyme processed more ApoE4 than ApoE3, chewing ApoE4 into smaller, less stable fragments. The researchers confirmed the observation in both isolated proteins and human cells. The finding suggests that people with ApoE4 could have less ApoE overall in their brain cells - and more of the breakdown products of the protein. "There's been an idea tossed around that ApoE4 breakdown products could be toxic. Now, knowing the enzyme that breaks it down, we have a way to actually test this idea." But it's not just a lack of full-length ApoE or an increase in its fragments that may be causing Alzheimer's in people with ApoE4. Researchers also found that ApoE4 - because it binds so well to HtrA1 - keeps the enzyme from breaking down the tau protein, responsible for tau tangles associated with Alzheimer's.

Link: http://www.salk.edu/news-release/new-mechanism-discovered-alzheimers-risk-gene/

Earlier today at the Rejuvenation Biotechnology 2016 conference, the SENS Research Foundation folk announced a $15,000 challenge grant for the present OncoSENS cancer research crowdfunding effort. All donations from here forward will be matched dollar for dollar from the grant, and the deadline for the fundraiser has been extended for another thirty days to give this a chance to run. The funds raised from the community through this initiative will be used to carry out the first high-throughput screening of drug candidates for cancers that use the alternative lengthening of telomeres (ALT) mechanism to maintain their growth. Finding ways to block ALT is a necessary part of any future universal cancer therapy based on preventing telomere extension in cancer cells: all cancers must do this to grow, and without it they will wither away. The matching fund is provided by the generosity of an anonymous donor and Christophe and Dominique Cornuejols, who you will recall have helped to build the matching funds for the past few years of Fight Aging! SENS fundraisers. Their efforts are very much appreciated! You can find the announcement at 5:18 in the conference livestream from earlier today:

Rejuvenation Biotechnology Conference, Wednesday Morning Lifestream, 5:18

Cancer will be controlled, the only question is how long it takes to achieve that goal. The next generation of immunotherapies and other very targeted approaches to kill cancer cells with few side-effects will greatly improve patient outcomes for all of the most common cancers. These therapies will still, however, have the disadvantage of being very tailored to specific cancers and attributes of cancer cells. It takes a lot of time and money to produce a new treatment for cancer, and if that treatment is specific to only one or only a few of the hundred of subtypes of cancer ... well, that isn't very efficient. There is only so much funding and only so many researchers. Tackling cancer one type at a time is just not the way to win on a short timeframe.

The strategy and economics of the situation are why it is so very important that work on a universal cancer therapy prospers. The most targetable mechanism that is known to be necessary for all cancers is telomere lengthening. Telomeres are sequences of repeated DNA that cap the ends of chromosomes, and a little of that length is lost with each cell division. This is a part of the limiting mechanism that prevents the overwhelming majority of ordinary somatic cells in our bodies from running amok to divide and replicate endlessly: cells with short telomeres self-destruct or become senescent, in either case dividing no more. Cancers can grow destructively because the mutated state of their cells has unlocked one of the few possible ways to lengthen telomeres. A range of research groups are working on the production of therapies to block telomere extension that occurs through telomerase activity, but next to no-one is working with ALT. Because individual tumors evolve rapidly, blocking both telomerase and ALT will be necessary: blocking only telomerase has already been demonstrated in animal studies to cause a cancer to switch over to ALT. Thus the SENS Research Foundation, supported by philanthropic donations from people like you and I, has stepped in to pick up the slack and get this job done. Do you want a future free from cancer? Then here is a chance to help make that happen: donate to the OncoSENS fundraiser.

The advent of tools capable of accurately assessing the state of biological aging, such as measurement of changes in DNA methylation patterns, means that researchers can now produce additional and more robust data on quite small differences in longevity that exist when comparing various human populations. Measurement doesn't say much about why these differences exist: there we are back to discussing the degree to which it is genetics versus lifestyle and culture. Nonetheless, this particular study provides good evidence for the utility of DNA methylation as a biomarker of aging, given that the results match up fairly well with those obtained from statistical population data. Having a reasonably accurate measure of biological age is very important for the future development of rejuvenation therapies, as it will make it much faster and cheaper to determine what works and what doesn't work. The cost of research and development will be greatly reduced if researchers can immediately test the results of a potential rejuvenation therapy rather than having to wait and see what it does to health and life span.

"Latinos live longer than Caucasians, despite experiencing higher rates of diabetes and other diseases. Scientists refer to this as the 'Hispanic paradox.' Our study helps explain this by demonstrating that Latinos age more slowly at the molecular level." Latinos in the U.S. live an average of three years longer than Caucasians, with a life expectancy of 82 versus 79. At any age, healthy Latino adults face a 30% lower risk of death than other racial groups. Researchers used several biomarkers, including an "epigenetic clock", to track an epigenetic shift linked to aging in the genome. Epigenetics is the study of changes to the DNA molecule that influence which genes are active but don't alter the DNA sequence itself. The team analyzed 18 sets of data on DNA samples from nearly 6,000 people. The participants represented seven different ethnicities: two African groups, African-Americans, Caucasians, East Asians, Latinos and an indigenous people who are genetically related to Latinos. Called the Tsimane, the latter group lives in Bolivia.

When the scientists examined the DNA from blood - which reveals the health of a person's immune system - they were struck by differences linked to ethnicity. In particular, the scientists noticed that, after accounting for differences in cell composition, the blood of Latinos and the Tsimane aged more slowly than other groups. The research points to an epigenetic explanation for Latinos' longer life spans. For example, the biological clock measured Latino women's age as 2.4 years younger than non-Latino women of the same age after menopause. "We suspect that Latinos' slower aging rate helps neutralize their higher health risks, particularly those related to obesity and inflammation. Our findings strongly suggest that genetic or environmental factors linked to ethnicity may influence how quickly a person ages and how long they live."

The Tsimane aged even more slowly than Latinos. The biological clock calculated the age of their blood as two years younger than Latinos and four years younger than Caucasians. The finding reflects the group's minimal signs of heart disease, diabetes, hypertension, obesity or clogged arteries. "Despite frequent infections, the Tsimane people show very little evidence of the chronic diseases that commonly afflict modern society. Our findings provide an interesting molecular explanation for their robust health." In another finding, the researchers learned that men's blood and brain tissue ages faster than women's from the same ethnic groups. The discovery could explain why women have a higher life expectancy than men.

Link: http://www.newswise.com/articles/it-s-true-latinos-age-slower-than-other-ethnicities

This open access paper provides a perspective on some of the mechanisms of stiffening of blood vessels, though curiously without talking much about cross-linking of important structural molecules in the extracellular matrix. This stiffening is one of the most dangerous and damaging immediate consequences of the cell and tissue damage that lies at the root of aging. It causes hypertension, a condition of chronic high blood pressure, and a consequent detrimental remodeling of heart tissue. This leads to many of the varieties of cardiovascular disease, including an increased rate of breakage of tiny blood vessels in the brain, each destroying a tiny amount of tissue, but collectively causing a deterioration of cognitive function. Ultimately this results in vascular dementia, heart failure, and other fatal conditions. But it all starts with a loss of elasticity in blood vessels driven by mechanisms such as senescent cell accumulation, cross-link formation, and calcification in blood vessel walls.

Stiffening of the aorta and large elastic arteries is a hallmark of vascular aging. It has a number of adverse haemodynamic consequences, including a major contribution to isolated systolic hypertension. When measured by aortic pulse wave velocity (aPWV), it is highly predictive of clinical cardiovascular disease events independent of blood pressure, both in the general population and in groups with additional risk factors. Formerly thought to be simply a marker of atherosclerosis, the pathology of aortic stiffening may differ, at least in part, from that of atherosclerosis. Thus, in primate models of atherosclerosis, aPWV is reduced compared to non-atherosclerotic controls, at least in the early stages of atherosclerosis. In humans, aPWV is largely independent of risk factors other than age and blood pressure and is not elevated in the presence of non-calcified atheromatous plaque. The prognostic importance of arterial stiffening and the fact that it may be driven by a specific pathology distinct from atherosclerosis makes it an appealing target to prevent cardiovascular disease events.

In older subjects, calcification occurs in the media of the arterial wall around elastin fibres ('elastocalcinosis') and within atherosclerotic plaque in the intima. Although often regarded as distinct entities, intimal and medial calcifications often coexist. Arterial stiffening is closely associated with calcification, an association that could be explained by coexistent atherosclerosis. However, animal models show that medial calcification (in the absence of atherosclerosis) increases arterial stiffness, suggesting a direct causal relation between calcification and stiffening. Using combined computed tomography and magnetic resonance imaging to measure calcification and atheroma in the Twins UK population, we have shown that even though calcification often colocalises with atherosclerotic plaque, the association of stiffness with calcification is not explained by coexistent atheromatous plaque. Furthermore, the correlation between calcification and stiffness is explained by shared genetic factors distinct from those responsible for atherosclerosis. Arterial calcification is now known to be an active process resembling osteogenesis in which vascular smooth muscle cells undergo osteoblastic differentiation, expressing many of the proteins associated with bone formation and releasing vesicles into the extracellular matrix which serve as nucleation sites for the accumulation of hydroxyapatite crystals.

Whilst calcification may represent the later stages of a degenerative arteriosclerotic process that can be detected macroscopically, it is likely to be initiated by elastin degradation and a change in the type of collagen, which may also contribute to arterial stiffening independent of calcification. Such a degenerative process may relate to repetitive mechanical stress. It is thought to promote calcification through elastin-derived soluble peptides (matrikines or elastokines) which activate smooth muscle cell osteogenic differentiation and increase matrix affinity for nucleating mineral deposition. Matrix metalloproteinases (MMPs) degrade components of the extracellular matrix including elastin, and in vivo, MMP-mediated elastin degradation is closely associated with both medial calcification and increased arterial stiffness. MMPs are also implicated in cutaneous elastin degradation that may parallel changes in the arterial wall. MMP9 expression in the skin, for example, has been shown to relate to arterial stiffness.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949363/

There is plenty of evidence to show that comparative longevity for individuals within a species is to some degree inherited, running in families. Humans are no different in this regard. We might compare that with present thinking on the degree to which life expectancy in our species is genetic versus environmental, however: it is thought that genetic differences only become significant in old age, during the struggle of damaged systems to maintain some level of function. A commonly quoted assessment is that 75% of life expectancy variation is due to choice and environment, and only 25% is due to genetics. So what is the important inheritance here, genes or culture? I use the term culture in the very narrow sense of your upbringing, the habits, values, and knowledge you acquire or choose due to the influence of those around you. In the wealthier parts of the world the most important cultural outcomes for recent generations are whether or not you smoke, whether or not you become overweight, and whether or not you keep up with regular moderate exercise. Arguably formal education and a disposition towards personal wealth are important too, but the true nature of these relationships is very hard to disentangle from other associated factors when examining population statistics.

In the years ahead this will all change, and natural variations in life expectancy will become unimportant in comparison to whether or not people have access to rejuvenation therapies that can repair the molecular damage that causes aging. A class of therapy capable of adding ten healthy years to life would swamp all of the existing common lifestyle effects on human life span. After the advent of several of these types of therapy, long-term health will become almost entirely determined by medical technology. This is the goal to aim for, to lift up everyone into a future in which there is no more ill health or age-related disease, no more short straw in the genetic lottery, and life in good health is a choice for as long as desired. Freedoms of this sort must be built; they cannot simply be declared.

The paper here, like most assessments of the data for inheritance of longevity, doesn't have much to add on the contribution of genes versus environment. Genetic associations are known to exist, and they are found here as they are in other studies. I suspect that accurate assessments of the individual contributions to human longevity for all of these various factors, genes and lifestyle choices, will not be completed by the research community before they become moot. Medical progress will ultimately make natural variations in longevity just as irrelevant as natural variations in resistance to smallpox - an interesting historical question, but not one studied by any great number of people.

Long-lived parents could mean a healthier heart into your seventies

The longer our parents lived, the longer we are likely to live ourselves, and the more likely we are to stay healthy in our sixties and seventies. Having longer-lived parents means we have with much lower rates of a range of heart conditions and some cancers. A major study found that our chances of survival increased by 17 per cent for each decade that at least one parent lives beyond the age of 70. The researchers used data on the health of 186,000 middle-aged offspring, aged 55 to 73 years, followed over a period of up to eight years. The team found that those with longer lived parents had lower incidence of multiple circulatory conditions including heart disease, heart failure, stroke, high blood pressure, high cholesterol levels and atrial fibrillation. For example, the risk of death from heart disease was 20% lower for each decade that at least one parent lived beyond the age of 70 years. In addition, those with longer lived parents also had reduced risk of cancer; 7% reduced likelihood of cancer in the follow-up per longer-lived parent.

Although factors such as smoking, high alcohol consumption, low physical activity and obesity were important, the lifespan of our parents was still predictive of disease onset after accounting for these risks. The study built on previous findings which established a genetic link between parents' longevity and heart disease risk. That paper studied 75,000 participants in the UK Biobank, and found that offspring of longer-lived parents were more likely to have protective variants of genes linked to coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type 1 diabetes, inflammatory bowel disease and Alzheimer's disease.

"This work helps us identify genetic variations explaining the better health of people with longer-lived parents. We prominently found genetic factors linked to blood pressure, cholesterol levels and smoking, which underlines how important these avoidable and treatable risks are. However, we also found novel genetic factors, which could provide new clues to help us understand why having longer-lived parents has health benefits. This study provides additional fuel to really bolster research efforts by us and others in geroscience, a field that seeks to understand relationships between the biology of aging and age-related diseases. Aging is the most important risk factor for common chronic conditions such as heart disease, Alzheimer's and cancer, which are likely to share pathways with aging and therefore interventions designed to slow biological aging processes may also delay the onset of disease and disability, thus expanding years of healthy and independent lives for our seniors."

Longer-Lived Parents and Cardiovascular Outcomes

Cardiovascular risk assessment currently identifies higher risk individuals through parental histories of early onset myocardial infarction. However, having relatively long-lived parents is associated with markedly lower coronary heart disease (CHD) risks and longer survival. Parental longevity associations with other common cardiovascular outcomes are little studied. We estimated associations between parents' age at death and common incident conditions plus mortality in a large middle-aged cohort.

There are all sorts of interesting and potentially useful tools to be found in the bacterial world. In some cases the species itself can be repurposed as a tool, as is the case in this research. The scientists took a type of bacteria, magnetococcus marinus, that is sensitive to both magnetic fields and local oxygen level and adapted it to deliver drugs into the most active regions of a tumor:

Researchers have developed new nanorobotic agents capable of navigating through the bloodstream to administer a drug with precision by specifically targeting the active cancerous cells of tumours. This way of injecting medication ensures the optimal targeting of a tumour and avoids jeopardizing the integrity of organs and surrounding healthy tissues. As a result, the drug dosage that is highly toxic for the human organism could be significantly reduced. "These legions of nanorobotic agents were actually composed of more than 100 million flagellated bacteria - and therefore self-propelled - and loaded with drugs that moved by taking the most direct path between the drug's injection point and the area of the body to cure."

When they enter a tumour, the bacteria can detect in a wholly autonomous fashion the oxygen-depleted tumour areas, known as hypoxic zones, and deliver the drug to them. This hypoxic zone is created by the substantial consumption of oxygen by rapidly proliferative tumour cells. Hypoxic zones are known to be resistant to most therapies, including radiotherapy. To move around, the bacteria rely on two natural systems. A kind of compass created by the synthesis of a chain of magnetic nanoparticles allows them to move in the direction of a magnetic field, while a sensor measuring oxygen concentration enables them to reach and remain in the tumour's active regions. By harnessing these two transportation systems and by exposing the bacteria to a computer-controlled magnetic field, researchers showed that these bacteria could perfectly replicate artificial nanorobots of the future designed for this kind of task. "This innovative use of nanotransporters will have an impact not only on creating more advanced engineering concepts and original intervention methods, but it also throws the door wide open to the synthesis of new vehicles for therapeutic, imaging and diagnostic agents. Chemotherapy, which is so toxic for the entire human body, could make use of these natural nanorobots to move drugs directly to the targeted area, eliminating the harmful side effects while also boosting its therapeutic effectiveness."

Link: http://www.polymtl.ca/salle-de-presse/en/newsreleases/legions-nanorobots-target-cancerous-tumours-precision

This open access review of the mechanisms of aging is a followup of sorts to the noted Hallmarks of Aging paper, in which researchers followed the SENS model of breaking down aging into a set of actionable causes. There is some overlap between the SENS view of molecular damage and the Hallmarks view of metabolic dysregulation - cellular senescence is noted in both, for example - but from a SENS perspective the Hallmarks list includes a lot of things that are either markers of damage or later consequences of damage, not causes of aging. This well illustrates what has long been a major challenge in aging research, which is that cellular biochemistry is so very complex that there is still plenty of room to argue over whether important mechanisms in aging and age-related disease are causes or consequences of one another.

Getting the relationships right is vital to the development of life-extending therapies, as only the treatment of causes will prove to be very effective - and as things stand most of the field is working on patching over consequences instead, a strategy doomed to be both expensive and produce only marginal benefits. The only way to settle these debates over cause and consequence any time soon is to produce rejuvenation therapies that actually work, which is one of many reasons why advocacy for SENS research and development is so important. Sadly, in this paper as elsewhere, the ambitions with regard to aging and longevity are small: giving a greater priority to adjusting diet and lifestyle is the primary conclusion found at the end, and we all know just how little that can achieve in the grand scheme of things. No lifestyle will give you more than very tiny odds of reaching a century of aging, and no lifestyle choice can prevent you from aging and declining along the way. Only biotechnology that addresses the causes of aging can do more.

The human superorganism (i.e., the host and its microbiome) is a complex metabolic system in which nutrient intake, physical activity, and elimination of waste orchestrate anabolic and catabolic reactions that ultimately determine development, maturation, and aging. After many years of being subordinate to the surge in cellular and molecular biology, the study of metabolism is now experiencing its own Renaissance. A clear understanding is emerging of the key roles that metabolites play in all biological processes, including physiological and pathological aging.

We have previously classified the nine candidate hallmarks of aging into three categories. The primary hallmarks (genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis) are the main causes of molecular damage underlying aging. The antagonistic hallmarks (deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence) mediate beneficial effects at low levels and protect the organism from damage and nutrient scarcity but become deleterious at high levels. Finally, the integrative hallmarks (stem cell exhaustion and altered intercellular communication) are the culprits of aging and arise when the accumulating damage cannot be compensated by homeostatic mechanisms. All these denominators of aging have important repercussions on cellular metabolism. Here, we describe the links between each hallmark of aging and metabolic perturbations, discuss current strategies to manipulate metabolism for increasing healthspan and lifespan, and elaborate on the major threat posed to public health in the developed world, i.e., the incipient "westernization" of lifestyle.

Aging complicates the maintenance of cellular and organismal metabolic homeostasis, hence favoring an imbalance in metabolic landscape that self-amplifies and eventually becomes clinically manifest. Thus, anti-aging interventions such as calorie restriction may operate in the context of a metabolic reprogramming that (1) ensures efficient nutrient utilization and (2) enhances stress resistance. Although such a metabolic reprogramming may be extremely broad and hence difficult to modulate pharmacologically, it may be subjected to some unifying principles. In particular, the signal-transduction cascades and metabolic circuitries rewired in the course of aging may operate in the context of a limited number of modules that redistribute nutrients and other resources from anabolism to non-toxic catabolism, hence favoring homeostasis preservation.

Our current knowledge on the metabolic manipulations that may improve health in the elderly and hence extend longevity are still in their infancy, although there is no doubt that a combination of regular exercise and appropriate diet can delay the onset and progression of all the hallmarks of aging. Formulating dietary recommendations is complicated, and personalized advice from a nutritionist may be recommendable in some situations. Nonetheless, we surmise that an increase in food-free intervals, a reduction in overall caloric and animal protein intake, as well as a general shift from health-compromising food to a Mediterranean diet rich in fibers and complex carbohydrates may have sizeable anti-aging effects, especially when combined with regular physical activity.

Link: http://www.cell.com/cell/fulltext/S0092-8674(16)30981-3

This year's Rejuvenation Biotechnology conference, hosted by the SENS Research Foundation at the Buck Institute for Research on Aging, starts tomorrow, Tuesday August 16th. Like all of the initiatives undertaken by the SENS Research Foundation, this conference series is intended to accelerate the implementation of rejuvenation therapies based on repair of the cell and tissue damage that is the root cause of aging. Since the first of these therapies are presently in development in startup companies, and others will start to arrive in the years ahead if funding can be expanded for the necessary laboratory work, it is very much time to ensure that the technology transition from academia to industry goes smoothly. This means making connections, setting expectations, spreading an understanding of the present state of research, and putting together a community on the industry and investment side of the fence whose members are enthused and willing to get started. Nothing happens by magic in this world, and every step along the way to clinical therapies for human rejuvenation requires forethought, preparation, and hard work.

SENS Research Foundation exists to End Aging. Since 2009 we have worked to make the concept of Rejuvenation Biotechnology - the repairing of the damage which occurs to our bodies as we age - into a reality.

The 2016 Rejuvenation Biotechnology Conference is focused on taking the Rejuvenation Biotechnology Industry to the next level by addressing the question: what will it take to push emerging breakthroughs in regenerative medicine from proof-of-concept to implementation? This year's conference will answer this critical query by covering all the stages from securing funding, to production, to navigating regulation, to clinical evaluation and adoption of new treatments. Please take a look at our conference program to see all our amazing speakers.

If you have any questions while you are watching the conference just let us know by tweeting us at #RejBioCon and we'll try and get your questions answered during the Q&A or possibly after depending on how many questions there are. Just be sure you tell us which speaker you want us to ask.

Space for attendees was very limited for this convention, but fortunately in this modern day and age that doesn't stop the rest of us from listening in. The conference presentations and panels will be streamed live via YouTube:

• Rejuvenation Biotechnology Conference Tuesday 16th from 1PM-6PM PST
• Rejuvenation Biotechnology Conference Wednesday 17th from 8AM-12PM PST
• Rejuvenation Biotechnology Conference Wednesday 17th from 1PM-6PM PST

The Rejuvenation Biotechnology conference series has been well received in the community, and it fills an important role. That function, helping to pull together the collaboration and support that will accelerate progress towards effective treatment of the causes of aging, will hopefully broaden and be taken up by other independent organizations as more of the necessary medical technologies come closer to realization. If you'd like a sense of how things will proceed this year, you might take a look at the many videos from Rejuvenation Biotechnology 2014 and 2015. For those who prefer reading, BioWatch News ran an entire special issue focused on Rejuvenation Biotechnology 2014 - it's very good.

Ichor Therapeutics is spinning off a startup venture to work on turning SENS Research Foundation technology for the clearance of age-related metabolic waste into a treatment for macular degeneration. In the spirit of doing rather than just talking about doing, Fight Aging! has invested a modest amount to help fund this research and development project, alongside others you might recognize such as philanthropist Michael Greve. With all of the other fundraising going on at the moment, I should say that this is a very late notice of events that took place months ago; the funding round was being assembled around the same time as Fight Aging! invested in Oisin Biotechnologies at the start of the year. Raising funds for startups is one of those things that always takes longer than you think to finalize, however, even when accounting for the fact that it is going to take longer than you think.

Those familiar with the last decade of SENS rejuvenation research in the LysoSENS program will know that the metabolic byproduct called A2E is implicated as a contributing cause of retinal cell dysfunction and death in macular degeneration. This compound is one of many resilient types of waste making up the lipofuscin mix that builds up in older cells. These compounds are resistant to being broken down, so accumulate in the lysosomes, structures within the cell that act as recycling plants. As lysosomes become bloated they cease to function correctly, and cells fall into a garbage catastrophe, unable to maintain themselves in good condition. Many age-related conditions might be usefully slowed or reversed by ways to effectively clear out the important and most damaging forms of lipofuscin constituents from where they gather in the lysosome. It is good to see this work progressing.

Age-related Macular Degeneration (AMD) is a presently incurable eye condition leading to partial loss of vision and affects as many as 15 million Americans and millions more globally. AMD has a significant impact on an individual's quality of life through decreased independence and increased fall risk as well as the psychological and financial burden that vision loss can cause. Ichor Therapeutics began operating in the space in late 2014 after completing a material and technology transfer agreement with SENS Research Foundation for exclusive rights to a pre-clinical enzyme augmentation therapy platform for AMD and Stargardt's macular degeneration, a juvenile onset form of the disease. Another partnership fueling the scientific innovation at Ichor is with Syracuse University, a major research institution in the North Eastern United States. The partnership supports the long term corporate profitably of Ichor Therapeutics through a licensing agreement for exclusive rights to jointly developed intellectual property in the AMD market.

The recently completed transfer agreement provides additional resources to the well-established AMD research initiative at Ichor Therapeutics. Most recently, this initiative has received additional support in the form of a $600,000 program investment from Kizoo Tech Ventures, Fight Aging!, and several private investors. Ichor Therapeutics CEO Kelsey Moody said, "Our advances towards a treatment for AMD have excited many in the industry. We are fortunate to have such a deep network of scientific advisors, clinicians, collaborators, and investors who share our vision in advancing our therapeutic pipeline as quickly as possible." These resources and partnerships will continue to drive Ichor Therapeutics' AMD program, which has early results suggesting effective methods to treat the early, moderate, and late stages of AMD. Currently available treatments largely focus on the late stage only, leading to many patients going untreated. The implications of an Ichor developed therapy could mean millions of individuals could retain or regain their sight. To this end Ichor Therapeutics is continuing to develop lead candidates and assess safety and efficacy in mouse models of the disease.

Link: http://ichortherapeutics.com/ichor-nabs-600k/

Destroying and recreating the immune system is a potentially very effective way to treat autoimmune conditions, as the basis of that condition lies in the broken configuration and memory of existing immune cells. The aging immune system has similar problems in its population and cell behaviors, problems that might be removed by replacing all immune cells wholesale. Present strategies to destroy the immune system require harsh chemotherapy, however, which makes it hard to justify on a cost-benefit basis for anything except the most harmful of conditions. Undergoing chemotherapy of this nature has a high mortality rate, and long-term harm to the survivors is on a par or worse than life-long smoking. Chemotherapy will be replaced in the years ahead, however. The research noted here is one step towards selective removal of all immune cells without harmful side-effects, a capability that will open the door to a range of ways to safely rejuvenate an age-damaged immune system and bring an end to autoimmunity:

Blood stem cell transplantation, widely known as bone marrow transplantation, is a powerful technique that potentially can provide a lifelong cure for a variety of diseases. But the procedure is so toxic that it is currently used to treat only the most critical cases. Now, researchers have come up with a way of conducting the therapy that, in mice, dramatically lowers its toxicity. If the method eventually proves safe and effective for humans, it potentially could be used to cure autoimmune diseases like lupus, juvenile diabetes and multiple sclerosis; fix congenital metabolic disorders like "bubble boy" disease; and treat many more kinds of cancer, as well as make organ transplants safer and more successful.

To successfully transplant blood stem cells, a patient's own population of blood stem cells must be killed. Currently, this is done using chemotherapy or radiotherapy, treatments that are toxic enough to damage a variety of organs and even result in death. To avoid these terrible side effects, the researchers composed a symphony of biological instruments that clear the way for blood stem cell transplantation without the use of chemotherapy or radiotherapy. The scientists started with an antibody against a cell surface protein called c-kit, which is a primary marker of blood stem cells. Attaching the antibody to c-kit resulted in depletion of blood stem cells in immune-deficient mice. However, this antibody alone would not be effective in immune-competent recipients, who represent a majority of potential bone marrow transplant recipients. The researchers sought to enhance the effectiveness by combining it with antibodies or with biologic agents that block another cell surface protein called CD47. Blocking CD47 liberated macrophages to "eat" target cells covered with c-kit antibody.

With the CD47 marker blocked and the antibody attached to c-kit proteins, the immune system effectively depleted the animals' blood-forming stem cells, clearing the way for transplanted blood stem cells from a donor to take up residence in the bone marrow and generate a whole new blood and immune system. The success of these techniques in mice raises hopes that similar techniques will succeed in human patients. "If it works in humans like it did in mice, we would expect that the risk of death from blood stem cell transplant would drop from 20 percent to effectively zero. If and when this is accomplished, it will be a whole new era in disease treatment and regenerative medicine."

Link: http://med.stanford.edu/news/all-news/2016/08/researchers-devise-safer-method-for-bone-marrow-transplants.html

The protein growth differentiation factor 11 (GDF11) has been in the news over the past couple of years. In the course of conducting parabiosis research, in which the circulatory systems of old and young mice are linked, researchers established that levels of GDF11 decline with age in that species. Restoring youthful levels of GDF11 has been shown in some studies to improve numerous measures of age-related decline, perhaps largely through signaling that instructs stem cells to increase their tissue maintenance activities. Not all of the evidence is positive, however. There is an ongoing debate over whether or not studies were correctly interpreted, as GDF11 is similar enough to myostatin to confound some tools, a range of other objections and opposing evidence, and a first pass at obtaining human data suggests that GDF11 doesn't decline with age in our species in the way it does in old mice.

Does raising the level of GDF11 in humans have any sort of future as the basis for a therapy? In theory anything that can put stem cells back to work, reversing some of the characteristic age-related decline in stem cell function, is worth chasing to the same extent that stem cell therapies are worth chasing. The likely best outcomes are in the same ballpark, and work through similar mechanisms. This doesn't fix any of a range of important cell and tissue damage that causes age-related disease, but benefits are benefits. The question is whether or not GDF11 research is on the right track. At this point the balance of evidence for and against, coupled with questions about the methodology in some of the studies, suggests it is too early to tell - and at the very least there are a number of points that need clarification.

The study linked below falls on the negative side of the fence, showing no benefit to life span resulting from increased levels of GDF11 in a lineage of mice engineered to suffer accelerated aging. Evaluating results in accelerated aging models is a challenge, however. It all depends on the fine details of what exactly is involved in that accelerated aging - which is never actually accelerated aging, but rather some form of runaway biological damage that doesn't play a significant role in normal aging. That is good enough for some investigations, in which the precise nature of the damage isn't all that important, because the age-related condition of interest is very similar despite the very different nature of the low-level cell and tissue damage. Still, it has to be said that for every study in which the use of an accelerated aging lineage produced clear and unambiguously useful results, as was the case for senescent cell clearance back in 2011, there are half a dozen more in which the waters remain muddy. The researchers are trying hard to prove relevance in this paper, but I have to say that it still looks pretty muddy to me; there are any number of ways we might connect the particular approach to accelerated aging and GDF11 activities.

GDF11 administration does not extend lifespan in a mouse model of premature aging

The existence of "rejuvenating" factors in young blood capable of improving the function of aging stem cells was first demonstrated in 2005. A decade after this seminal contribution, the new wave of studies has been on the search for those circulating regulatory molecules that can restore the regenerative function of old stem cells and reverse aging. Among several cell-extrinsic factors and metabolites identified to date, GDF11 has been found to be one of the most powerful anti-aging candidates. Thus, it has been shown that GDF11 levels in blood decline with age, and that its supplementation to reach young physiological range in old mice improved the features and function of a number of age-deteriorated tissues, including heart, skeletal muscle and brain. However, recent reports have shown contradictory data questioning the capacity of GDF11 to reverse age-related tissue dysfunction. The availability of the Zmpste24-/- mouse model of accelerated aging, which shares most of the features occurring in physiological aging, gives us an excellent opportunity to test in vivo therapies aimed at extending lifespan both in pathological and normal aging. On this basis, we wondered whether the proposed anti-aging functions of GDF11 would have an overall effect on longevity.

We first determined whether GDF11 levels decline in our mouse model of premature aging in the same manner as it has been reported in physiological aging. We performed western-blot analyses with plasma samples obtained from the same wild-type and Zmpste24-/- mice at the age of 1.5 months and 3 months, to monitor a possible decline over time, considering that average lifespan of these mutant mice is 4 months and that accelerated aging symptoms start to manifest around the age of 2 months. We used the same commercial antibody as the one previously reported in the original study in which GDF11 was first identified as an anti-aging factor. We observed a marked decrease in GDF11 plasma levels in Zmpste24-/- mice compared with wild-type littermates at the age of 3 months.

To test our hypothesis about a possible role for GDF11 on lifespan extension, we did use the same commercial recombinant GDF11 (rGDF11) protein that has been used in those studies describing its anti-aging properties, and at a dosage capable of raising its levels in Zmpste24-/- plasma samples. However, rGDF11 daily treatment did not extend the lifespan of progeroid mice compared with vehicle-treated Zmpste24-/- littermates. It has been suggested that some of the original conclusions about GDF11 cardioprotective effects could be due to the decrease in body weight observed as a secondary effect of rGDF11 daily administration. Our results showed that rGDF11 treatment only caused a slightly reduction in the body weight of female Zmpste24-/- mice compared with vehicle-treated littermates during the first days of the experiment, whereas no significant differences were observed in the male cohort. In conclusion, our results demonstrate that circulating GDF11 levels are reduced in our mouse model of premature aging, which shares most of the symptoms that occur in normal aging. However, GDF11 protein administration is not sufficient to extend longevity in these progeroid mice. Although accelerated-aging mouse models can serve as powerful tools to test and develop anti-aging therapies common to both physiological and pathological aging, the existence of certain differences between the two processes implies that further investigation is still required to determine whether long-term GDF11 administration has a pro-survival effect on normal aged animals.

Here I'll point out an article of mixed quality - there's plenty to complain about, regardless of your views - but let me direct your attention to the core point being made, rather than the wrapping of that point, which is that working to end aging and greatly extend life is the most rational response to the situation we all find ourselves in. Radical life extension is the name given to the goal of postponing the degeneration, medical conditions, and death due to aging for decades or more, living far longer in good health. This outcome will require rejuvenation therapies that can repair the known forms of cell and tissue damage that cause aging. The first of these therapies are presently in development, the rest at various early stages in the laboratory. This should be a cause for celebration, massive funding, and accelerated development, but sadly not everyone considers it obvious that we should be heading down this road. The response from the average person in the street is usually that of course he or she doesn't want to live any longer than his or her parents, that of course this person wants to age and die on schedule. Yet that very same person will take full advantage of medical science now and in their old age. That striving to put an end to the suffering and death of aging is widely considered fringe or outlandish, that we have to advance arguments and advocacy to make progress towards this goal, is another sign that we humans are just not particularly rational.

Peter Thiel has plenty of crazy ideas, but his commitment to radical life extension isn't one of them. He has invested millions in the Methuselah Foundation and SENS Research Foundation, research organizations dedicated to extending the human lifespan by advancing tissue engineering, genomics, and regenerative medicine. Now, while much of the mainstream media will try to discredit the tech mogul on this seemingly outlandish issue, I'm not one of them. On this point, the man is right on target. Death is awful, and we need to get rid of it sooner rather than later. We also need to lose this idea that not wanting to die is somehow crazy or deviant. Not wanting to die is actually one of the most rational beliefs a person can have.

Thiel is not alone in his desire to stave off death. Inspired by advances in genetics, regenerative medicine, cellular biology, and cybernetics, an increasing number of people are calling for an end to aging and mortality. Aging, these self-proclaimed immortalists claim, is a disease that can and should be stopped. They argue that it's not an inexorable process, and that the human body, like any other machine, can be modified and restored to a former glory. And indeed, the science is starting to bear this out. There are things we can do to dramatically slow down aging, from the use of advanced "senolytic drugs" and the destruction of worn-out cells, through to mitochondrial and blood rejuvenation therapies. And by studying supercentenarians, we're learning about the genetic prerequisites for a long and healthy life.

Armed with these and other tools, doctors of the future will matter-of-factly prescribe these therapies to extend the lifespans of their patients. To do otherwise would be a violation of that famous oath they all take upon graduation. Organs worn out? Perhaps it's time to grow some new ones. Cells not reproducing properly? Let's replenish them with younger versions. Brain cells failing? Get yourself some synthetic replacements. Indeed, this tired idea that we'll eventually come up with some sort of magical longevity pill is nonsense; radical life extension will come in the form of multiple interventions and procedures, and few will question it.

Link: http://gizmodo.com/peter-thiel-is-right-about-one-thing-1785104345

There are many species for which maximum or even average life span is a question mark. This is a combination of too many species and too few researchers, especially when it comes to marine life, and the fact that for some negligibly senescent species there is no good way to measure age. Their vital statistics and biochemistry change so slowly over time that any estimate may be half a life span removed from the reality. This was the case for lobsters until quite recently, for example. In the research noted here, scientists attempt an new method of age estimation for Greenland sharks, another case in which determining the age of individuals - and thus the species life span - is both quite difficult and little worked on:

A large, almost-blind shark that lives in the freezing waters of the North Atlantic and Arctic oceans is officially the world's longest-living vertebrate. The Greenland shark (Somniosus microcephalus) has a lifespan of at least 272 years, and might live as long as 500 years1. That is older than the 211-year lifespan of the bowhead whale (Balaena mysticetus), the previous record-holder in the scientific literature. It also beats the popular - but unconfirmed - tale of a famous female Koi carp called Hanako, who supposedly lived to 226 years old. Marine scientists already knew that the Greenland shark was long-lived. The fish are enormous but grow slowly, suggesting a long lifespan. Adult Greenland sharks have been measured at more than 6 metres long - and researchers think that they could grow even longer. One 1963 study estimated that the species grows at less than 1 centimetre per year. Getting a definitive measure of the shark's age, however, has proved tricky. Conventionally, researchers count layers of calcified tissue that grow on a fish's fin scales or other bony structures - rather like counting tree rings. But Greenland sharks have small, spineless fins, and their vertebrae are too soft for countable layers to be deposited.

To assess age, the team decided to measure levels of radioactive carbon-14 in fibres in the centre of the shark's eye lens. Such measurements reflect levels of radiocarbon in the ocean when the lens was first formed. Measurements of 28 female Greenland sharks, made during surveys in 2010-13, suggested that the largest of them (at 5.02 metres long) must have been between 272 and 512 years old at the time. The shark's longevity probably arises because it expends very little energy, owing to its cold body temperature and enormous size. Not all cold, large species live to such an exceptional age, so it would be intriguing to know whether the shark has any particular quirks or molecular tricks that contribute to its long lifespan. The study also shows that Greenland shark females don't reach sexual maturity until around 150 years old - suggesting that a century of heavy fishing could wipe out the entire species.

Link: http://www.nature.com/news/near-blind-shark-is-world-s-longest-lived-vertebrate-1.20406

The article on longevity science that I'll point out today continues a frustrating recent trend of failing to note one of the most important portions of the aging research field: SENS rejuvenation research. This is a puzzling omission, especially now that senescent cell clearance as a rejuvenation therapy is proven and heading for the clinic - a goal that SENS supporters have been advocating for fifteen years or so. For most journalists, there is no way to quickly and easily distinguish between any of the possible approaches to intervene in the aging process and thus extend healthy life. Being journalists, they are in the business of page views and rapid production of articles, not accuracy. So the typical approach here is to pull a half dozen of the options from the list and talk about them, giving them all equal weight. This is unfortunate, as the various lines of research leading to treatments for aging are far from equal in their challenges and their potential outcomes.

We can broadly divide the aging research situation into two camps. One the one side are ways to modestly slow aging, which is to say slow the rate at which molecular damage accumulates to cause dysfunction, disease, and death. Researchers investigate the operation of metabolism and try to alter it safely and beneficially. These research initiatives typically look like very traditional molecular biology and drug development programs, often pulling drugs from the existing stockpile because they might marginally impact the pace of aging. Attempts to recreate some of the health and life expectancy benefits of calorie restriction or exercise are a common theme, which if completely successful would add perhaps five to ten years to life span, if such a therapy was used throughout life. None have come even close to a fraction of that goal so far: the field is littered with expensive failures.

On the other side of the fence are ways to repair the molecular damage that causes aging, and here there are few limits to the years of additional healthy life that can be added. A repair can be carried out many times, after all. These therapies are as well defined as they can be in advance of their construction, or in the early stages of development in some cases: a mix of small molecule and other drug development to clear metabolic waste, gene therapies of a few varieties, and cell therapies to round out the mix. If repair of damage is complete and comprehensive, and carried out every few years, a person would have an indefinite life span - he or she would never get old, and if already old that burden could be reversed. The first prototype damage repair therapies will be far from complete or comprehensive, of course, but single treatments should produce outcomes that are large in comparison to lengthy periods of a treatment that merely slows aging. The more damage that is repaired, the better the result. Repairing the damage means actual rejuvenation: turning back the clock, trying to defeat aging, not just adjust the downward spiral a little.

For advocates who are trying to ensure that the research community adopts damage repair as the dominant strategy, it is frustrating to have the press telling the public that slowing aging is all there is, or painting specific efforts to slow aging (capable of extending life only a little) as being equivalent to specific efforts to reverse aging (capable of extending life greatly). The article linked here is a particularly egregious example of this sort of thing. It starts out and ends with quotes from people long involved in advocating and funding SENS rejuvenation research, and then completely fails to mention the SENS Research Foundation or the SENS approaches to repairing the damage that causes aging. The author wanders off on a tour of ways to slow aging as though that is the sum of the field. While I recognize that journalists, in their haste to fill the news hole, do this and worse to every topic under the sun, that doesn't stop it from being very annoying when it is a familiar, even important topic. It is vital to our future that repair of molecular damage becomes the mainstream of aging research as soon as possible, as that means the difference between living for a very long time in good health, or not achieving that goal. Unfortunately, for now and the foreseeable future that involves a reliance on philanthropic funding, as the mainstream of aging research is still set on slowing aging only. To the extent that journalists get everyone hyped up about lines of research - metformin, parabiosis, rapamycin, and so on - that cannot possibly produce large effects in humans, that damages the cause by producing cycles of hype and disappointment, an outcome that emerges precisely because people are not backing the right horse. Large effects are out there to be claimed, but not by merely slowing aging.

Adding ages: The fight to cheat death is hotting up

Michael Rae eats 1,900 calories a day, 600 fewer than recommended. He has been constraining his diet this way for 15 years. In some animals calorie restriction (CR) of this kind seems to lessen the risk of cancer and heart disease, to slow the degeneration of nerves and to lengthen life. Mr Rae, who works at an anti-ageing foundation in California, thinks that if what holds for rodents holds for humans CR could offer him an extra seven to 15 years of healthy life. No clinical trials have yet proved this to be the case. But Mr Rae says CR dieters have the blood pressure of ten-year-olds and arteries that are clean as a whistle. But his diet, and the life extension he thinks it might bring, are also a means to an end. Mr Rae, who is 45, thinks radical medical advances that might not merely slow but stop, or reverse, ageing will be available in the not-too-distant future. If CR gets him far enough to benefit from these marvels then a few decades of deprivation might translate into additional centuries of life. He might even reach what Dave Gobel, boss of the Methuselah Foundation, an ageing-research charity, calls "longevity escape velocity", the point where life expectancy increases by more than a year every year. This, he thinks, is the way to immortality, or a reasonable approximation thereof.

That all remains wildly speculative. But CR is more than just an as-yet-unproven road to longer human life. Its effects in animals, along with evidence from genetics and pharmacology, suggest that ageing may not be simply an accumulation of defects but a phenomenon in its own right. In a state of nature this phenomenon would be under the control of genes and the environment. But in a scientific world it might in principle be manipulated, either through changes to the environment (which is what CR amounts to) or by getting in among those genes, and the metabolic pathways that they are responsible for, with drugs. A treatment based on such manipulation might improve the prospects of longer and healthier life in ways that drugs aimed at specific diseases cannot match. Something which slowed ageing down across the board might fit the bill. And if it delays the onset of a range of diseases it might also go some way to reducing the disability that comes with age. An ongoing long-term study at Newcastle University has been looking at the health and ageing of nearly 1,000 subjects now aged 85. At this point they have an average of four to five health problems. None of them is free from disease. Most researchers in the field scoff at talk of escape velocities and immortality. But they take seriously the prospect of healthier 85 year olds and lifespans lengthened by a decade or so, and that is boon enough.

Before discovering whether anti-ageing drugs might be able to deliver such things, though, researchers need to solve a daunting regulatory conundrum. At the moment the agencies that allow drugs to be sold do not consider ageing per se to be an "indication" that merits therapy. It is, after all, something that happens to everyone, which makes it hard to think of as a disease in search of a cure, or even a condition in need of treatment. Unless ageing is treated as an indication, anti-ageing drugs can't get regulatory approval. And there's little incentive to work on drugs you can't sell. If regulators were to change their stance, though, the interest would be immense. A condition that affects everyone is as big a potential market as can be imagined. And there are hints that the stance may indeed be changing. Two existing drugs approved for other purposes - metformin, widely used and well tolerated as a treatment for diabetes, and rapamycin, which reduces the risk of organ transplants being rejected - look to some researchers as though they might have broad anti-ageing effects not unlike those claimed for CR.

The extent to which any of this technology will help will depend on how old those it is used on are when it comes into its own. The scope for radically changing the lifespan of a 65-year-old is much smaller than that of a 20-year-old, let alone an embryo. But the amount that is lost by getting things wrong goes up in exactly the same way. The idea that radical biotechnology can lead to longer lifespans than that of Jeanne Calment, a French woman whose recorded lifespan of 122 years has never been bettered, seems at best a plausible speculation. To say - as Aubrey de Grey, a noted cheerleader for immortality, has done - that the first person to live to 1,000 has probably already been born seems utterly outlandish. But thinking through Calment's life might give you pause. When she was born, in 1875, the germ theory of disease was still a novelty and no one had ever uttered the word "gene". When she died in 1997 the human genome was almost sequenced. All of modern medicine and psychiatry, barring general-purpose anaesthesia, was developed during her lifetime. If a little girl born today were to live as long - and why should she not? - she would see the world of 2138. The capabilities of medicine at that point will surely still be limited. But no one can guess what those limits will be.

It should go without saying, but sadly doesn't, that the scope for radically changing the lifespan of a 65-year-old is dependent on the degree to which the damage of aging can be repaired. Slowing the pace of aging is of no use to the old, those people who are already heavily damaged and failing, suffering and with a high mortality rate. If you want to rescue the old, and prevent people from becoming old and frail and in pain, then the only strategy that can deliver that result is repair of cell and tissue damage. This exactly describes the therapies laid out in the SENS vision, and which are presently under development in a few laboratories and companies. If we want a future of longevity and health, this seed must grow.

Inflammation in the brain contributes to the progression of Alzheimer's disease. This has been known for some time, but there has been surprisingly little progress in building anti-inflammatory treatments. Some years ago, one approach using existing anti-inflammatory drugs failed in clinical trials, for example. This might be explained by the fact that the immune cells of the brain are quite different from those of the rest of the body, and neuroinflammation is consequently different in its details when compared with inflammation in other tissues. Here, researchers are working on a similar approach that might have more success, but given the history to date optimism may be misplaced. Certainly moving towards rapid testing in humans for any results of this nature in mice that were obtained using existing drugs seems to be a sensible approach:

In the study transgenic mice that develop symptoms of Alzheimer's disease were used. One group of 10 mice was treated with mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug (NSAID), and 10 mice were treated in the same way with a placebo. The mice were treated at a time when they had developed memory problems and the drug was given to them by a mini-pump implanted under the skin for one month. Memory loss was completely reversed back to the levels seen in mice without the disease.

"There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer's disease worse. Our research shows for the first time that mefenamic acid can target an important inflammatory pathway called the NLRP3 inflammasome, which damages brain cells. Until now, no drug has been available to target this pathway, so we are very excited by this result. However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don't always faithfully replicate the human disease. Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs. We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans."

Link: http://www.manchester.ac.uk/discover/news/treatment-option-for-alzheimers-disease-possible/

One way to demonstrate that senescent cells, whose numbers grow with age, do in fact contribute meaningfully to age-related disease despite making up only a small proportion of tissues, is to add more of them to an animal model via a cell transplant and then see what happens. Researchers here take that approach to show that senescent cells are one of the contributing causes of osteoarthritis. Various studies place the proportion of senescent cells in different tissues in older individuals of different species in a large range from 1% to as much as 20%, with lower numbers being more common. These cells secrete a mix of signals that cause inflammation and changes in the operation of surrounding cells and the structure of the nearby extracellular matrix. At present a couple of startup companies are working on the clinical development of means to clear senescent cells from the body, one of the first forms of rejuvenation therapy to reverse a root cause of aging, so we'll be seeing more of this sort of research in the next few years.

Researchers have reported a causal link between senescent cells - cells that accumulate with age and contribute to frailty and disease - and osteoarthritis in mice. "Osteoarthritis has previously been associated with the accumulation of senescent cells in or near the joints, however, this is the first time there has been evidence of a causal link. Additionally, we have developed a new senescent cell transplantation model that allows us to test whether clearing senescent cells alleviates or delays osteoarthritis."

Using the new model, researchers injected small numbers of senescent and non-senescent cells from ear cartilage into the knee joint area of mice. After tracking the injected cells in the mice for more than 10 days using bioluminescence and fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging, they found that the injection of the senescent cells into the knee region caused leg pain, impaired mobility and characteristics of osteoarthritis, including damage to surrounding cartilage, X-ray changes, increased pain and impaired function. "We believe that targeting senescent cells could be a promising way to prevent or alleviate age-related osteoarthritis. While there is more work to be done, these findings are a critical step toward that goal."

Link: http://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-link-senescent-cells-to-most-common-form-of-arthritis/

From the perspective of health and longevity, the three most damaging things that people commonly do to themselves are (a) take up smoking, (b) lead a sedentary lifestyle, and (c) become obese. A sizable percentage of the population in the wealthier regions of the world falls into at least one of those buckets. The result for near all such people is higher lifetime medical expenses, greater ill health, and a shorter life. The damage done scales by the degree to which an individual smokes, fails to exercise, or puts on weight: there is plenty of evidence to show that even a little additional weight is harmful in the long term, for example. I think that by now the consequences of smoking are widely appreciated, but awareness that choosing to lead a sedentary lifestyle or to carry a lot of excess fat tissue is just as bad? That has yet to spread to the same degree. The open access paper I'll point out today is one of those that finds the losses of life or health caused by obesity and inactivity to be greater than the losses caused by smoking.

How do these choices produce damage that looks a lot like accelerated aging, increasing the incidence of age-related disease, and causing higher mortality rates? I shouldn't have to dwell on the results of smoking for this audience: greatly increased inflammation; particulate matter in the lungs; increased risk of cancers, fibrosis, and cardiovascular disease; and so on. How is it that inactivity and obesity can achieve the same level of harm? In the case of obesity, visceral fat tissue is the driver of damage. It is a very active tissue, producing significant changes in the operation of metabolism and the organs it wraps: metabolic syndrome, type 2 diabetes, and so forth. Visceral fat tissue also produces higher levels of chronic inflammation throughout the body through its interaction with immune cells, and inflammation speeds the development of cardiovascular disease, dementia, and most of the other ultimately fatal age-related diseases. In the case of a sedentary lifestyle, it is easier to look through the literature to find the gains produced by exercise rather than searching for the losses produced by a lack of exercise. Exercise slows the stiffening of blood vessels that leads to cardiovascular disease, increases cellular maintenance activities, improves the immune system by culling unwanted cells, and much more. Like calorie restriction, exercise changes almost every measure of metabolism for the better.

Thus we have this paper, which like so many others catalogs the damage that people inflict upon themselves through poor choices. One day, probably later in this century, none of this will much matter, because medical science will be able to rescue everyone from the consequences of such poor choices - and then add decades of additional healthy life on top of that, by addressing the root causes of aging. We are not there yet, however, and in a world in which progress is rapid, every additional few years of expected life span might make the difference between dying too soon and living to benefit from the first effective rejuvenation therapies. Far and away the most reliable way to add those years today is to take better care of your long-term health.

Smoking, physical inactivity and obesity as predictors of healthy and disease-free life expectancy between ages 50 and 75: a multicohort study

A study based on data from 11 European countries estimated that 60% of deaths from all causes could be attributed to behaviour-related risk factors. Furthermore, the importance of health behaviours for the prevention of chronic diseases, such as type 2 diabetes, coronary heart disease and cancer, is widely acknowledged. Smoking, physical inactivity and obesity are among the top 10 behaviour-related risk factors for burden of diseases in developed countries, and they have also been shown to be associated with shorter health expectancy and life expectancy (LE). The cumulative impact of multiple behaviour-related risk factors on health expectancy is of interest because studies show that people who engage in multiple risk behaviours have higher mortality, increased risk of chronic diseases and poor cognitive and lower physical functioning compared with people who have no or only one behaviour-related risk factor.

Previous studies have estimated healthy years and disability-free years separately for smoking and obesity. In addition, there are at least two large studies that used information on past trends or current levels of obesity and smoking to estimate the combined effect of obesity and smoking on quality-adjusted LE and disability-free LE. Of the two risk factors, obesity appeared to be the main driver for shortened disability-free LE. However, neither of these studies considered low physical activity among the risk factors. This is a limitation, as regular physical activity is known to be associated with reduced risk of several chronic diseases, better physical and cognitive functioning in old age and higher longevity. To address some of these limitations, we examined the extent to which the co-occurrence of three modifiable behaviour-related risk factors, namely smoking, physical inactivity and obesity, predicted healthy LE and chronic disease-free LE in a large dataset of older men and women in England, Finland, France and Sweden. In addition, we estimated the associations of individual risk factors with these outcomes.

Compared with men and women with at least two of the smoking, physical inactivity and obesity risk factors, people with no risk factors could expect to live on average 8 years longer in good health and 6 years longer free of chronic diseases between the ages of 50 and 75 years. The reduction in healthy and chronic disease-free LE was greater for those with multiple behaviour-related risk factors than those with a single risk factor, a finding observed in all four cohorts. Of the individual behaviour-related risk factors, physical inactivity was associated with the greatest reduction in healthy years and obesity with greatest reduction in chronic disease-free years. In all cohorts of this study, healthy LE was longer than chronic disease-free LE. This has also been observed in other studies using multiple types of health indicators to calculate health expectancy. This is expected because suboptimal self-rated health is a holistic measure and it captures a wider range of health-related phenomena beyond chronic disease. Therefore, individuals with chronic diseases may consider their health good if the disease does not hamper everyday life.

NAD, nicotinamide adenine dinucleotide, plays a central role in energy metabolism, and of late has attracted more attention from researchers who aim to modestly slow aging by adjusting the operation of metabolism. Tinkering with NAD levels though any number of different ways appears to produce some benefits in mice, but these are not sizable outcomes. Essentially this looks only incrementally better for normal animals than the marginal results produced for many forms of dietary supplementation in mouse studies.

Researchers examined the role of NAD precursor molecules on mitochondria by specifically disrupting the "NAD salvage pathway," in mouse skeletal muscle. This pathway consists of a series of enzymes that recycles building block molecules to make fresh NAD to power reactions throughout the cell, and especially within the mitochondria, the cell component that makes energy for the body from ingested food. Chemical reactions involving NAD are fundamental to metabolizing all fats and carbohydrates, yet NAD is degraded in response to such physiological stresses as DNA damage, and its concentration declines in several tissues over the natural course of aging.

The team generated mice in which they could restrict the amount of NAD in specific tissues in order to simulate this aspect of normal aging in otherwise healthy mice. Surprisingly, young knockout mice were found to tolerate an 85 percent decline in intramuscular NAD content without losing spontaneous activity or treadmill endurance. However, when these same mice hit early adulthood (three to seven months of age), their muscles progressively weakened and their muscle fibers atrophied. "Their muscle tissue looked like that of Duchenne muscular dystrophy [DMD] patients. The genes that were turned on and the presence of inflammatory immune cells in the muscles lacking NAD looked very similar to what we see in DMD." The team next sought to test whether a dietary NAD precursor might remedy the muscle pathology in the mice. The muscle decline was completely reversed by feeding the mice a form of vitamin B3, called nicotinamide riboside (NR).

Additionally, the team found that induced lifelong overexpression of Nampt, an enzyme important in making NAD, prevented the natural decline in NAD and partially preserved exercise capacity in aged mice. "This was supporting evidence that strategies to enhance muscle NAD synthesis might help to combat age-associated frailty." Researchers plan to follow up on the unexpected muscular dystrophy finding, asking if NAD is also depleted in some forms of dystrophy and if restoring NAD might help ameliorate certain features of the disease. Though the researchers previously found that enhanced NAD synthesis does not benefit muscle performance in young mice, these new findings suggest that it may be useful for combating age-related declines in muscle function.

Link: http://www.eurekalert.org/pub_releases/2016-08/uops-hmr080216.php

The popular press here covers the ambition of the scientific mainstream to modestly slow aging. Many researchers don't even want to talk about extending life, but only a small expansion of healthspan. This lack of ambition, and refusal to engage with the large body of evidence that suggests we can do far better, is why we need organizations like the SENS Research Foundation. It is possible and plausible to extend healthy life and overall lifespan indefinitely by implementing the approach of repairing the cell and tissue damage that causes aging. Yet all too much of the rhetoric and effort in the scientific community still goes towards tinkering with the operation of metabolism to slightly slow the pace at which damage accumulates - a clearly far inferior approach, that can at best produce only marginal outcomes.

With all of that, it is still a little odd to see senescent cell clearance, a part of the SENS repair strategy, showing up in articles like this, and given no greater weight than, say, treating people with metformin, which can't possibly have anywhere near as beneficial effect. Journalists typically don't distinguish between the potential value and outcome of different approaches to aging - it is all the same to them, just a flat list. That's something of a problem when the differences are enormously important and the expected outcomes are night and day. If there is to be significant progress towards healthy life extension in our lifetimes, the better strategies, those involving damage repair, must gain far greater support.

Imagine a day in the not-too-distant future. You're in your late 40s, and it's time for a special doctor's visit. The physician reviews your lifestyle, sleep habits and health history and orders some blood work to compare certain biomarkers with baseline measures taken when you were in your 20s. Then she gives you a personalized prescription for change that includes a diet that mimics the effects of fasting and a drug that helps your cells clear out malfunctioning proteins. The goal? To make you age more slowly and lengthen your "healthspan." If it sounds like science fiction, you're right - for now. But researchers in the field of geroscience, which explores the relationship between aging and diseases like cancer, heart disease and Alzheimer's, see that day coming. They are marshalling evidence that the same cellular processes that drive aging also result in those diseases, and that it's possible to slow the damage down. "The idea is that if you can treat the underlying causes of aging, you can delay all of these things as a group.That's a whole different way of thinking about medicine." The goal is not to extend lifespan, though that may indeed happen. Instead it's to extend the length of time you're healthy and active.

Working with a range of organisms from yeast to worms to rodents, scientists have homed in on several interrelated processes they suspect drive aging. Proteostasis, for one, is a fancy name for the quality-control system at work in your cells. Like a factory, a cell has ways to ensure the proteins it makes are up to snuff. If they're not, the malfunctioning proteins are supposed to be broken down and used to build new proteins or as energy. Researchers are looking for interventions, whether lifestyle or drugs, that might repair this age-related quality-control decline. Another area of exploration is inflammation. Low-grade, chronic systemic inflammation in the absence of an infection is a factor in most age-related diseases; it's even known as "inflammaging." The sources of it aren't well known, but scientists are investigating possible contributors, including a state called cellular senescence. Researchers wondered what would happen if senescent cells were removed. In mice, they've shown that certain drugs called senolytics can do just that - and slow the progression of age-related changes and even partially reverse them. Other drugs, too, are being eyed for their potential. A top contender, which has increased both lifespan and healthspan in mice by targeting a protein that controls key cellular functions, is rapamycin, used in people to prevent rejection of transplanted organs. Researchers now studying whether rapamycin has a similar effect in pet dogs, which might be great models for aging research because they share an environment with humans and are genetically varied.

Link: http://health.usnews.com/wellness/articles/2016-08-09/the-future-of-aging

Today I'll link to an open access review paper on the topic of inflammaging: what it is, what is known of its mechanisms, and approaches to building treatments. The view on treatments is very mainstream and unambitious, in that it doesn't go beyond supplementation, calorie restriction mimetics, and other drugs with marginal effects, such as metformin. This is driven by a strategic approach that ignores the search for root causes in favor of evaluating the dysfunctional system as a whole and seeking to alter its operation, to force it into a mode of operation that resembles that of youth and health. This view of research and development is precisely why the mainstream is struggling to make much of an impact in the treatment of aging, and why they see the control of aging as a distant goal: trying to make a damaged machine run well without repairing the damage is a very challenging task. If we are to see progress in the treatment if aging, it will come from those researchers who aim to repair the low-level biological damage that causes aging, not merely paper over it.

That said, you may find the rest of the paper to be an interesting view of the way in which the immune system runs awry in later life. The authors here differentiate between inflammaging and immunosenescence, though I'm not convinced that these are really distinct enough to be considered two separate things given the present understanding of immune dysfunction in aging. Inflammaging is very focused on chronic inflammation, as you might imagine, while immunosenescence is focused on the declining effectiveness of the immune response. I see these as two perspectives on the same very complex phenomenon. Chronic inflammation increases with age, and contributes to all of the common age-related conditions. Becoming overweight, and thus carrying around excess visceral fat tissue, is one way to produce greater inflammation. Even if you stay in shape, however, the immune system becomes increasingly disarrayed in ways that provoke inflammation. The molecular damage of aging and a lifetime of exposure to pathogens produces an aged immune system that is both overactive and ineffective at the same time. Inflammation is a necessary part of the immune response, but if the switch is jammed in the on position, that inflammation produces a growing burden of damage to tissues and organs.

What to do about all of this? Well, not the items on the list provided in this paper, that is certain. For my money, the same general approaches to immune aging advocated in the SENS view of rejuvenation therapies should put a dent into inflammaging. These include: selectively removing immune cells that have become uselessly specialized to herpesviruses and do nothing but take up space; restoring youthful function in the thymus to increase the rate at which new immune cells are generated; supplying periodic infusions of immune cells created from the patient's own cells; and beyond that the standard SENS plan of repairing all known cell and tissue damage. Senescent cells cause inflammation, for example, and their removal is on the SENS agenda. Since senescent cell destruction is a going concern in the laboratory we should have a good view of its impact on inflammation in aging a few years from now. In the view of aging as an accumulation of damage, problems in old people that can be traced to signaling issues - differences in levels of specific proteins - are reactions to the presence of rising levels of molecular damage. Remove all of the damage and the signaling should revert to that of a young individual. This is more or less the opposite view on strategy from the systems biology perspective put forward in this paper.

An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment

A main feature of the aging process is a chronic progressive increase in the proinflammatory status, which was originally called "inflamm-aging". Inflamm-aging is the expansion of the network theory of aging and the remodeling theory of aging. The network theory of aging posits that aging is indirectly controlled by the network of cellular and molecular defense mechanisms. The remodeling theory, which was put forward to explain immunosenescence, is the gradually adaptive net result of the process of the body fighting malignant damage and is a dynamic process of optimization of the trade-off in immunity. In the process of aging, some researchers pointed out that the phenomenon where adaptive immunity declines is called immunosenescence, while the phenomenon where innate immunity is activated, coupled with the rise of proinflammation, is called inflamm-aging. Some regard the chronic inflammatory process with age as inflamm-aging, while others proposed the oxidation-inflammation theory of aging. Despite the lack of agreement on definitions and terminology, there is consensus that the primary feature of inflamm-aging is an increase in the body's proinflammatory status with advancing age.

The inflammation during inflamm-aging is not in a controlled inflammatory state. Inflammation is a series of complex response events which are caused by the host system facing a pathogen infection or various types of tissue injury. These response events are characterized by interactions between the cells and factors in the microenvironment and by regulation of the balance between physiological and pathological signaling networks. In common conditions, inflammatory responses disappear when proinflammatory factors in infection and tissue injuries are eliminated and then change into a highly active and well regulated balanced state, which is called resolving inflammation. However, in the presence of some as yet uncertain factors, such as persistent and low intensity stimulation and long-term and excessive response in target tissues, inflammation fails to move into a steady state of anti-infection and tissue injury repair; instead the inflammation continues and moves to a nonresolving inflammation state.

Inflamm-aging is a determinant of the speed of the aging process and of lifespan and is highly related to Alzheimer's disease, Parkinson's disease, acute lateral sclerosis, multiple sclerosis, atherosclerosis, heart disease, age-related macular degeneration, type II diabetes, osteoporosis and insulin resistance, cancer, and other diseases. Inflamm-aging also increases morbidity and mortality, significantly harming the health of patients, and causes a decline in the quality of life of patients. Chronic, subclinical inflammation and immune disorders coexist in the process of inflamm-aging. Epidemiological studies show that with age there is an imbalance in the loss of old bone and the formation of new bone. Inflamm-aging may be one of the contributing factors to the imbalance and to the subsequent excessive loss of bone.

Based on the essential effects and our understanding of inflammatory cytokine pathways in the process of inflamm-aging, we can begin to explore the inflammatory cytokine network and perform a quantitative evaluation of inflamm-aging. Inflammatory cytokines, including interleukins, tumor necrosis factor, and interferon, mediate their effects by binding to their receptors and competing in a complex cell-cell network. These cytokines act in both paracrine and autocrine ways to exert direct effects on the microenvironment. This plays an important regulatory role by activating inflammatory and immune cells and by releasing cytokines. Inflammatory cytokines form a complex network which extends in all directions and throughout the whole body. The inflammatory cytokine network can be divided into the proinflammatory cytokine network and anti-inflammatory cytokine network. As with the immune reaction, the inflammatory reaction is also a normal defense function. A moderate inflammatory reaction is advantageous to the body, whereas a high reaction is harmful and the outcome of these reactions is determined by changes in the inflammatory cytokine network. The dynamic balance between the proinflammatory cytokine network and the anti-inflammatory cytokine network maintains the normal function of inflammation in body. Once the balance is broken, pathological inflammation occurs. Therefore, we infer that the cause of inflamm-aging is an imbalance in the proinflammatory cytokine and anti-inflammatory cytokine networks, which leads to a proinflammatory status with increasing age. This may be the mechanism of inflamm-aging.

In summary, inflamm-aging and the inflammatory cytokine network are both classical systems biology issues. The inflammatory cytokine network is involved in the process of inflammation and senescence and may be the ideal breakthrough point of research into inflamm-aging. Omics, such as genomics, transcriptomics, proteomics, and metabolomics, are excellent methods to solve systemic biology problems. Therefore, under the guidance of systems biology, it would be novel strategy to conduct basic research into inflamm-aging using omics methods to identify characteristic inflammatory cytokine genes in the process of aging and to uncover new mechanisms to regulate inflammatory cytokines during inflamm-aging. This will also illustrate the mechanism of inflamm-aging and provide new ways to assess inflamm-aging.

At present there are only a few active cryonics providers, organizations that can cryopreserve an individual at death in order to maintain the structure of the mind indefinitely, waiting on a future in which the technology exists to allow restoration to active life. Cryonics offers the only shot at a longer life in the future for those who will age to death prior to the advent of working rejuvenation therapies. The odds are unknown, but certainly infinitely better than those associated with any of the other available options at the end of life. Most cryonics providers and their support organizations are in the US, and the oldest have been in business since the 1970s. Another more recently established provider operates in Russia. That leaves much of the world without any easy access to cryonics as a service, though volunteer organizations in a number of countries are working towards the establishment of providers at varying speeds and with varying degrees of success. One of the more recent of these is the European CryoSuisse, whose principals will be hosting the 1st International Cryonics Conference this coming November:

Cryonics is an experimental medical procedure to save human lives. Very low temperatures are used to effectively halt the time - for decades or centuries, until the day when the medicine of the future is capable of reviving the patient and cure his illnesses. Cryonics is based on the most recent insights of cryobiology and medicine. Already today, human embryos are routinely cryopreserved at low temperatures and re-animated later. Even for individual organs, cryonic techniques are already in use. A good cryopreservation of patients which today's medicine can no longer help is already possible. CryoSuisse, the Swiss Society for Cryonics, advocates the promotion, further advancement and practical application of cryonics - in order to give as many people as possible the chance to continue their lives in the future.

How does it work?

Nowadays, many serious illnesses can be cured which had been fatal as recently as one century ago (e.g., tuberculosis, smallpox or kidney failure). One can expect that medicine will proceed just as fast during the centuries to come. The cryonicist waits until the illness he suffered from can be cured. In other words, cryonics is an ambulance service through time.

Are the body tissues not destroyed by the cold?

At temperatures below 0 °C, water freezes into ice crystals. With their sharp edges, ice crystals destroy individual cells and tear tissues apart. Therefore, cryonics does not freeze the body, but vitrifies it. To this end, the bodily fluids of the human are replaced by cryoprotectants which protect the cells and prevent the formation of ice crystals. In this way, the body is transformed into a glass-like state where cells and tissues retain their original structures.

But can this glass also be converted into a fluid again?

Yes it can, this is scientifically proven. For example, researchers have thawed a kidney which had been vitrified at -130 °C and successfully transplanted it into a rabbit. The transplanted kidney recovered quickly to its normal function.

Then why is it that there are no reports about humans who were revived from this state?

Although some individual organs can already be cryopreserved, it has not been possible so far to cryopreserve a living being and revive it thereafter. There are several research programs to improve the technique though. Nevertheless, cryonics already makes sense: The fact that patients cannot be revived using today's techniques does not mean that it's not possible in future.

Link: http://cryosuisse.ch/

Here, researchers discuss the use of the gene editing technology CRISPR to combat persistent herpesviruses such as cytomegalovirus (CMV). This is of interest as CMV is implicated in the age-related decline of the immune system, a large part of the frailty of old age. Near all people are infected by CMV by the time they reach old age, and ever more immune cells in the limited number that can be maintained become uselessly specialized to combat CMV, unavailable for other work. These growing efforts are futile, however, as CMV like all herpesviruses cannot be cleared by our immune systems.

What to do about this? Since CMV doesn't actually cause any harm in most people beyond this slow corruption of the immune system, the most straightforward approach is to clear out the unwanted immune cells, a goal that is becoming very plausible in this age of multiple approaches to targeted cell destruction. Clearing out CMV will only be helpful if it is done early enough, however, and the utility of that depends on the pace at which the damage is done. If, like many aspects of aging, damage occurs at a slow pace throughout much of life but accelerates dramatically after age 60 or so, then a therapy to remove CMV may be worth the effort if carried out early enough. If a patient's immune system is already greatly disordered by CMV, then removing the virus from the body won't make a great deal of difference. It won't put things back to the way they were before.

So far, treatment for herpesviruses has been incapable of fully eliminating the virus from its host, meaning the latent infection is lifelong. The virus continues to replicate, which results in flare-ups of disease symptoms in the host. Current treatment for herpesviruses simply mutes the disease symptoms during these flare-ups, but fails to fully eliminate the infection, which will remain latent throughout the life course. Researchers posited that the precision of CRISPR gene editing technology could break the DNA of a herpesvirus, thereby interrupting viral replication. Next, if CRISPR could reach and destroy all existing copies of the virus while also halting replication, then the infection itself could be eliminated.

The researchers tested their theory in three different strains of herpesviruses: Epstein-Barr virus (EBV), Herpes simplex viruses (HSV-1) and (HSV-2), and human cytomegalovirus (HCMV). The results indicate that CRISPR can be used to eliminate replication in all three strains of the virus, but that the technology was so far only successful in actually eradicating EBV. Researchers think this may be because the EBV genome is located in in dividing cells that are easily accessible to CRISPR. Comparatively, the HSV-1 genome targeted by CRISPR is located in closed-off, non-replicating neurons, which makes reaching the genome much more challenging.

"We first need to explore whether these potent anti-viral activities hold up in animal studies, and eventually humans before they may be applied as a future therapy. The first stop is to perform in vivo studies in animal models for these viruses. If these are successful, testing in humans may be the next step. However, there are several hurdles that need to be taken. I think the direct applications to treat EBV and HCMV infections may be challenging, as infected cells can travel to many sites in the body and are hence difficult to reach. For HSV-1, HSV-2, or VZV, delivery may be more straight-forward, as here the viruses reside in limited numbers of neurons at defined areas in the human body, such as the trigeminal ganglia. These sites may be reached by e.g. local administration of neurotropic viral delivery vectors. We envision that delivery of anti-viral CRISPR/Cas9 to latently infected cells may destroy the virus invader, curing the cell in question and preventing future outbreaks. Or, alternatively when we cannot remove the latent genome, pre-load the cell with an anti-viral mechanism that can target newly generated virus once the latent virus become activated. Hence, hopefully we can cure infected individuals, or prevent serious damage upon reactivation of these viruses."

Link: http://blogs.plos.org/speakingofmedicine/2016/08/04/crispr-puts-up-a-fight-against-persistent-herpesviruses-a-short-animation/

This year's SENS rejuvenation research crowdfunding event puts the spotlight on the SENS Research Foundation's cancer program. So far more than 300 people have donated, and more than $26,000 has been raised; with ten days left to go, it won't take that much more of an effort to reach the same number of donors and the same level of support given to last year's fundraiser, and which led to the success in that research program. As for all of the SENS research initiatives in the science of aging, the SENS Research Foundation's work on cancer aims to support a big, bold goal in medicine: to build a single type of therapy that can be used to effectively treat all forms of cancer. When achieved, that will greatly increase the pace of progress towards control of cancer, the goal of finally ending cancer as a threat to health. At present the cancer research community spends much of its time and funding on approaches that are highly specific to only one or only a few of the hundred of subtypes of cancer. That is no way to win any time soon, as even with the vast funding devoted to cancer research, there are just too many forms of cancer and too few researchers. What is needed is to change the strategy, to focus on approaches to the treatment of cancer that are no more expensive to develop, but that far more patients can benefit from.

The most promising approach to a universal cancer therapy is to block telomere lengthening in cancerous tissues. Telomeres are a part of the mechanism that limits cell division in all human cells other than stem cells, repeating DNA sequences at the ends of chromosomes that shorten every time a cell divides. In order to achieve unfettered growth all cancers must bypass this limit by continually lengthening their telomeres, a goal that is achieved through mutations that allow cancer cells to use telomerase or the alternative lengthening of telomeres (ALT) processes. If both telomerase and ALT can be blocked in cancer tissue, then the cancer will wither; this is such a fundamental piece of cellular machinery that there is no expectation that cancer cells could find a way around it. Block only one of these two methods of telomere lengthening, however, and the cancer will probably switch to use the other. This has been observed in mice.

Thus it is very important that the research community deploy both telomerase and ALT blockades as a part of a prospective universal cancer therapy. Unfortunately while a number of groups are working on telomerase interdiction, and telomerase is very well studied these days, ALT is still poorly characterized, at the frontiers of what is known of cell biology. ALT doesn't occur in normal cells, and thus despite the fact that 10% of cancers make use of it, only recently have the necessary tools been developed to work towards understanding and intervention. The SENS Research Foundation is picking up the slack in this overlooked area of development, and with our support is working towards ensuring that the first universal cancer therapies can in fact target both telomerase and ALT, and therefore succeed.

The existence of cancer therapies that are both effective and cost-effective is going to become increasingly important as other rejuvenation therapies arrive in the clinic over the next few decades. Senescent cell clearance is under development in startup companies, for example, and a few other lines of research aimed at repairing the damage that causes aging are probably only a few years away from the same point. Certainly the 2020s are going to see multiple competing approaches to clearing out the damage of aging, and the first impact on age-related disease and mortality will occur in the public at large. None of these therapies are going to do much to reverse the random mutational damage in nuclear DNA that drives cancer, however, though they may well help to halt the decline of the immune system's ability to destroy cancerous cells before they become established. Fixing random DNA damage is a hard problem, and viable solutions will probably arrive very late in the progression of rejuvenation biotechnology. In the transitional world in which a lot of older people are living for longer and in better health, but with a high burden of mutational damage, it will be ever more necessary to control cancer through medicine.

Looking at the big picture, then, supporting the SENS approach to cancer makes sense: it is a great way for people like you and I to do our part to help build the sort of future that we want to live in.

Blood pressure increases with age, driven by loss of elasticity in blood vessels, among other things, leading to the medical condition of hypertension. Here, researchers examine the complex associations between higher blood pressure and greater loss of cognitive function in later life; while it is well known that hypertension damages the physical structure of the brain, to pick one example, when it comes to the end result of cognitive decline a full catalog of the contributing factors and how these processes interact in detail has yet to be established. That said, it is certainly possible to accelerate the progression of higher blood pressure by leading a sedentary lifestyle or becoming overweight, and both of those line items correlate well with greater cognitive decline. While that much is under our control, there is unfortunately all too little that can be done about stiffening of blood vessels at the present time. Real progress on that front will require implementation of some of the SENS rejuvenation therapies, such as a way to break down the cross-links that build up in the extracellular matrix of blood vessel walls.

Despite strong evidence for a positive association between midlife hypertension and late-life cognitive impairment, the relationship between late-life hypertension and cognitive function remains unclear. Observed inconsistencies between studies partly reflect variations in study design and populations. Another likely factor is unmeasured heterogeneity, within populations, as regard the timing and duration of exposure to hypertension, which in turn could influence its effects and potential modifiability. Such investigations would benefit from a proxy measure representing the duration of exposure to hypertension. A potential proxy or surrogate measure is pulse pressure (PP), partly reflecting arterial stiffness, measured as the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP). PP is potentially a better measure of the chronic effects of hypertension than blood pressure itself. PP increases with age and is associated with a number of cardiovascular risk factors and outcomes. Arterial stiffness appears related to Alzheimer's disease (AD) pathology, providing a potential vascular marker that is more closely related to AD than other cardiovascular measures. However, evidence remains conflicted as to the association of cognitive performance with arterial stiffness, whether measured as PP or through ultrasound determined pulse wave velocity.

Here, we explored the relationships between longitudinal change in PP and cognitive performance in multiple cognitive domains over 5 years and how these relationships were influenced by initial (baseline) blood pressure (BP). As an increase in PP typically reflects significant vascular remodeling and stiffening, we hypothesized that those with increasing PP over time would have a greater decline in cognition. When evaluating distinct longitudinal profiles of PP change over the same time period and accounting for attrition, we identified differences in cognitive change that (1) varied by trajectory of PP change, (2) varied by cognitive domain, (3) varied by age, between the youngest-old and oldest-old, and (4) was significantly influenced by baseline SBP. Importantly, we found that an increasing or persistently high PP was associated with less cognitive decline than in those with low, stable PP but only if baseline SBP was below the median. However, in those starting with higher baseline SBP, it was age, rather than PP group, that influenced cognitive decline the most, with increasing age being associated with greater decline. These findings underscore the importance of identifying the sources of heterogeneity within a population to understand the complex relationships between late life vascular health and cognitive decline and possibly help explain some of the discrepancies in the literature.

The four PP trajectory groups that we identified appear to capture the major categories along a spectrum of possible patterns (stable high or low and increasing or decreasing). They also suggest that different pathways to a specific PP level, rather than the PP itself, have distinct implications for cognition. We can only speculate about the potential mechanisms underlying the noted associations between PP and cognition. These results might indicate that with advancing age, which is also associated with an age-related arterial stiffening, that cognitive function, particularly executive function, becomes increasingly reliant on an additional mechanisms such as adequate cardiac output. However, with advancing age and chronic exposure to higher PP this eventually becomes detrimental, as was supported by the findings in those starting with higher SBP. This was supported by a recent study showing that those with previously elevated SBP were at greatest risk for having evidence of regional white matter changes that support executive cognitive function. In the groups with slowly and rapidly increasingly PP, there was a general pattern of less decline in cognitive function that was most pronounced in those starting at lower SBP. Our findings support speculation that an initial elevation in PP might in fact provide some protection against the effects of hypoperfusion on cognition, particularly in the oldest-old.

Link: http://dx.doi.org/10.1016/j.dadm.2016.03.008

A number of research groups are engaging in mapping the biochemistry of limb and organ regeneration in species capable of such regrowth, such as salamanders and zebrafish. The hope is that the underlying systems of regeneration are merely inactive in mammals, not missing entirely, and therefore somewhere in all of this lies the basis for a therapy to provoke regrowth of missing tissues in adult humans. Whether or not this is the case is yet to be determined, though some of the evidence is promising: scarless healing of minor wounds present in MRL mice; the same outcome induced via inhibition of Cxcr4; the ability to selectively block zebrafish regeneration with the human ARF gene; and others. There are also the evolutionary arguments, such as those put forward by the researchers here. The more that researchers find very similar mechanisms of regeneration in widely diverse species, the more likely it is that those mechanisms also exist to be accessed in mammals.

Many lower organisms retain the miraculous ability to regenerate form and function of almost any tissue after injury. Humans share many of our genes with these organisms, but our capacity for regeneration is limited. Until the advent of sophisticated tools for genetic and computational analysis, scientists had no way of studying the genetic machinery that enables regeneration. Using such tools, scientists have identified common genetic regulators governing regeneration in three regenerative species: the zebrafish, a common aquarium fish originally from India; the axolotl, a salamander native to the lakes of Mexico; and the bichir, a ray-finned fish from Africa. The discovery of genetic mechanisms common to all three of these species, which diverged on the evolutionary tree about 420 million years ago, suggests that these mechanisms aren't specific to individual species, but have been conserved by nature through evolution.

The discovery of the common genetic regulators is expected to serve as a platform to inform new hypotheses about the genetic mechanisms underlying limb regeneration. The discovery also represents a major advance in understanding why many tissues in humans, including limb tissue, regenerate poorly - and in being able to possibly manipulate those mechanisms with drug therapies. "Limb regeneration in humans may sound like science fiction, but it's within the realm of possibility. The fact that we've identified a genetic signature for limb regeneration in three different species with three different types of appendages suggests that nature has created a common genetic instruction manual governing regeneration that may be shared by all forms of animal life, including humans."

In particular, the scientists studied the formation of a mass of cells called a blastema that serves as a reservoir for regenerating tissues. The formation of a blastema is the critical first step in the regeneration process. Using sophisticated genetic sequencing technology, researchers identified a common set of genes that are controlled by a shared network of genetic regulators known as microRNAs. The study also has implications for wound healing, which, because it also requires the replacement of lost or damaged tissues, involves similar genetic mechanisms. With a greater understanding of these mechanisms, treatments could potentially be developed to speed wound healing, thus reducing pain, decreasing risk of infection and getting patients back on their feet more quickly.

Link: https://mdibl.org/press-release/from-sci-fi-to-reality-unlocking-the-secret-to-growing-new-limbs/

Single issue political parties are near invisible in the US, thanks to the political duopoly that manifests as an outcome of the use of first-past-the-post election rules. In many European countries more representative voting rules allow for the existence of a much larger number of competing parties, and as a result forming a political party to advance a single issue is a entire viable way to run a long-term advocacy campaign. You only have to look at the many environmentalist Green parties, or the more recent growth of the Pirate party, or even the lasting message provided by the Official Monster Raving Loony Party of the UK to see that this can work. Attention can be captured, and a message delivered, even if no governing seats are ever won. A number of advocates for longevity science in Europe have started parties, and have for the past few years put in the hard work to make waves. Most are associated with the International Longevity Alliance, and it is the German Partei für Gesundheitsforschung, the Party for Health Research, that I'll point out today.

The Party for Health Research folk are strong supporters of the SENS rejuvenation research approach to the medical control of aging. Aging is caused by an accumulation of various forms of cell and tissue damage, and repairing that damage is the best way forward to end the frailty and disease that accompanies aging. In the past the Party for Health Research has organized activities including petitions to government to fund this branch of aging research. From the point of view of the continued growth of the movement, it is encouraging to see that these volunteers have now qualified to run in the upcoming elections to the Berlin state parliament. Every long journey consists of a series of small steps. I believe that the Party for Health Research is the first single issue longevity party to make this leap, and congratulations are due to those who put in the work to make it happen.

We reached quorum, and are admitted to the elections in Berlin!

We have collected 2314 signatures, enough to reach the quorum of 2,200 signatures and can thus stand in the election to the Berlin House in September on the ballot! Thanks to all helpers!

Election program in 2016 for election to the Berlin House of Representatives

Most people in Germany fall ill and die of old age diseases like Alzheimer's, cancer, heart attack, stroke and type 2 diabetes. Age-related diseases cause a lot of suffering and immense costs and concern each of us. Today biotechnologies enable us now to finally develop effective therapies against the full range of age-related illnesses and ailments. Age-related illnesses caused by certain developments inside and outside the cells. By repairing these changes at the molecular and cellular level it will be possible in future to cure age-related diseases. The Party for health research advocates for more research against diseases of aging, so that these therapies will be developed faster and they arrive soon enough to benefit people who are already older today. Therefore, the party sets for Health Research committed to build more research institutes in Germany, the work on this issue, and train more researchers in the relevant fields. The party will form a coalition with one or more other parties and even only address health research. In all other political issues, the party does not want to interfere. This can be handled by the coalition partners.

We want to spend an additional one percent of the state budget in the development of therapies against diseases of aging. Since all people are directly or indirectly affected by diseases of aging, all would benefit. To finance this one percent is to be subtracted from each other budgetary item. About half of these additional investments should flow in the construction and operation of new research facilities. With the other half more scientists will be trained in the relevant fields such as biochemistry and molecular biology. For the corresponding departments at the universities of Berlin are to be expanded.

I believe that as research and development of the means to control aging by repairing its causes begins to show signs of concrete progress outside the laboratory, as the first therapies start to emerge, we will see ever more of this sort of political activism in Europe. It will slowly sink in that aging is the greatest cause of death and disease, and that perhaps something can be done, and that will give rise to far greater support for this and other forms of advocacy. The Party for Health Research volunteers are now starting their campaign; there are posters on the website, and posters going up in Berlin. The one pictured below says "Cancer? Alzheimer's? Stroke? NO, THANKS! For more pharma-industry-independent research for better medicine against age-related diseases, vote for the Party For Health Research."

The adult brain adds new neurons at a very slow pace. Exercise increases that pace, so it is a place to start when trying to determine the likely outcome of therapies that greatly increase the generation of new neurons. As they are developed, such therapies will likely come to have an important place in the near future toolkit of rejuvenation therapies. The generation of new neurons diminishes with age, and is an important part of the plasticity of the brain, determining the ability to learn, change, and heal minor damage. At this point, many of the possible outcomes of a greater supply of new neurons remain debated, with studies still taking place. The contradictory animal data covering effects on memory noted here is just one example.

Research has found that exercise causes more new neurons to be formed in a critical brain region, and contrary to an earlier study, these new neurons do not cause the individual to forget old memories. Exercise is well known for its cognitive benefits, thought to occur because it causes neurogenesis, or the creation of new neurons, in the hippocampus, which is a key brain region for learning, memory and mood regulation. Therefore, it was a surprise in 2014 when a research study found that exercise caused mice to forget what they'd already learned. "It was a very well-done study, so it caused some concern that exercise might in some way be detrimental for memory."

The animal models in the exercise group - in the previous study - showed far more neurogenesis than the control group, but contrary to what one might think, these additional neurons seemed to erase memories that were formed before they started the exercise regimen. To test this, the researchers removed the extra neurons, and the mice suddenly were able to remember again. "The mice who exercised had a large number of new neurons, but somehow that seemed to break down the old connections, making them forget what they knew."

Researchers decided to replicate this earlier research, using rats instead of mice. Rats are thought to be more like humans physiologically, with more-similar neuronal workings. They found that - luckily for runners everywhere - these animal models showed no such degradation in memories. "We had completely contradictory findings from the 2014 study. Now we need to study other species to fully understand this phenomenon." The researchers trained their animal models to complete a task over the course of four days, followed by several days of memory consolidation by performing the task over and over again. Then, half the trained animal models were put into cages with running wheels for several weeks, while the control group remained sedentary. The rats who ran further over the course of that time had much greater neurogenesis in their hippocampus, and all rats who had access to a wheel (and therefore ran at least some), had greater neurogenesis than the sedentary group. On an average, they ran about 48 miles in four weeks, and neuron formation doubled in the hippocampus of these animals.

Importantly, despite differing levels of increased neurogenesis, both moderate runners and brisk runners (those who ran further than average) in the new study showed the same ability as the sedentary runners to recall the task they learned before they began to exercise. This means even a large amount of running (akin to people who perform significant amount of exercise on a daily basis) doesn't interfere with the recall of memory.

Link: https://vitalrecord.tamhsc.edu/new-neurons-dont-cause-you-to-forget-old-memories/

Researchers here find yet another reason to avoid becoming overweight, in that the brains of people who are overweight tend to lose white matter at an accelerated rate. The mechanism involved remains to be determined, but based on past research, the greater levels of chronic inflammation produced by larger amounts of visceral fat tissue would seem to be a good place to start looking.

Our brains naturally shrink with age, but scientists are increasingly recognising that obesity - already linked to conditions such as diabetes, cancer and heart disease - may also affect the onset and progression of brain ageing; however, direct studies to support this link are lacking. In a cross-sectional study - in other words, a study that looks at data from individuals at one point in time - researchers looked at the impact of obesity on brain structure across the adult lifespan to investigate whether obesity was associated with brain changes characteristic of ageing. The team studied data from 473 individuals between the ages of 20 and 87.

The researchers divided the data into two categories based on weight: lean and overweight. They found striking differences in the volume of white matter in the brains of overweight individuals compared with those of their leaner counterparts. Overweight individuals had a widespread reduction in white matter compared to lean people. The team then calculated how white matter volume related to age across the two groups. They discovered that an overweight person at, say, 50 years old had a comparable white matter volume to a lean person aged 60 years, implying a difference in brain age of 10 years. Strikingly, however, the researchers only observed these differences from middle-age onwards, suggesting that our brains may be particularly vulnerable during this period of ageing.

Despite the clear differences in the volume of white matter between lean and overweight individuals, the researchers found no connection between being overweight or obese and an individual's cognitive abilities, as measured using a standard test similar to an IQ test. "We don't yet know the implications of these changes in brain structure. Clearly, this must be a starting point for us to explore in more depth the effects of weight, diet and exercise on the brain and memory."

Link: http://www.cam.ac.uk/research/news/brains-of-overweight-people-ten-years-older-than-lean-counterparts-at-middle-age

The open access paper linked below provides another reason to be optimistic about the therapies to clear senescent cells from old tissues that are presently under development. Here, the researchers created genetically engineered mice in which they could selectively trigger senescent cell death in lung tissues. In older mice, the result was improved pulmonary function, and other improvements in the state of lung tissue - turning back the clock on some of the detrimental age-related changes that take place in the lungs.

Cells become senescent in response to damage or environmental toxicity, or at the end of their replicative lifespan, or to assist in wound healing. The vast majority either destroy themselves or are destroyed by the immune system, but a few manage to linger on. Those few grow in numbers over the years, and more so once the immune system begins to decline and falter in its duties. Ever more senescent cells accumulate in tissues with advancing age, and they secrete a mix of signals that can encourage other cells to become senescent, increase inflammation, and destructively remodel nearby tissue structures. In small numbers senescent cells can help to resist cancer or assist healing, but in large numbers they contribute meaningfully to all of the symptoms and conditions of old age. They are one of the root causes of aging.

Building therapies to destroy senescent cells is the best, easiest, and most direct response. If carried out sufficiently well it would remove this contribution to the aging process entirely, and fortunately the cancer research community has been working on targeted cell destruction for many years now: the technologies exist and just need to be hammered into shape. This class of rejuvenation therapy has been advocated as a part of the SENS vision for the medical control of aging for going on fifteen years now, but only in recent years has the research community made useful progress. As for so many promising lines of research related to bringing aging under medical control, it has been next to impossible to raise funds for this work. The most critical studies in senescent cell clearance, those that proved the case beyond any reasonable doubt, were funded through philanthropy, as is often the case for work at the true cutting edge of medical science. The tipping point has come and gone now, however. At present commercial development is underway. Oisin Biotechnologies and UNITY Biotechnology are building various types of therapy to eliminate senescent cells, and I'm sure they'll be joined by other efforts as more evidence rolls in from animal studies.

Of particular interest in the research results linked here is that tissue elasticity improved. Loss of elasticity is of great importance in the aging of many parts of the body, such as skin and blood vessels. In blood vessels, for example, loss of elasticity leads to hypertension which causes cardiovascular disease and then death. It remains an open question as to which of the primary forms of cell and tissue damage are more important in this process of stiffening. If senescent cell clearance helps meaningfully for blood vessels, then we should all be very thankful, as therapies to remove senescent cells will be arriving in the clinic years in advance of rejuvenation treatments that can address other likely causes of loss of elasticity, such as persistent cross-link formation in the extracellular matrix.

The method of senescent cell elimination that the scientists employed in this study is not something that can be turned into a therapy, since it depends on creating a genetically altered lineage of mice, in which cells are primed to accept a self-destruct trigger that operates only on senescent cells. Its utility lies in the ability to remove senescent cells precisely in a given tissue, and at a given time. That precision means that researchers can be more certain that senescent cell clearance is the cause of the observed benefits. Given the growing number of ways to target senescent cells for clearance that can be turned into human therapies, it is fortunately not an issue that the experimental tests are using a more restricted approach. Removal of these cells is the important target, and any safe and effective methodology should do the job just fine.

Elimination of p19ARF-expressing cells enhances pulmonary function in mice

While there is no doubt that cellular senescence prevents cancer, an increasing amount of evidence suggests that cellular senescence is involved in other biological processes and pathologies. Cellular senescence has been shown to contribute to embryonic development, wound healing, and tissue regeneration. Additionally, it has become more evident that cellular senescence contributes to tissue aging. Senescent cells accumulate in many tissues during aging and are considered to underlie aging-associated pathologies. The contribution of senescent cells in aging-associated phenotypes may depend on signaling, such as senescence-associated secretory phenotype (SASP), because the population of senescent cells is very small, even in very old human tissue.

Two major tumor suppressor pathways, namely, the p19ARF (p14ARF in humans)/p53 and p16INK4a/Rb pathways, play critical roles in the induction and maintenance of cell cycle arrest during cellular senescence. In the present study, we established a transgenic model from which it was possible to eliminate p19ARF-expressing cells using a toxin-mediated cell knockout system. Similar to INK4a, the expression of ARF has been shown to increase during aging in the mouse. Using the transgenic model, we successfully eliminated ARF-expressing cells from the lung tissue of 12-month-old animals. The ablation of ARF expression abolished the expression of other senescent markers, including INK4a and p21, suggesting that the expression of ARF reflects the accumulation of senescent cells in tissues. The elimination of p19ARF-expressing cells in lung tissue ameliorates the aging-associated loss of tissue elasticity. Moreover, the expression of a large number of aging-associated genes was reversed after the removal of p19ARF-expressing cells. Taken together, these findings highlight the role of p19ARF in lung tissue aging and indicate that the aging phenotype in lung tissue may be reversed by eliminating p19ARF-expressing cells from tissue.

Senescent cells are known to have an effect on their surrounding "nonsenescent" cells through SASP. Our results suggest that the population of p19ARF-expressing cells was very small, even in adult lung tissue (approximately 1% of the lung mesenchymal population). Nevertheless, our microarray data indicate that these "rare" p19ARF-expressing cells strongly influence gene expression in lung tissue. Hundreds of genes are upregulated and downregulated during aging in the lung, and more than half of these aging-associated genes show p19ARF dependence. Since senescent cells induce senescence-like gene expression in their surrounding cells through SASP, it is reasonable to assume that changes in aging-associated genes in lung tissue do not simply reflect the events within p19ARF-expressing cells, but also include global changes in lung tissue cells that are mostly nonsenescent.

We performed pulmonary function tests on these mice. Static lung compliance (Cst) was significantly higher in older animals than in young animals. The treatment resulted in the marked recovery of lung elasticity (decrease in Cst). Similarly, the treatment reversed aging-associated changes in dynamic compliance, dynamic resistance, tissue elastance, and tissue damping. These results clearly indicated that the p19ARF-expressing cells that accumulated in 12-month-old lung tissue had deleterious effects on pulmonary function and that aging-associated declines in pulmonary function were ameliorated by the elimination of these p19ARF-expressing cells. We also examined the effects of ARF-expressing cell elimination on even older animals. Tumor-free female mice between 20 and 22 months old were treated 1 month. Pulmonary function tests revealed that tissue compliance in older mice was similar to that in 12-month-old mice. The treatment reduced tissue compliance in older animals; however, this effect was less than that observed in 12-month-old mice. Collectively, these results indicated that p19ARF-expressing cells provoked the loss of elastic fibers in lung tissue and were also responsible for the increase in lung compliance in aged animals.

One of the themes that has emerged from the past few years of studies on the epidemiology of activity versus inactivity is the suggestion that time spent sitting is harmful regardless of whether or not an individual exercises. This relationship is extracted from statistical studies across populations, and as is usual in these matters the conclusion is disputed. In general, it is a good idea to give little weight to any one such epidemiological study and look instead for the consensus across many studies. That a sedentary lifestyle is bad for health and that regular moderate exercise is good for health is not in dispute, but arguments take place over the interpretation of population data for more subtle aspects of the relationship between these two things. This latest research should be added to the existing stack and considered in that context:

Ever since a study back in 1953 discovered that London bus drivers were at greater risk of heart disease compared to bus conductors, scientists have found increasing evidence that lack of physical activity is a major risk factor for several diseases and for risk of early death. Recent estimates suggest that more than 5 million people die globally each year as a result of failing to meet recommended daily activity levels. Studies in high-income countries have suggested that adults spend the majority of their waking hours sitting down. Current physical activity guidelines recommend that adults undertake at least 150 minutes of moderate intensity exercise per week.

In a recent analysis that draws together a number of existing studies, an international team of researchers asked the question: if an individual is active enough, can this reduce, or even eliminate, the increased risk of early death associated with sitting down? In total the researchers analysed 16 studies, which included data from more than one million men and women. The team grouped individuals into four quartiles depending on their level of moderate intensity physical activity, ranging from less than 5 minutes per day in the bottom group to over 60 minutes in the top. Moderate intensity exercise was defined as equating to walking at 3.5 miles/hour or cycling at 10 miles/hour, for example. The researchers found that 60 to 75 minutes of moderate intensity exercise per day were sufficient to eliminate the increased risk of early death associated with sitting for over eight hours per day. However, as many as three out of four people in the study failed to reach this level of daily activity.

The greatest risk of early death was for those individuals who were physically inactive, regardless of the amount of time sitting - they were between 28% and 59% more likely to die early compared with those who were in the most active quartile - a similar risk to that associated with smoking and obesity. In other words, lack of physical activity is a greater health risk than prolonged sitting. "There has been a lot of concern about the health risks associated with today's more sedentary lifestyles. Our message is a positive one: it is possible to reduce - or even eliminate - these risks if we are active enough, even without having to take up sports or go to the gym."

Link: http://www.cam.ac.uk/research/news/an-hour-of-moderate-exercise-a-day-enough-to-counter-health-risks-from-prolonged-sitting

It is known that leading an inactive life, one lacking in physical exercise, has a fairly large negative effect on health and life expectancy. In a similar way to past studies that assessed the overall cost of obesity across populations, researchers here investigate one methodology by which it is possible to estimate the global cost of sedentary lifestyles:

A study has revealed that in 2013, physical inactivity cost $67.5 billion globally in healthcare expenditure and lost productivity, revealing the enormous economic burden of an increasingly sedentary world. Based on data from 142 countries, representing 93.2 per cent of the world's population, this study provides the first-ever global estimate of the financial cost of physical inactivity by examining the direct health-care cost, productivity losses, and disability-adjusted life years (DALYs) for five major non-communicable diseases attributable to inactivity: coronary heart disease, stroke, type 2 diabetes, breast cancer and colon cancer.

"Physical inactivity is recognised as a global pandemic that not only leads to diseases and early deaths, but imposes a major burden to the economy. Based on our data, physical inactivity costs the global economy $67.5 billion in 2013, with Australia footing a bill of more than AUD $805 million. At a global and individual country level these figures are likely to be an underestimate of the real cost, because of the conservative methodologies used by the team and lack of data in many countries. Increasing physical activity levels in communities is an important investment that governments should consider which could lead to savings in healthcare costs and more productivity in the labour market."

The $67.5bn in total costs, including $53.8bn in direct cost (healthcare expenditure) and 13.7bn in indirect costs (productivity losses), breaks down as follows. $31.2bn for total loss in tax revenue through public healthcare expenditure; $12.9bn as the total amount in private sector pays for physical inactivity-related diseases (e.g. health insurance companies); $9.7bn as the total amount households paid out-of-pocket for physical inactivity-related diseases. Type 2 diabetes was the costliest disease, accounting for $37.6bn (70 percent) of direct costs.

Link: http://sydney.edu.au/news-opinion/news/2016/07/28/physical-inactivity-cost-the-world--67bn-in-2013-says-first-ever.html

The Request for Startups (RFS) is something lately popularized by the venture incubator Y Combinator, a part of their shifting approach to the field. Having achieved sufficient growth and cultural dominance, they now have the ability to play a greater role in shaping the future, insofar as startups and the entrepreneurial community as a whole are tools to create change. To the extent that the Y Combinator principals would like to see specific changes in to world take shape over the decades ahead, they would like to help nudge that along by funding credible startups in some areas presently neglected. So they put out the RFS, a notice they they are willing to listen to pitches and are interested in funding startups in a set of specific fields or with specific focuses. The name is a play on the technical standards practice of putting forward protocol definitions in the form of Request for Comments, RFC. Standards of all sorts become known by their RFC number, and referring to RFC 1234, RFC 3456, and the like in the course of development is very common in software engineering circles.

The few SENS rejuvenation therapy startups launched and underway over the past year or two have adequately demonstrated that there is no real shortage of venture funding for our corner of the medical biotechnology field at the present time. If anything there is far more money on the sidelines waiting for an opportunity than there are SENS-relevant companies to invest in. This is partly a function of the era, in which various self-serving decisions by the powers that be have created a flood of easy money in search of returns, any returns, but more importantly it is a function of the fact that the SENS approach to treating aging is only just starting to emerge from the laboratory. SENS is all about repairing the clearly identified forms of cell and tissue damage that cause aging, which if done well enough should postpone aging indefinitely in younger adults, and at least partially rejuvenate the old. There are numerous types of damage, so while forms of senescent cell clearance are under development in various companies, items like cross-link clearance or mitochondrial DNA repair are still years out, and other problems may still be working their way through the laboratory ten to fifteen years from now.

Given the imbalance between available funding and relevant available startups, I think it would be a good plan for the SENS Research Foundation, or other parts of our community such as the Methuselah Foundation, to publish, maintain, and publicize a Request for Startups - a moderately detailed set of areas that investors in the SENS network are interested in funding. The aging research community is small and highly connected, and it can be argued that the SENS Research Foundation staff are very familiar with a large fraction of all of the research groups who might produce work leading to a startup to develop a possible SENS repair therapy. As matters progress, however, that fraction is going to become smaller. The world is a large place. As new groups focused on aspects of SENS emerge, some form of prominent banner will be useful, influencing unaffiliated researchers in the direction of considering the leap to run a startup. Further, I think that it isn't yet widely known that anyone who turns up with a credible technology and team to start for-profit clinical development of a SENS rejuvenation therapy will have no problems whatsoever in raising funds. In the non-profit laboratory world, aging researchers operate in a very resource poor environment; funding for any type of initiative is hard to come by. It is not always obvious to people immersed that culture that a wealth of funding awaits just on the other side of the conceptual wall that is crossed when moving into for-profit work. How many projects relevant to SENS exist out there, languishing for lack of funding, and where the researchers are not in contact with the SENS Research Foundation? I'd argue that we'll never know the answer to that question unless we aggressively advertise the fact that investors are interested.

It is of course frustrating to see so little interest in funding research while so much money is waiting on the sidelines for that research to reach the point of viable commercial development. It is like watching someone fail to connect the obvious two dots to improve their present situation. Changing this state of affairs is a big challenge, somewhat beyond the scope of this post: I've written on the topic in the recent past. Reforming the investment world to the point at which it is understood that investing in companies is not as effective in many situations as investing in research and then in the resulting companies that emerge from that research ... well, that is the work of a lifetime for some career advocate or leader in the venture community. Sadly all too few investors are in it to change the world, but when it comes to aging research the primary goal is exactly this: to change the world, to eliminate the suffering and death caused by aging. Life trumps money, and money is only useful for what it can do, not what it is. Investing in SENS rejuvenation research and development is one of the growing number of ways in which money can be traded for an expectation of more healthy life in the years ahead.

The recently launched SENS Project|21 is the obvious home for a rejuvenation biotechnology Request for Startups, given the pledge of $5 million in research funding and $5 million in venture investment by Michael Greve earlier this year as a starting point for the initiative. But there are a number of other places such a call to action could usefully reside. This is something for the broader community to think about as we move closer to the advent of the first treatments for the causes of aging.

Based on the evidence accumulated from many years of studies of flies and nematodes, intestinal function is fairly central in aging and longevity. This is one of those things that probably doesn't translate so well to higher, more complex, and larger species, but the general principle of better organ function correlating to better health and a longer life expectancy is something to hold on to. In this open access paper the the increased activity of the cellular housekeeping mechanisms of autophagy, produced alongside greater longevity by the practice of calorie restriction, is investigated in the context of intestinal function in nematodes:

Dietary restriction (DR) without inducing malnutrition has robust beneficial effects on lifespan in many species, including humans. The cellular recycling process of autophagy contributes to DR-mediated longevity. Autophagy is triggered by nutrient scarcity and increases the degradation of cytosolic molecules and organelles in the lysosomes. Using the nematode Caenorhabditis elegans as a model organism, we previously showed that genes involved in autophagy are required for lifespan extension through DR; however, it is not clear whether autophagy in individual tissues plays critical roles in DR-mediated longevity.

Here, we investigated the contribution of autophagy in genetically dietary-restricted eat-2 mutants. Our major findings include: (i) Inhibition of autophagy in the intestine prevents the long lifespan observed in eat-2 mutants; (ii) the intestine of eat-2 mutants contains an expanded lysosomal compartment and flux assays indicate increased autophagosome turnover, consistent with elevated autophagy in this tissue; (iii) intestinal autophagy is required for the improved intestinal integrity observed in eat-2 mutants; (iv) autophagy inhibition impairs motility in older animals; and (v) inhibition of autophagy in the intestine accelerates the motility decline in eat-2 mutants. Collectively, these studies suggest a critical role for intestinal autophagy in dietary-restricted animals, and highlight the importance of this process in maintaining fitness and longevity.

Link: http://dx.doi.org/10.1371/journal.pgen.1006135

More of the cellular housekeeping process of autophagy appears to be an unalloyed good: more repair means less damage. It shows up in a range of interventions that modestly slow aging in mice and other species, such as calorie restriction. In fact it may even be essential to the ability of calorie restriction to extend healthy life spans in these studies. One place in which greater levels of autophagy might do some good is in the development of atherosclerosis, a pervasive age-related condition in which an overreaction to minor molecular damage in blood vessel walls snowballs into zones of inflammation and growing plaques made up of fats and dead cells. Eventually these plaques cause ruptures or blockages of major blood vessels that are frequently fatal. Higher levels of autophagy should slow the pace of progression of this problem through increased clearance of plaque materials, though it seems clear from the data here that much more aggressive interventions to clean up the waste and damage will be needed to solve it completely. The effects are small.

Spermidine is an endogenous biological polyamine that exhibits broad longevity-extending activities via the induction of autophagy. Because basal autophagy is atheroprotective during early atherosclerosis but dysfunctional in advanced plaques, the aim of the present study was to assess the potential beneficial effects of autophagy induction by spermidine on atherosclerotic plaque progression and composition. Apolipoprotein E-deficient (ApoE-/-) mice prone to development of atherosclerosis were fed a Western-type diet for 20 weeks with or without 5 mM spermidine in the drinking water.

Analysis of plaques in the aortic root, proximal ascending aorta and brachiocephalic artery showed that spermidine changed neither the size of the plaque nor its cellular composition. However, spermidine treatment significantly reduced necrotic core formation (6.6 ± 0.5% vs. 3.7 ± 0.5% in aortic root) and lipid accumulation inside the plaque (27 ± 3% vs. 17 ± 1% oil red O positivity in thoracic aorta). In vitro experiments showed that macrophages, unlike vascular smooth muscle cells (VSMCs), were relatively insensitive to autophagy induction by spermidine. Along these lines, spermidine triggered cholesterol efflux in autophagy-competent VSMCs (5.7 ± 1.2% vs. 8.7 ± 0.2%), but not in autophagy-deficient VSMCs or macrophages. Analogous to the experiments in vitro, spermidine affected neither necrosis nor lipid load in plaques of autophagy-deficient ApoE-/- mice.

In conclusion, spermidine inhibits lipid accumulation and necrotic core formation through stimulation of cholesterol efflux, albeit without changing plaque size or cellular composition. These effects, which are driven by autophagy in VSMCs, support the general idea that autophagy induction is potentially useful to prevent vascular disease.

Link: http://dx.doi.org/10.1016/j.atherosclerosis.2016.07.899

Here I'll link to a recent press article on Ambrosia, a company currently working to obtain more human data on the effects of transfusing young blood plasma into old individuals. The aim is to see whether or not this can usefully change the balance of signaling molecules to, say, spur greater stem cell activity. There has been a trial in Alzheimer's patients, but some signs in animal studies that transfusions from young to old don't do much. It seems useful to speed up the process of determining whether or not transfusions are an interesting line of research, or something that only looked promising. That means more patients and larger trial populations, which Ambrosia is working on.

These transfusion initiatives are one of a number of outgrowths of parabiosis research in mice. Heterochronic parabiosis is the name given to connecting the circulatory systems of an old and a young individual. The older mouse shows a modest rejuvenation in a number of measures of aging, and the younger mouse shows some greater signs of aging - though most of the focus here has been on the old mouse. In recent years this technique has been used to search for potentially actionable differences in levels of specific signal molecules circulating in the bloodstream. For example, stem cell activity declines with aging, and this is likely governed by signaling processes. If levels of the most relevant molecules could be adjusted in old individuals, it might be possible to produce benefits that look quite similar to those of stem cell therapies: increased regeneration and tissue maintenance. This class of approach puts damaged, aged cells back to work, and does little to address causes of aging based on accumulation of metabolic waste, such as cross-links that stiffen blood vessels, but to the degree that it can improve health it is probably worthy of further investigation in the same way as stem cell therapy was back in the day.

One potential shortcut to the production of therapies is to perform transfusions: deliver young blood or young plasma to old individuals. I call this a potential shortcut because it really is still very uncertain as to (a) whether or not the whole process works in humans anywhere near as well as it works in mice, and (b) whether or not transfusions will recapture the effects of parabiosis to a useful degree. The evidence in mice suggests so far that it may not. It is possible to paint all sorts of scenarios in which the fact that old and young cells are in contact, feeding signals to one another in a feedback loop, is necessary to produce beneficial changes in the old individual. It is also possible to imagine signals with a short half-life, that won't be recaptured in transfusions, or changes in the old environment that are based on an increased level of specific signal molecules. That increased level won't be changed in the slightest by the arrival of some amount of young blood plasma. Only reduced levels are likely to be impacted that way.

In any case, testing and perhaps ruling out the fast path of transfusions seems like a fair plan. If it works, it will draw in more funding to build the better option of manipulating signal molecule levels directly. It if doesn't work, that result will direct scientists to focus on more productive lines of research and development. There is some grumbling from the expected quarters over the structuring of this present initiative by Ambrosia, but getting it done is better than not getting it done. The data will be useful in the sense that only sizable effects are interesting, and thus before and after data for participants will be convincing. Marginal effects, of the sort in which it would have been useful to have a control group to establish whether or not any benefits actually resulted, would mean that this probably isn't worth further exploration. Still, this well demonstrates the fact that many scientists who work within the heavily regulated, slow, and repressive system of medical development really don't like it when people try to get things done more rapidly and more inventively. To the extent that it closes down productive avenues, this is a dangerous attitude.

Young blood antiaging trial raises questions

It was one of most mind-bending scientific reports in 2014: Injecting old mice with the plasma portion of blood from young mice seemed to improve the elderly rodents' memory and ability to learn. Inspired by such findings, a startup company has now launched the first clinical trial in the United States to test the antiaging benefits of young blood in relatively healthy people. But there's a big caveat: It's a pay-to-participate trial, a type that has raised ethical concerns before, most recently in the stem cell field. The firm's co-founder and trial principal investigator is a 31-year-old physician named Jesse Karmazin. His company, Ambrosia in Monterey, California, plans to charge participants $8000 for lab tests and a one-time treatment with young plasma. The volunteers don't have to be sick or even particularly aged - the trial is open to anyone 35 and older. Karmazin notes that the study passed ethical review and argues that it's not that unusual to charge people to participate in clinical trials.

"There's just no clinical evidence [that the treatment will be beneficial], and you're basically abusing people's trust and the public excitement around this," says neuroscientist Tony Wyss-Coray of Stanford University in Palo Alto, California, who led the 2014 young plasma study in mice. Wyss-Coray has since started a company, Alkahest, that, with Stanford, has launched a study of young plasma in 18 people with Alzheimer's disease, evaluating its safety and monitoring whether the treatment relieves any cognitive problems or other symptoms. The company covers the participants' costs. Wyss-Coray expects results by the end of this year.

In Ambrosia's trial, 600 people age 35 and older would receive plasma from a donor under age 25, according to the description registered on ClinicalTrials.gov, the federal website intended to track human trials and their results. Karmazin says each person will receive roughly 1.5 liters over 2 days. Before the infusions and 1 month after, their blood will be tested for more than 100 biomarkers that may vary with age, from hemoglobin level to inflammation markers. The $8000 fee will cover costs such as plasma from a blood bank, lab tests, the ethics review, insurance, and an administrative fee, Karmazin says. "It adds up fairly quickly."

The scientific design of the trial is drawing concerns as well. "I don't see how it will be in any way informative or convincing," says aging biologist Matt Kaeberlein of the University of Washington, Seattle. The participants won't necessarily be elderly, making it hard to see any effects, and there are no well-accepted biomarkers of aging in blood, he says. "If you're interested in science," Wyss-Coray adds, why doesn't such a large trial include a placebo arm? Karmazin says he can't expect people to pay knowing they may get a placebo. With physiological measurements taken before and after treatment, each person will serve as their own control, he explains. Doubts aside, Ambrosia's trial has already attracted attention from the investment company of billionaire Peter Thiel.

Average telomere length decreases with aging, and is commonly measured in immune cells taken from a blood sample. Telomeres are a part of the mechanism that limits the number of times most cells can divide. Tissues are made up almost entirely of such limited cells, each losing a little telomere length during each division. When telomeres become short, the cell self-destructs or becomes senescent and ceases to divide. An associated stem cell population supports the tissue by delivering a continual supply of new daughter cells with long telomeres to replace the losses. Thus average telomere length is a function of cell division rates and cell replacement rates. Since stem cell activity declines with aging, it shouldn't be surprising to see that average telomere length does as well. In fact average telomere length in immune cells is highly variable between individuals, and even with circumstances for the same individual, and the rate of decline is small. It thus makes a pretty terrible measure of aging, a point reinforced by the numbers in this open access paper.

In the current study, we first examined the cross-sectional associations between leukocyte telomere length (LTL) and age, and, like previous reports, we found an inverse relationship with increasing age. Second, using up to five measurements across 20 years, we found that LTL decreases with age in a two-slope model with a small acceleration of decline after 69.3 years of age. Men have shorter telomere lengths than women, and genetic variation has an additional influence on overall LTL.

Several earlier studies have reported an inverse association between age and telomere length, as did we, and we further demonstrated that women have longer LTL, which is in line with earlier research. Taking our results and prior literature together, shorter telomeres in men could result from very small but consistent attrition throughout adulthood rather than a steeper decline compared to women in old age. Moreover, previous literature from cross-sectional and longitudinal studies has suggested a linear relationship between telomere length and age. We found both the one-slope and the two-slope models to be significant, with a substantially better fit of the latter. While the overall average trend was linear, there was systematic variability around the average trend, better described in a two-slope model accounting for more individual differences. The magnitude of this age-related decline was small overall, and with slight acceleration in the old-old. This observation is in line with earlier research in the field where faster decline in LTL is believed to take place in childhood and old age.

The two-slope trajectory analyses supported both familial and non-familial influences on LTL, with equal contributions to average LTL level (at age 69) and non-familial sources featuring more prominently in the change before age 69 than after age 69. This suggests that in young-old age, individual-specific lifestyle factors may prove more relevant to accelerated LTL shortening above and beyond familial and environmental contributions to overall LTL; however, in old-old age, familial factors may become increasingly salient to accelerated LTL shortening. Moreover, we note that the variation in rate of change was larger in young-old age; hence, evaluating variation in trajectories beyond the assumption of simple linearity and average trends is important for understanding etiological underpinnings.

Link: http://dx.doi.org/10.18632/aging.100995

Among the many noteworthy achievements in modern medicine over the past few decades is the reduction in heart attack risk, alongside reduced rates of many other aspects of cardiovascular disease. The data I'll point out here is but one example in a much broader trend. This is the higher end of what can be achieved through compensatory medicine for age-related disease, a set of increasingly sophisticated efforts to patch over the consequences of dysfunctional tissues, but without actually repairing the molecular damage that causes that dysfunction. Keeping a damaged machine functioning without repairing it is expensive and challenging. To go beyond the incremental improvements produced by medical science in the recent past, it will be necessary to change the high level strategy, and start to address the root causes of aging and age-related disease rather than merely papering over the problem.

Heart attack rates among an ethnically diverse population of more than 3.8 million Kaiser Permanente members in Northern California fell 23 percent from 2008 to 2014. Researchers studied rates of heart attacks by severity, age, gender, and diabetes status. While the incidence of heart attacks was highest in men, older age groups, and people with diabetes, similar declines in heart attack rates were seen across all subgroups - including those most at risk and with the highest rates, as well as among lower-risk patients, such as younger patients and women. The findings of this latest study build on research published in 2010 that demonstrated a 24 percent decline in heart attacks between 1999 and 2008.

A key difference in the two time periods studied was the type of heart attack that accounted for the majority of the declines. More severe but less common heart attacks, known as ST-elevation myocardial infarction or STEMI, which typically require an immediate procedure to open a blocked artery, fell by 62 percent from 1999 to 2008. The number of these heart attacks fell by an additional 10 percent from 2008 to 2014, resulting in a total reduction of 72 percent in these severe heart attacks from 1999 to 2014. The more common but less severe heart attacks, known as non-ST-elevation myocardial infarction or NSTEMI, showed the greatest decline from 2008 to 2014. These types of heart attacks peaked in 2004 and have fallen 33 percent through 2014. When taken together, there was a 40 percent reduction in all types of heart attacks across Kaiser Permanente in Northern California from the peak in 2000 through 2014, the most recently studied year. "While the decline in severe heart attacks across our population has been astonishing, we now see consistent declines in all types of heart attacks. Reductions in less severe heart attacks, which are nearly four times as common as the severe heart attacks, drove the bulk of the recent decline. But what is most heartening is that these reductions were consistent across every demographic and risk group we examined."

Link: http://www.eurekalert.org/pub_releases/2016-08/kp-hac080116.php

Tempus fugit. I'm just about old enough to remember a time in which 2020 was the distant future of science fiction novels, too far away to be thinking about in concrete terms, a foreign and fantastical land in which anything might happen. Several anythings did in fact happen, such as the internet, and the ongoing revolution in biotechnology that has transformed the laboratory world but leaks into clinics only all too slowly. Here we are, however, close enough to be making plans and figuring out what we expect to be doing when the the third decade of the 21st century gets underway. The fantastical becomes the mundane. We don't yet have regeneration of organs and limbs, or therapies to greatly extend life, but for these and many other staples of golden age science fiction, the scientific community has come close enough to be able to talk in detail about the roads to achieving these goals.

Of all the things that researchers might achieve with biotechnology in the near future, control over aging is by far the most important. Aging is the greatest cause of death and suffering in the world, and none of us are getting any younger. That may change, however. SENS, the Strategies for Engineered Negligible Senescence, is a synthesis of the scientific view of aging as an accumulation of specific forms of cell and tissue damage, pulling in a century of evidence from many diverse areas of medical science to support this conclusion. Aging happens because the normal operation of our cellular biochemistry produces damage, wear and tear at the level of molecules and molecular structures, and some of that damage accumulates to cause failure of tissues and organs, and ultimately death. That explanation for aging is coupled to the SENS portfolio of research programs that aim to repair this damage: for every type of damage, the appropriate form of repair technology can be described in great detail. The only thing remaining is to build these repair therapies and test them, to see whether or not they produce the expected result of rejuvenation and longer healthy lives.

It has taken a long time, twenty years or so, to make the treatment of aging a mainstream idea in the research community, and for the public to start to catch up. It hasn't helped that the pursuit of rejuvenation has been a realm occupied only by frauds and the delusional for millennia. It has taken many years of hard work for the evidence and the results indicating that rejuvenation can be achieved to circulate and be more widely accepted. Still, the SENS approach to aging, to head straight for damage repair and rejuvenation, and none of this messing around with drugs to try to slightly slow the pace at which damage accumulates, remains a minority vision at this time. Nonetheless, SENS researchers and advocates have made great progress on very little funding, and as a result we now near the point at which the first results will emerge from the labs into the wider world.

The next five years are critical precisely because the first few startup companies to work on the first rejuvenation therapies following the SENS model of damage repair will succeed or fail in this short span of time. The most important of these companies are probably Oisin Biotechnologies and UNITY Biotechnology, both working on senescent cell clearance. They have what looks like the best chance of success given the present state of the science, and are already well underway. Technical success does not necessarily translate to rapid clinical availability in medicine, however. You only have to look at Pentraxin Therapeutics and their work on transthyretin amyloid clearance to see that: they have been locked into a development program with GlaxoSmithKline that took six years to get to a small clinical trial, and there is no sign that this will move any faster following the success of that trial, or that it will be made available for anyone other than late stage amyloidosis patients. Clearance of transthyretin amyloid should be undergone by every human being every few years after the age of 40, given that buildup of this form of amyloid contributes to heart disease and a range of other conditions - but that development group simply isn't heading in that direction. It is one thing to catch the interest of Big Pharma, another thing entirely to make them work rapidly, or to agree with the vision of treating aging as a medical condition.

Thus there is a very large difference between (a) a world in which companies conservatively sell to Big Pharma or raise funds themselves to creep through the regulatory process to gain approval for use with a tiny number of patients in the late stages of aging, and (b) a world in which the first destination is clinical availability via medical tourism in regulatory regions where only safety must be demonstrated, and anyone can walk in and undergo treatment. Stem cell medicine would be nowhere near as far along without the decade of its widespread availability outside the US and Europe. I am very much in favor of a similar progression of availability and development for the range of potentially useful human gene therapies that will be developed in the years ahead, and for the first SENS rejuvenation technologies, such as senescent cell clearance.

Nonetheless, whether or not the outcome is much delayed availability of therapies, success in building a company based on SENS therapies is a very important step. It will in some cases, as for Oisin Biotechnologies, bring significant funding for other lines of SENS research as various advocates and the SENS Research Foundation are early investors. More importantly, success in clinical development of a treatment that meaningfully addresses easily measured metrics of aging after one set of treatments - metrics such as the epigenetic clock based on DNA methylation, or inflammation, or skin elasticity, or blood vessel elasticity, and so on - will be widely noted. That will go a long way towards opening many doors to much larger sources of funding. Either this happens soon, for the companies already under way, or they will fail, possibly damaging the view of SENS even should that failure happen for reasons unrelated to the technical aspects of the work. Failure will push back ultimate success in the medical control of aging for years, and that has an enormous cost associated with it: tens of millions of lives lost, and hundreds of millions suffering due to age-related conditions that might otherwise have been turned back. The SENS Research Foundation staff realize this well, and hence their focus on Project|21, launched earlier this year.

In short, this is an important time, and we should all put some thought into how we might best support the work on rejuvenation biotechnology that is presently taking place.

Fibrosis is a form of inappropriate scarring, connective tissue forming where it should not inside organs, destroying the structures necessary for correct function. Fibrosis is involved in many age-related diseases, notably in liver conditions, for example. Researchers have in the last couple of years made a few initial inroads in targeting cell behavior to reduce fibrosis in some organs, but there is still comparatively little that can be done for patients suffering fibrotic conditions. Better and more universal approaches to block the mechanisms of fibrosis are needed, but as the publicity materials here indicate, the process of discovery is still in comparatively early stages.

Researchers have utilized the new software tool to evaluate the perturbation status of many signaling pathways. This new system aimed to identify robust biomarkers of fibrotic disease and develop effective targeted therapy. Fibrosis, a progressive accumulation of extracellular matrix, can occur in a wide range of organs and potentially distort their structure and function; most commonly it affects lung and hepatic tissues, causing idiopathic pulmonary fibrosis (IPF) and liver fibrosis respectively. Fibrosis accounts for up to 45% of deaths in the developed world, yet to date no effective therapeutic treatment has been developed. "Currently, there are no approved anti-fibrotic remedies and no reliable fibrotic biomarker. Our system can detect hidden fibrotic molecular signatures based on a pathway network analysis, and identify specific fibrogenic molecular changes regardless of detecting platform and tissue of origin. Despite many efforts, fibrosis is often misdiagnosed. Our system is supposed to help with proper and timely diagnostic."

With broad screening across multiple fibrotic organs, the platform identified pathogenic pathways that served as potential targets for the anti-fibrotic therapy. This approach led to a selection of the list of small molecules and natural compounds by their ability to minimize the signaling pathway difference between a fibrotic and a healthy state of the tissue. Further work with provides promising opportunities to identify conserved biological pathways that play a critical role in fibrosis development. "We have discovered previously-undetected pro-fibrotic signatures in glaucoma, based on pathway analysis. This new knowledge will allow us to cooperatively select and develop anti-fibrotic small molecule interventions to minimize or reverse this fibrotic state, and restore the tissue to normal function."

Link: http://www.eurekalert.org/pub_releases/2016-07/imi-psi072916.php

Mitophagy is the process by which damaged or excess mitochondria in cells are destroyed, their parts recycled. Mitochondria, and in particular the level of damage in mitochondria, are important in aging. For most things that are important in aging, there is also a fair amount of evidence suggesting relevance to cancer, and mitochondria are no exception. Researchers here consider some of the known links between the modulation of mitophagy and the development of cancer, and taken as a whole the evidence suggests anything but a simple relationship. Depending on the particular context, when it comes to cancer it can be argued that either less mitophagy or more mitophagy is a bad thing. This is not the case for aging, in which greater mitophagy should always be beneficial, to the extent that it maintains lower levels of mitochondrial damage and the harms that result from that damage.

Macroautophagy, hereafter referred to as autophagy, is a highly conserved degradation process targeting large and possibly toxic structures in the cell. Mitochondria-selective autophagy (mitophagy) plays a pivotal role in the maintenance of mitochondrial homeostasis, regulating the size and quality of the mitochondrial population. In addition, mitophagy eliminates damaged mitochondria under diverse stress conditions. Healthy mitochondria are also removed when attenuation of mitochondrial function is required upon hypoxia, caloric restriction, or during certain developmental processes. Mitochondrial surveillance and quality control mechanisms, including mitophagy, decline with age and in several pathologies, causing progressive deterioration of mitochondrial function. Deregulation of mitophagy is closely linked to cancer development and progression. Thus, elucidation of the mechanisms governing mitophagy holds promise for novel anticancer interventions.

In C. elegans, inhibition of mitophagy increases mitochondrial mass, uncouples respiration from ATP production, enhances mitochondrial ROS production, and increases cytoplasmic calcium levels. These phenotypes are commonly observed in aged animals, and across large evolutionary distance. Increased ROS contribute to carcinogenesis by causing DNA damage and triggering aberrant alterations in gene expression. Therefore, in addition to the manifestation of pro-aging phenotypes, impairment of mitophagy potentially facilitates tumorigenesis. Yet cancer cells within several types of solid tumors induce autophagy and mitophagy to adjust to their microenvironment of limited nutrient and oxygen availability. In the largely hypoxic solid tumor environment, energy production shifts from oxidative phosphorylation to glycolysis, leading to increased glucose uptake and reduced oxygen consumption, a phenomenon known as the Warburg effect. Mitophagy induction has thus been proposed to be part of a hypoxia adaptation response that promotes cancer cell survival.

Notably, we found that DCT-1 upregulation under mitophagy-inducing conditions is mediated by SKN-1, the nematode homolog of mammalian Nrf2, a transcription factor that becomes activated upon oxidative stress to preserve mitochondrial homeostasis. SKN-1 also stimulates the expression of core mitochondrial components, promoting the assembly of fresh mitochondria. Our findings reveal a new layer of mitophagy regulation, which interfaces with mitochondrial biogenesis resulting in rejuvenation of the cell's mitochondrial pool. These observations highlight SKN-1/NRF2 as a new anticancer target whose activation could induce both mitophagy and mitochondrial biogenesis. This dual coordinating role may shield mitochondrial metabolism from oncogenic transformation by opposing the Warburg effect to increase healthspan. Decreased insulin signaling is an evolutionarily conserved molecular pathway that promotes longevity. We have shown that mitophagy is a significant contributor to lifespan extension under low insulin conditions. Indeed, inhibition of mitophagy shortens the lifespan of long-lived animals carrying lesions in daf-2, the gene encoding the sole insulin/IGF-1 receptor homolog in C. elegans. SKN-1 and DAF-16 underlie mitophagy induction under low insulin signaling conditions.

In summary, mitophagy is emerging as a nexus of cellular and organismal physiology. Several mitophagy promoting conditions engage distinct transcription factors that impinge on cancer-associated processes. The extent of mitophagy induction is critical for the onset and progression of carcinogenesis. Impairment of mitophagy in healthy tissues can promote tumor formation and mobility of cancer cells, whereas mitophagy induction in hypoxic solid tumors promotes adaptation and tumor cell survival. Coordination of mitochondrial biogenesis and removal could provide a new pathway to circumvent the adverse effects of mitophagy in this context. Further dissection of this pathway could unravel new potential anticancer interventions targeting tumorigenesis by promoting mitochondrial rejuvenation.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845207/