Fight Aging!

The accumulation of transthyretin amyloid deposits in tissues is one of the contributing causes of aging. There are perhaps a score of different amyloids found in older humans, each the solid form of a particular protein broken in a particular way, and all a side-effect of the normal operation of cellular metabolism. In some cases it isn't all that clear as to what harms an amyloid causes, while at the other end of the spectrum of knowledge lies the amyloid-β associated with Alzheimer's disease - a very active and well-funded research community has mapped a great deal of the biochemistry of this amyloid and the ways in which it produces dysfunction and death in brain cells. I suspect that were the same level of attention directed towards other amyloids, harms would be identified. As supporting evidence for this hypothesis, I'll note that over the years transthyretin amyloid has been moving steadily from scientific ignorance of the damage it does towards a greater understanding of the negative impacts it has on health and mortality.

Nearly a decade ago, investigations into the causes of mortality in supercentenarians pointed to transthyretin amyloid as a majority cause of death: it chokes the cardiovascular system, leading to heart failure. It may well be that transthyretin amyloidosis provides the present outer limit to human life span, or at least until it is addressed. A couple of years ago, researchers associated transthyretin amyloid with heart failure in younger cohorts of old people - it isn't just the oldest old who are impacted significantly by amyloid in heart tissue. Another line of research that has developed in the past few years is the association of transthyretin amyloid with cartilage degeneration and osteoarthritis, which is the topic of the open access paper noted below, as well as in related conditions such as spinal stenosis.

A number of different approaches to clearing out transthyretin amyloid are in development. They are a little further along, on average, than much of the portfolio of potential rejuvenation therapies largely because of the existence of a rare inherited condition, transthyretin-related hereditary amyloidosis, in which mutation leads to the rampant accumulation of this amyloid at a young age. However, funding should expand and progress speed up the more that transthyretin amyloid is conclusively linked to common age-related conditions. Among the efforts worth keeping an eye on: a few years ago, a trial successfully demonstrated clearance of amyloid using a combination of CPHPC and anti-SAP antibodies; the SENS Research Foundation has funded work on catalytic antibodies for amyloid; there are other antibody initiatives at varying stages; and RNA interference also seems promising. One or more of these approaches will push forward into clinical availability sooner or later. When successful this will join the ranks of other proven rejuvenation therapies: ways to turn back the causes of multiple age-related diseases by repairing the forms of cell and tissue damage that lie at the root of aging.

Transthyretin deposition promotes progression of osteoarthritis

Osteoarthritis (OA) is the most prevalent human joint disease with age being the main risk factor. There are currently no established approaches to prevent or slow the progression of OA. A large number of therapeutic targets have been identified and successfully tested in animal models. However, thus far clinical trials targeting these pathways have failed. Changes in articular cartilage appear to be the earliest event in disease initiation and are likely to be the main drivers of disease progression, but all the joint tissues are affected by the disease process. Age-related changes in cartilage have been characterized, but the mechanisms that mediate the effect of age on OA are unknown.

In studies of articular cartilage, menisci, and synovium from arthritic joints, the prevalence of amyloid deposits was between thirty and one hundred percent of joints examined. Amyloid deposits in OA synovium were ranged from 8% to 25% of the patients. The most common precursor is the thyroxin (T4) and retinol transporter protein transthyretin (TTR). TTR is protein is composed of four identical subunits. TTR amyloid formation requires tetramer dissociation into monomers that misfold and aggregate to initiate the amyloidosis cascade. In contrast with the less common forms of inherited transthyretin amyloidosis, the more prevalent senile systemic amyloidosis (SSA) is caused by the deposition of amyloid derived from wild-type TTR. It occurs mainly in elderly males, with its clinically dominant manifestations related to deposits of wild-type TTR in the myocardium.

We have previously reported that all human cartilage samples collected at the time of joint replacement surgery were positive for amyloid and TTR. In addition, we showed in studies of primary cultured chondrocytes that exposure to amyloidogenic TTR affected chondrocyte survival and induced the expression of OA-related genes. These findings raise the question of whether the deposits contribute to the process of cartilage degradation. It is also possible that the damaged tissues create an environment which supports TTR aggregation, which in turn could amplify the OA process. The objective of this study was to investigate the role of TTR in vivo in mice transgenic for 90-100 copies of the wild-type human TTR (hTTR-TG mice) using an experimental OA and aging model.

We used mice with transgenic overexpression of human rather than mouse TTR as the mouse protein is kinetically several orders of magnitude more stable than the human protein and hence is not subject to amyloid formation, which depends on tetramer dissociation. The hTTR-TG mouse strain that we have studied showed human TTR deposits between 12 and 17 months of age in the kidneys and heart. In mice over 18 months of age, TTR-related deposits were found in 84% in the kidneys and 39% in the heart. The main observation from the present study is that hTTR-TG mice develop more severe cartilage damage and synovitis than wild-type mice in the surgically induced OA model and aging model. This suggests that OA-related cartilage changes promote TTR deposition, which, in turn, seems to amplify the OA damage.

The hTTR-TG mice did not present abnormalities in skeletal development and there were no differences in joint pathology compared to wild-type mice by 12 months. However, at 18 months, hTTR-TG mice developed significantly increased OA degeneration and synovial changes compared to wild-type. One of the main mechanisms of TTR amyloid pathogenesis is cytotoxicity. We showed that amyloidogenic TTR-induced cell death in cultured chondrocytes and one of the histological features of the hTTR mice was reduced cartilage cellularity. Thus, it appears that this is also one factor contributing to the increased OA severity in these mice. Together with prior observations that aging and OA in humans are associated with TTR and amyloid deposition in cartilage, the present findings suggest that reducing TTR amyloid formation can be a new therapeutic approach for OA.

FOXO3A is one of the very few genes shown to have an association with human longevity in more than one study population, though this is neither a sizable nor reliable effect. We all age for the same underlying reasons, and on a schedule that should by rights be held as remarkable for its comparative lack of variation, rather than for the degree of variation we do observe. The scope of that natural variation in the processes of aging is a matter of thousands of individually tiny contributions from single genes, and most of that in the late stages of life, at the point where damaged systems are failing and flailing.

Those contributions are heavily dependent on one another, and vary enormously from individual to individual, from region to region, from lifestyle to lifestyle. That is why investigation of the genetics of long-lived individuals is not a field that will produce sizable gains in human longevity. It just isn't the right place to find large improvements in human health, or ways to turn back aging rather than slightly reduce the pace at which it progresses. Nonetheless, considerably more effort has been put into this sort of genetic investigation than is put into approaches that are actually relevant to the development of actual, working rejuvenation therapies, as is illustrated by the overly enthusiastic paper on FOXO genes linked here.

Specific mechanisms involved in cellular processes that cause aging are a different story, however. FOXO4 has a role in maintaining the harmful state of cellular senescence, for example, and sabotaging that specific mechanism has been shown to selectively push senescent cells into self-destruction with little in the way of side-effects. All such senolytic therapies have the potential to produce sizable and reliable benefit. The point is that we shouldn't be looking to natural variations between individuals as the place to find potential paths to treat aging. We should be looking to the causes of aging, and where they can be turned back most effectively.

Several pathologies such as neurodegeneration and cancer are associated with aging, which is affected by many genetic and environmental factors. Healthy aging conceives human longevity, possibly due to carrying the defensive genes. For instance, FOXO (forkhead box O) genes determine human longevity. FOXO transcription factors are involved in the regulation of longevity phenomenon via insulin and insulin-like growth factor signaling. Only one FOXO gene (FOXO DAF-16) exists in invertebrates, while four FOXO genes, that is, FOXO1, FOXO3, FOXO4, and FOXO6 are found in mammals. These four transcription factors are involved in multiple cellular pathways, which regulate growth, stress resistance, metabolism, cellular differentiation, and apoptosis in mammals.

FOXOs are mainly involved in the regulation of metabolism, regulation of reactive species, and regulation of cell cycle arrest and apoptosis. FOXO1 regulates adipogenesis, gluconeogenesis, and glycogenolysis. Mechanistically, the unphosphorylated FOXO1 binds to the insulin response sequence present in the promoter region of G6P (glucose-6 phosphatase) in the nucleus. It leads to the accelerated transcription resulting in the enhanced production of glucose in the liver. Adipogenesis is negatively regulated by FOXO1 through its binding to the promoter region of PPARG (peroxisome proliferator-activated receptor gamma) and inhibiting its transcription. Moreover, FOXO1 functions as an association between transcription and insulin-mediated metabolic control; thus, FOXO1 is a promising genetic target to manage type 2 diabetes.

FOXO3 probably induces apoptosis either upregulating the genes needed for cell death or downregulating the anti-apoptotic factors. In addition, FOXO3 has been found to regulate the Notch signaling pathway during the regeneration of muscle stem cells. Moreover, antioxidants are thought to be upregulated by FOXO3 to protect human health from oxidative stress. Additionally, FOXO3 is documented to suppress tumour growth. Thus, tumour development may occur if FOXO3 is deregulated. Most importantly, FOXO3 are described to play a role in long-term living.

FOXO4 is involved in the regulation of various pathways associated to apoptosis, longevity, cell cycle, oxidative stress, and insulin signaling. FOXO4 is associated with longevity through the insulin and insulin-like growth factor signaling pathway. Finally, mutation-triggered Akt phosphorylation results in the inactivated FOXO4. It deregulates the cell cycle and activates kinase inhibitors involved in the cell cycle. It leads to the prevention of tumour progress into the G1 phase of cell division.

Numerous strategies for future research can be predicted. For instance, the triggering of FOXO-mediated processes in the tissues with metabolically different features can be valuable to explore the mechanism of FOXO-mediated longevity. In addition, the human FOXO sequence variations and their effect on the resulting proteins should be studied, the possible findings can also reveal the underlying mechanisms of FOXO-induced healthy aging. The delay in age-related pathologies including cancer and neurodegenerative diseases and living long life depends on the control of morbidity. It is therefore an exciting area of study to investigate potential antiaging compounds; however, their testing in clinical setup would need biomarkers to assess aging rate. Owing to the potential effect of FOXOs on health issues, the future therapies could be based on the FOXOs.

Link: https://doi.org/10.1155/2017/3494289

Researchers here report on the role of lipid peroxidation in the pathology of Alzheimer's disease, in particular as a way to explain why some variants of apolipoprotein E (APOE) appear to be linked to a greater risk of developing this neurodegenerative condition. Alzheimer's is a complex biological failure state built of many interdependent chains of cause and effect, and thus the one small area touched on in this research, somewhere in the midst of this sea, can be linked to a range of other processes and failures observed in the brain tissue of patients and animal models. To pick a few examples: rising levels of inflammation and oxidative stress; the failure of lysosomes - and thus failure to recycle metabolic waste - in the glial support cells in the brain; and also the changing behavior and generally greater dysfunction of these glial cells with increasing age.

Researchers discovered in 2015 that a number of genes involved in neurodegeneration promote damage to neurons and glia by inducing high levels of free radicals (oxidative stress) and accumulation of lipid droplets in glia. This work sets the stage for the current study. "Using electron microscopy, we observed lipid droplet accumulation in glia before obvious symptoms of neurodegeneration. In the presence of high levels of oxidative stress, neurons produce an overabundance of lipids. The combination of free radicals and lipids, which produces peroxidated lipids, is detrimental to cellular health. Neurons try to avoid this damage by secreting these lipids, and apolipoproteins - proteins that transport lipids - carry them to glia cells. Glia store the lipids in lipid droplets, sequestering them from the environment and providing a protective mechanism."

The team discovered that the storage of lipid droplets in glia protects neurons from damage as long as the free radicals do not destroy the lipid droplets. When the lipid droplets are destroyed, cell damage and neurodegeneration ensues. "Our research brought us to a fascinating and unexpected finding. Approximately 15 percent of the human population carries apolipoprotein APOE4. Since APOE4 was first linked to Alzheimer's disease almost 30 years ago, it remains the strongest known genetic risk factor for this disease. Meanwhile, APOE2, which is slightly different from APOE4, is protective against the disease. This evidence suggests that APOE is important for proper brain function, but we know little about how APOE itself may lead to Alzheimer's disease".

The researchers found that apolipoproteins APOE2, APOE3 and APOE4 have different abilities to transfer lipids from neurons to glia and hence differ in their ability to mediate the accumulation of lipid droplets. "APOE2 and APOE3 can effectively transfer lipids into glia. On the other hand, APOE4 is practically unable to carry out this process. This results in a lack of lipid droplet accumulation in glia and breakdown of the protective mechanism that sequesters peroxidated lipids. This fundamental difference in the function in APOE4 likely primes an individual to be more susceptible to the damaging effects of oxidative stress, which becomes elevated with age."

Link: https://www.bcm.edu/news/brain/breakdown-brain-cell-collaboration-alzheimers

Fibrosis is the result of dysfunctional regenerative processes, such as those operating in old tissues. Instead of rebuilding the structures that should exist, instead regeneration is characterized by the formation of scar-like collagen deposits that disrupt normal tissue layout and function. This is particularly important in the age-related decline of organs such as the kidney, lung, liver, and heart: where correct function is absolutely vital, or where precise tissue structure is absolutely vital. Regeneration is a coordinated dance between immune cells, senescent cells, and the cells that will do the work of rebuilding: a mix of stem cells, progenitor cells of various types, and ordinary somatic cells. With age, the immune system becomes inflammatory and disarrayed, stem and progenitor cells are less activity, and growing numbers of persistent senescent cells pump out signals that disrupt the intricate relationships needed for regenerative processes to operate.

Recent research is making it clear that lingering, persistent senescent cells are an important cause of fibrosis. However, it remains the case that most researchers interested in fibrosis are still operating in the paradigm of mapping regulatory genes and proteins throughout a tissue, rather than looking for a set of cells that are at fault. The mapping proceeds in the hope of finding target proteins that can be blocked, enhanced, or otherwise manipulated in order to change cell behavior during regeneration - to dial down fibrosis. In the paper noted here, the authors settle on Wnt/β-catenin signaling as a potential target, and indeed demonstrate that absent this signaling process mice produce less scarring and fibrosis after injury to heart tissue.

If you read through the paper, there isn't any mention given to cellular senescence, but we can look elsewhere to find a number of studies that implicate Wnt/β-catenin signaling in the machinery and reactions that push cells into a senescent state. So what these researchers appear to have demonstrated is that reducing the degree to which heart injury results in increased cellular senescence also reduces fibrosis and scarring - which dovetails nicely with what other researchers are uncovering of the role of senescent cells in this aspect of aging. Suppressing the creation of senescent cells isn't, to my eyes, as desirable as destroying them after the fact with senolytic therapies, however. Senescent cells do have a transient role to play in healing. Continual suppression will make healing less effective overall, even as it reduces fibrosis in older individuals. On the other hand, periodic elimination of lingering senescent cells should allow patients to obtain all of the benefits of reduced inflammation, unimpaired regeneration, and minimal fibrosis.

Study Explores the Biology of Mending a Broken Heart

The Wnt/β-catenin signaling pathway is involved in several of the body's fundamental biological processes. After heart injury, however, Wnt/β-catenin signaling ramps up in cardiac fibroblast cells to cause fibrosis, scarring and harmful enlargement of the heart muscle, according to the researchers. "Our findings provide new insights on what causes cardiac fibrosis and they open the potential for finding new therapeutic approaches to fight it and preserve heart function. Wnt/β-catenin signaling is involved in many normal and disease processes and it's tough to target therapeutically. But the idea that early targeting of fibrotic response in cardiac disease may improve muscle function and stop disease is an exciting new direction."

In the current study, researchers used a newly developed line of genetically bred laboratory mice that allowed them to determine how important Wnt/β-catenin signaling is in cardiac fibroblast cells. Fibroblasts are important to building the connective tissues and structural framework cells that help hold the body together. But in the context of heart disease, researchers are learning resident cardiac fibroblast cells cause a deadly mix of tissue fibrosis, scarring and diminished function.

To simulate cardiac injury in the mice, researchers conducted a procedure called trans-aortic constriction to restrict blood flow through the heart. Some of the mice were bred so that following cardiac injury they did not express cardiac Wnt/β-catenin in fibroblasts. Control mice in the study continued to express Wnt/β-catenin following heart injury. The control mice exhibited extensive fibrosis, scarring, and diminished heart function. Mice not expressing Wnt/β-catenin had diminished fibrosis and scarring and the animals' heart function was preserved.

Loss of β-catenin in resident cardiac fibroblasts attenuates fibrosis induced by pressure overload in mice

Cardiac fibrosis, commonly seen with a variety of cardiac injuries, can significantly reduce tissue compliance and disrupt cardiac conduction, thus contributing to morbidity and mortality associated with heart disease. The hallmark of cardiac fibrosis is increased fibrillar collagen, which contributes to reduced cardiac output and can ultimately lead to heart failure. Cardiac fibroblasts (CFs) that arise from epicardial and endothelial progenitors in the developing heart are the predominant collagen-producing cell type in pathologic cardiac fibrosis. Although these resident CFs maintain a quiescent phenotype under physiological conditions, they can be activated in response to various types of cardiac injury. Importantly, the regulatory mechanisms that lead to increased collagen production from resident CFs under pathophysiologic conditions, ultimately leading to heart failure, have not been fully elucidated.

Wnt/β-catenin signaling is induced in areas of inflammation, scar formation, and epicardial activation in mouse models of ischemic injury. However the role of Wnt/β-catenin signaling in myocardial interstitial fibrosis independent from scar formation has not been determined. In addition, the requirement for Wnt/β-catenin signaling specifically in resident CFs and direct downstream targets related to cardiac fibrosis have not been reported previously. Recently developed inducible Cre-expressing mouse lines are effective for manipulation of gene expression in resident CF lineages. Using this approach to specifically target activated CFs is of use in studies of CF-specific regulatory mechanisms in cardiac fibrosis.

The requirements for Wnt/β-catenin signaling specifically in resident and activated CFs after cardiac pressure overload were examined using an engineered loss of β-catenin. Here, we demonstrate that cardiac pressure overload leads to increased Wnt/β-catenin signaling in CFs, while loss of β-catenin results in improved cardiac function, blunted cardiac hypertrophy, reduced interstitial fibrosis and decreased expression of fibrotic extracellular matrix (ECM) protein genes 8 weeks post trans-aortic constriction (TAC). Further, β-catenin loss of function mutation in CFs directly reduces cardiomyocyte hypertrophy. Together, these data support a regulatory role for Wnt/β-catenin signaling in fibrosis due to CFs after cardiac injury.

Epigenetic clocks based on the measurement of changing patterns of DNA methylation are perhaps the most promising approach to the production of a biomarker of aging - a way to quickly assess an individual's biological age, allowing assessment of the effectiveness of potential rejuvenation therapies in a rapid, low-cost manner. They are certainly far more accurate and useful on an individual basis than is the case for telomere length measured in the immune cells called leukocytes taken from a blood sample. The latter metric is really only reliable over large populations of individuals, and even then there are studies that find a poor or absent correlation with health outcomes. That these two measures should correlate with one another is to be expected, but in practice that isn't the case; I'd tend to blame that on the poor quality of telomere length as a metric. Here, researchers manage to generate a correlation by using a measure that mixes DNA methylation with immune system values known to change with aging, but I think that on balance all this says is that certain aspects of immune aging are related to one another.

Aging eludes precise definition at the systemic level and denotes a multitude of processes at the cellular level. Two of these processes - age-dependent telomere shortening and DNA methylation (DNAm) profiles of cytosine phosphate guanines (CpGs) have been used as indices of biological age. The age estimates resulting from multivariable regression models of DNAm profiles are referred to as "DNAm age" or "epigenetic age". The discrepancy between DNAm age and chronological age is an estimate of the "epigenetic age acceleration", which has been found to increase in Down syndrome, obesity, HIV and early menopause. Notably, measures of epigenetic age in blood have been reported to be predictive of all-cause mortality after adjusting for chronological age and traditional risk factors.

A recent meta-analysis showed that among several estimates of epigenetic age acceleration, one particular measure, i.e., extrinsic epigenetic age acceleration (EEAA), was superior in predicting all-cause mortality, but the reason for this has remained unclear. EEAA is defined as the weighted average of DNAm age and imputed proportions of naïve CD8+ T cells, memory CD8+ T cells and plasmablasts. Here we show a novel correlation between leukocyte telomere length (LTL) and EEAA. We infer that this correlation reflects the aging of the immune system, as expressed in the age-dependent change of the proportions of naive CD8+ T cells and memory CD8+ T cells.

The two key observations of this study are: (a) LTL is inversely correlated with EEAA; and (b) the LTL-EEAA correlation largely reflects the proportions of imputed naïve and memory CD8+ T cell populations in the leukocytes from which DNA was extracted. These correlations were independently replicated in two well-characterized cohorts, providing confidence in their validity. To our knowledge, this is the first study showing association between LTL and a specific formulation of the epigenetic age, but only when it was weighted by the proportions of T naïve cells, T memory cells and plasmoblasts (i.e., the EEAA). A previous study, using the Hannum formulation for DNAm age, showed no significant association between LTL and epigenetic age. Overall, these findings might explain the ability of EEAA to predict all-cause mortality, given that EEAA captures not only leukocyte DNAm age but also a key aspect of immune senescence (principally naïve and memory T cells), which increases risks of a host of age-related diseases and of death.

Link: https://doi.org/10.18632/aging.101293

Excess visceral fat is bad for you. One primary reason is that fat cells interact with the immune cells called macrophages to produce higher levels of chronic inflammation, and that in turn accelerates the progression of age-related dysfunction and disease. Further, as aging progresses even normal levels of fat tissue become ever worse for health, due to a variety of detrimental changes in the immune system and tissues - the accumulation of forms of molecular damage that generate further inflammation and other tissues.

The research noted here outlines yet another way in which the relationship between fat and macrophages sabotages the prospects of older individuals: it appears that one part of the damage done to the normal operation of metabolism is that the activities of inflammatory macrophages make it harder to reduce fat tissue through activity and diet. Everyone past a certain age notices that maintaining a thinner physique becomes ever more work, and here is one of the reasons as to why this is the case. As with all matters involving inflammation in fat tissue, it remains to be seen how much of this is due to the growing presence of senescent cells with age, potent sources of inflammation and tissue dysfunction as they are.

Older adults, regardless of body weight, have increased belly fat. However, when they need to expend energy, older people do not burn the energy stored in fat cells as efficiently as younger adults, leading to the accumulation of harmful belly fat. The underlying cause for this unresponsiveness in fat cells was unknown. In a new study, researchers focused on specialized immune cells known as macrophages, which are typically involved in controlling infections. They discovered a new type of macrophage that resides on the nerves in belly fat. These nerve-associated macrophages become inflamed with age and do not allow the neurotransmitters, which are chemical messengers, to properly function.

The researchers also isolated the immune cells from fat tissue of young and old mice, and then sequenced and computationally modelled the genome to understand the problem. "We discovered that the aged macrophages can break down the neurotransmitters called catecholamines, and thus do not allow fat cells to supply the fuel when demand arises." The researchers found that when they lowered a specific receptor that controls inflammation, the NLRP3 inflammasome, in aged macrophages, the catecholamines could act to induce fat breakdown, similar to that of young mice.

In further experiments, the researchers blocked an enzyme that is increased in aged macrophages, restoring normal fat metabolism in older mice. This enzyme, monoamine oxidase-A or MAOA, is inhibited by existing drugs in the treatment of depression. "Theoretically one could repurpose these MAOA inhibitor drugs to improve metabolism in aged individuals." The researchers cautioned that more research is needed to specifically target these drugs to belly fat and to test the safety of this approach. In future research, the team will further examine the immune cells and their interaction with nerves, and how this neuro-immune dialogue controls health and disease. If controlling inflammation in aging immune cells can improve metabolism, it may have other positive effects on the nervous system or on the process of aging itself.

Link: https://news.yale.edu/2017/09/27/battling-belly-fat-specialized-immune-cells-impair-metabolism-aging

Jim Mellon and Al Chalabi's new book Juvenescence: Investing in the Age of Longevity is, I think, an important milestone, and the Juvenescence team were kind enough to send me a review copy a few days ago, prior to today's launch. Why important? It is the first time that a group of financially influential individuals have come out and, at length and in detail, outlined why exactly they support the cause of rejuvenation research and why they think it has a good chance of success in the near future. Of course people such as Peter Thiel and Michael Greve have declared much the same degree of support in the past, and their material contributions have helped the SENS approach to rejuvenation research reach its present state of progress, but their public outlines have so far appeared in summary form, rather than producing a book-length treatment of the topic. In fairness, producing a book is a major investment in time, always a scarce resource for people managing large amounts of wealth - I have certainly been putting off that exercise for at least a decade so far, and I am about as far removed from having the workload of a billionaire as any of the rest of the audience here.

The importance isn't that Juvenescence is a book, per se, but rather that it is a comprehensive outsider's consideration of the prospects, delivered by the principals of an investment group who intend to make a mark in the clinical translation of therapies to turn back aging. Fields need outsider views, they need the process by which outsiders become enthusiastic, join in, and bring their own package of biases, optimism, and new ideas. Without this there is only stagnation, which is exactly what had happened to aging research prior to the turn of the century. That stagnation is why the field required people like Aubrey de Grey and organizations such as the Methuselah Foundation and SENS Research Foundation to advocate for better ways forward, to take the knowledge that existed about the causes of aging and actually apply it, rather than sitting around pretending that aging was intractable. Now we have arrived at a stage in which larger amounts of outside investment and startup companies are required to take progress from the laboratory to the clinic, and that makes the contributions of vocal investment figures such as Jim Mellon very welcome. The market for working rejuvenation therapies will be enormous, a huge tidal wave of change and financial growth:

Jim Mellon's investment philosophy, which has led him to be recognised as one of the most successful investors of his generation, is underpinned by his ability to identify so-called "money-fountains" - market trends which will lead to step changes and the resulting investment opportunities. "This is the biggest money fountain idea that Al and I have ever seen. The longevity business has quickly moved from wacky land to serious science, and within just a couple of decades we expect average human life expectancy in the developed world to rise to around 110."

In this book, you will learn about one of the hottest new areas of research, one that is being unravelled for the first time ever: how to treat ageing as if it were a disease. We are so excited about these developments that we have started a new company named after this book. Juvenescence has a mission to find diagnostic and therapeutic agents in order to treat ageing as well as associated diseases. We are hopeful that this business will be the most profitable of our companies to date and will provide at least part of the "solution" to ageing, should one ever be found.

Very few disagree with Ashley Montagu, the long-lived 20th century anthropologist, who said that "the idea is to die young as late as possible." Achieving Montagu's goal is the central aspiration of our book. Today, we are finally at a tipping point where what was once pure science fiction is transitioning into scientific reality. Just as with aviation a century ago, anti-ageing science is about to take flight. The incremental addition of 30 years or so to average lifespans over the next two or three decades will represent the single greatest investment opportunity in recorded history.

Delving beneath this high level overview, what are the more nuanced views of Mellon's team at Juvenescence? They believe the processes of aging should be officially classified as a disease, because that will expand and speed progress towards working therapies for aging. They support the view of aging as damage accumulation and thus the SENS approaches of damage repair, such as senolytic therapies to clear senescent cells, but not necessarily as the only or the most effective way forward. They have a mix of views on the utility of genetic information, on investigations of the detailed operation of metabolism, on adjusting metabolism to modestly slow aging through drug candidates such as rapamycin, and on a range of other items that I suspect will largely turn out to be distractions of limited utility, in the near term at least. They think that the current forest of competing scientific views of aging will converge to one true understanding fairly soon. They are agnostic on the degree to which healthy human life span can be extended in the decades ahead once past the point of ensuring that nearly everyone reaches 110 years of age: they acknowledge the possibilities of de Grey's acturial escape velocity and Kurzweil's "bridge to a bridge" taxonomy of life-extending therapies and the likely time of their arrival. That incremental progress should lead to large gains over time, the point being that an extra 20 to 30 years of life will allow new and better therapies to arrive and produce even greater gains. Mention is given to the prospect of radical life extension and indefinite life spans outlined by transhumanists and other futurists, but the Juvenescence team don't put their support behind such ideas. Adding a few decades of additional health and life, however? That is, correctly I think, declared to be very plausible, and a goal to work towards, with the first therapies enabling the start of this improvement nearly in clinics now.

After the initial blurb, Juvenescence provides an overview of the molecular biochemistry of aging, targeted at laypeople, a tour of the current state of the science, and particularly of the current differences of opinion and theory, such as programmed theories versus aging as damage accumulation. All of this is presented in such a way as to reinforce the main point that aging can now be considered a treatable medical condition. This is a tough set of summaries to write for an unfamiliar audience, as one has to provide enough of the details to explain why it is that the current state of the science is meaningfully different from that of a generation past, that now is the time, that now is different from all of the times past when someone stood up to (falsely) claim a way to influence the aging process. But providing any of the details is like pulling on a piece of thread - soon you need more details to justify what was said about the former details. Biochemistry is enormously complex, and the fine distinctions matter at every level. It is a real challenge to find the stopping point that avoids all of the pitfalls: failing to justify the claims; burying the reader; omitting items in a way that will lead to later confusion. One of the strengths of Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime was that it didn't try to cut the thread, and just went all the way to outlining in detail the relevant biochemical mechanisms. Here, for a different audience, that isn't possible. The authors do a good job, but I suspect that the initial promise of a vast future market for longevity science is very much required for the intended readership to work through the first few dozen pages covering the important details of aging, piece by piece.

Obviously, the target audience for Juvenescence is not us. Well, maybe those of us who intend to start companies in the next decade or so, as a reminder that Juvenescence, the business development company, would like to invest. The target audience is investors and analysts who are currently unfamiliar with longevity science, everyone involved in the decision chain that leads to capital flowing into an industry. Early participation in a new market is great way to become wealthy, provided that the new market does in fact take off rapidly enough. I don't think there is any doubt that longevity assurance therapies will become an industry greater than every present area of medical science - every human over the age of 40 is a customer at some price point. The open question is just when and how fast it will take off. Groups like the SENS Research Foundation have been working on that at the interface between the academic and business worlds. Juvenescence is intended to work on this at the interface between the finance and business worlds, to accelerate the process. Nothing magically just happens without effort in this world of ours: it takes work to ensure that technologies are handed off between researchers and developers, and also to ensure that venture funding is available.

This is a very modular book: the chapters stand alone; the overall thesis is built upon, repeated, and reinforced in each section; small few-page self-contained sections contain overviews of specific important topics, such as inflammaging, basics of genetics and gene expression, DNA damage, and so forth. It is intended to be picked up and read in small bursts by busy people. After the tour of the science of aging come chapters exploring the current spectrum of work on specific age-related diseases and interventions into processes of aging: the details of specific approaches in development, from parabiosis to calorie restriction mimetics to senolytics to stem cell therapies and most of what is in between, including a number of other SENS proposals; the animal models used in the laboratory and how they relate to the activities of a few companies in the space; showcases of specific groups that the Juvenescence team currently supports or intends to support, such as In Silico Medicine, the SENS Research Foundation, and the Buck Institute for Research on Aging. Investment topics are considered in a similar capsule format: lists of companies in the space that are likely investment targets of one sort or another; likely societal changes and benefits brought by extended longevity; benchmarks for how to think about how this area of medical technology will likely shape the next few decades.

Noted opinion leaders in the field of aging research are given their own sections - again, recall that this is a book targeted at investors, who will want to know who to talk to in order to validate the Juvenescence thesis - ranging from David Sinclair and Nir Barzilai, who have worked on approaches I think are not all that useful, to Aubrey de Grey and Laura Deming, who put repair of molecular damage and radical life extension front and center. There are also a few choice quotes on just how difficult it is to get anything out of the California Life Company where Cynthia Kenyon is now working; Jim Mellon and company are the latest folk to come to the conclusion that all the secrecy there is hiding nothing of relevance to the field.

Getting information on what Cynthia Kenyon, or Calico, is up to is a bit like getting the KGB to reveal its secrets in the old Soviet days. For mere authors such as us, there is no way that we could get past the gatekeepers of a company whose motto was until recently "Don't be Evil". It has now been changed to "Do the right thing" but might have better been changed to "Say Nothing". Scientists generally have been disappointed with Calico's progress. Nir Barzilai has been quoted as saying: "The truth is, we don't know what they're doing, but whatever it is doesn't really seem to be attacking the problem."

In reading all of this, I did discover items that I wasn't aware of; that David Sinclair's Life Biosciences is presently involved in developing a senolytic therapy and intends to target fibrosis at the outset, for example. The book is an interesting mix of support for the SENS rejuvenation biotechnology vision on the one hand, and on the other interest in metabolic tinkering of the sort that probably won't produce significant results. It also echoes many of the themes assembed by Kurzweil and Grossman in Fantastic Voyage, their specific view of better maintaining health with today's methods in order to remain healthy for long enough to take advantage of the first (and then incrementally improving) longevity enhancement therapies - there is a possibly too lengthy section on basic good health practices after the fashion of Kurzweil's Bridge One. It remains to be seen how the Juvenescence team will follow up on their evaluation of the field with investments beyond the first few made to date. Clearly we stand at a point of transition, and not just growth in this field, but in the first proof of principle rejuvenation therapies. What will happen once senolytics are proven far more effective than any other presently near-term approach of metabolic adjustment in humans? Will those other approaches wither away, or will that take a lot longer to occur? It will be interesting to watch how the investment community and markets react to this sort of discovery. Without a concrete underlying assemblage of theory, such as SENS, to explain why some things work and some things don't, investors will be throwing darts. The challenge is that for an outsider, how does one tell the difference between the likely prospects of damage repair approaches such as those of SENS, and the likely prospects of, say, metformin or rapamycin or other metabolic adjustment approaches?

Juvenesence is a valuable survey of the field as it stands today; I think it worth reading even if you are familiar with the past few years of progress. It isn't clear from the contents as to whether or not Jim Mellon and the others at Juvenescence have yet digested and built upon this survey to the point of forming their own robust understanding of the expectation value of different classes of approach to aging. For me, that took years and reading a lot of papers. But do they and other well-heeled investment groups need to achieve that goal right this instant? They could, for example, instead take a ten year longer view of the situation, make generally sensible bets in a variety of approaches, and let the market and the realities of development sort out the answer. So long as a reasonable fraction of their bets are backing the implementation of SENS and SENS-like repair biotechnologies, the job will get done, and lives will be extended. In the process of this, investors will in the fullness of time develop their own understandings as to why certain things work, and will hopefully come to the conclusion that it is as simple as identifying the root cause, original damage in human biochemistry, and then repairing it. The approaches that work will win out in the end, given enough funding for the field to progress at an optimal pace.

This open access review discusses what is known of the way in which the function and structure of axons in nerve tissue decline over the course of aging, walking through evidence linking this degeneration to the various pillars of aging defined a few years back. Axons are fibers connecting nerve cells, usually those in close proximity to one another, but over distances of up to a few feet in cases such as the spinal cord cells that communicate with nerve cells in the feet. That connectivity is of course vital to the operation of the nervous system, and especially the brain. Axonal degeneration is one of many well-studied items that appear to be a downstream consequence of fundamental causes of aging, such as as those outlined in the SENS proposals for rejuvenation research projects. That downstream consequence then expands out to cause many more forms of failure in the brain and other systems.

The effects of aging on the brain are multiple and importantly, age constitutes the main risk factor for the development of neurodegenerative disorders (NDs), characterized by progressive neuronal death and loss of specific neuronal populations. For a better comprehension of the molecular and cellular changes that occur during aging, seven pillars of aging were defined, which are common processes involved in most chronic disorders that take place in an aging organism. These seven pillars are proteostasis, adaptation to stress, inflammation, stem cells and regeneration, epigenetics, metabolism, and macromolecular damage. Notably, changes in these cellular events are common to most NDs, suggesting that similar mechanisms might at least partially explain different age-related diseases.

Axonal degeneration, which occurs at early stages of NDs, also takes place as a consequence of normal aging. Indeed, many cellular processes that are altered with advanced age have shown to contribute to axonal pathology. Importantly, the degeneration of axons represents an early event during the development of NDs, preceding both cell death and the onset of clinical symptoms, which has important therapeutic implications. Although, the molecular basis of the transition that makes an individual to develop neurodegeneration with advanced age is currently unknown, increasing evidence support the potential role of axonal degeneration in this transition.

The process of axonal degeneration is an essential developmental event that consists in the selective destruction of axons. It is an evolutionary conserved process that can be activated by different stimuli including mechanical damage, axonal transport defects or by drugs used for chemotherapy. Although, the exact molecular and cellular pathways by which axonal degeneration occurs remain to be fully clarified, key contributing factors have been identified in the last decade. After nerve transection, axons undergo three phases: a latent phase, axonal fragmentation and axonal disintegration. The latent phase stills poorly understood but it is known that axons remain apparently normal for 1-2 days in mice after nerve injury, and can still conduct action potential. In the last stage, all the structures inside the axon are degraded. Disintegration of axonal cytoskeleton is followed by myelin degradation and macrophage infiltration that clear cell debris.

We have demonstrated that mitochondrial dysfunction is a key process associated to axonal degeneration. The degeneration of axons was shown to be associated to the formation of the mitochondrial permeability transition pore (mPTP) between the inner and outer mitochondrial membrane. mPTP formation triggers the mitochondrial permeability transition (mPT), which leads to an increase in axonal reactive oxygen species (ROS) followed by intra-axonal calcium release. Interestingly, blocking mPTP either pharmacologically or genetically, by removal of the mPTP component Cyclophilin D (CypD), significantly delays axonal degeneration. Notably, formation of the mPTP has been linked to the pathogenesis of NDs.

Increasing evidence suggest that axonal degeneration occurs before cell body loss and notably, prior to the onset of clinical symptoms in different age-related diseases. Hence, the understanding of the molecular and cellular mechanisms underlying this potentially reversible phase is critical for the development of therapeutic strategies aimed at the prevention and intervention of these disorders.

Link: https://doi.org/10.3389/fnins.2017.00451

Carrying additional weight in the form of visceral fat tissue is harmful to health and life expectancy over the long term. This fat is metabolically active, producing significant increases in chronic inflammation, and that in turn drives the development and progression of all of the major age-related diseases. A couple of studies from a few years back put some numbers to the direct financial costs for an individual, finding that lifetime medical costs trend upwards as excess body weight increases, even as life expectancy decreases. This study is similar in nature:

Helping an adult lose weight leads to significant cost savings at any age, a new study suggests. From the findings, a 20-year-old adult who goes from being obese to overweight would save an average of $17,655 in direct medical costs and productivity losses over his or her lifetime. If the same person were to go from being obese to a healthy weight, an average savings of $28,020 in direct medical costs and productivity losses can occur. Helping a 40-year-old adult go from being obese to overweight can save an average of $18,262. If the same person went from being obese to normal weight, an average savings of $31,447 can follow.

A high body mass index (BMI)diabetes, cardiovascular disease and some cancers. Subsequently, a high BMI and associated conditions can lead to high medical and societal costs and productivity losses. More than 70 percent of adults in the United States are considered to be overweight or obese, which in direct medical expenses alone costs nearly $210 billion per year. "Over half of the costs of being overweight can be from productivity losses, mainly due to missed work days but also productivity losses. This means that just focusing on medical costs misses a big part of the picture, though they're a consideration, too. Productivity losses affect businesses, which in turn affects the economy, which then affects everyone."

For the study, the researchers developed a computational simulation model to represent the U.S. adult population to show the lifetime costs and health effects for an individual with obesity, overweight and healthy weight statuses at ages 20 through 80 in increments of 10. The model used data from the Coronary Artery Disease Risk Development in Young Adults (CARDIA) and Atherosclerosis Risk in Communities (ARIC) studies and included 15 mutually exclusive health statuses that represented every combination of three BMI categories (normal weight, overweight and obesity) and five chronic health stages. The model simulated the weight and health status of an adult as he or she ages year by year throughout his or her lifetime to track the individual medical costs and productivity losses of each person. The estimated direct medical costs to the insurer and health care facility, productivity losses and sick time were included.

The research team found that cost savings peak at age 50 with an average total savings of $36,278. After age 50, the largest cost savings occur when an individual with obesity moves to the normal weight category as opposed to the overweight category, emphasizing the importance of weight loss as people age. "Most previous models have taken into account one or a few health risks associated with obesity. Subsequently, the forecasted costs may be unrealistic. In our study, the model we developed takes into account a range of immediate health complications associated with body weight, like hypertension or diabetes, as well as all major long-term adverse health outcomes, including heart disease and some types of cancer, in forecasting the incremental health effects and costs to give a realistic calculation."

Link: https://www.jhsph.edu/news/news-releases/2017/weight-loss-for-adults-at-any-age-leads-to-cost--savings-study-suggests.html

Work on GDF11 is one of a number of examples that illustrate why one should always wait a year or two before becoming too excited about a novel line of research into mechanisms of aging or potential treatments for aging. Investigation of GDF11 grew out of heterochronic parabiosis studies, in which the circulatory systems of old and young mice are linked. The old mice show benefits, and the early theories as to why this is the case focused on the possibility of beneficial factors in young blood. GDF11 was identified as one candidate. The initial research results in 2013 and 2014 garnered considerable attention, and suggested that a straightforward increase in circulating levels of GDF11 could improve stem cell function and a range of other measures of decline in old mice.

In the few years since then, however, these results have been challenged on a number of fronts. Firstly as to whether or not assays were actually correctly measuring GDF11 levels versus levels of the very similar protein myostatin. Despite their similarities the two have very different functions. Replication has also been an issue. Researchers have shown, for example, that GDF11 appears not to decline with age in humans, unlike the conclusions drawn from the earlier mouse studies. Further, administration of GDF11 doesn't extend life in the progeroid mouse models that are widely used as a testbed to obtain faster data for therapies that might adjust the pace of aging. Additionally, the hypothesis that the benefits of parabiosis arise from factors in young blood is looking somewhat weak these days, given the more recent production of compelling evidence to suggest that it is more a matter of dilution of harmful factors in old blood.

As a final nail, and as illustrated by the paper below, the biochemistry of GDF11 in mice appears to be significantly more nuanced than a simple decline with age - given better assays and measures in different tissues, levels of GDF11 seem to do just about everything except the expected, and there is little of the earlier understanding to be found in the later, better data. This is definitely a part of the field where observers should step back for a few more years, let researchers sort out the contradictions, and then see if there is anything of interest left over at the end of the day.

Modulation of GDF11 expression and synaptic plasticity by age and training

The growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β (TGFβ) superfamily, homologous to another muscle-derived hormone, myostatin (MSTN). Although GDF11 and MSTN share 89% amino acid sequence identity within the C-terminal region, these proteins may have different functions. MSTN is expressed predominantly in skeletal muscle and plays an evolutionarily conserved role in antagonizing postnatal muscle growth. In fact, disruption of MSTN in many mammals (e.g. mice or cattle) causes muscle hypertrophy. In contrast, GDF11's functions in postnatal tissues are less known because of perinatal mortality of GDF11 knockout animals. Nevertheless, various works have suggested a broader role of GDF11 in mammalian development and identified GDF11 as a hormonal regulator of different organs including brain and skeletal muscle. More recently it has been reported that overexpression of GDF11 in mice results in substantial atrophy of skeletal and cardiac muscle, inducing a cachexic phenotype not seen in mice expressing similar levels of MSTN.

Recently, studies have focused on the search for regulatory molecules that can reverse aging. Among these factors, GDF11 has been identified as a potential anti-aging candidate. However, some data on GDF11 expression and function are contradictory and GDF11 role in aging is still matter of lively debate. Indeed, initial studies in rodent models exploiting heterochronic parabiosis (in which circulatory systems of young and aged animals are connected) or using recombinant protein treatment, identified GDF11 as a molecule capable of rejuvenating cerebral, cardiac, skeletal muscle functions and attributed the diminished regenerative capacity of skeletal or cardiac muscle and brain of old mice to the decrease of GDF11 serum levels. Afterwards, other reports questioned the age-related decline of circulating GDF11 and showed that GDF11 increases with age causing inhibition of muscle regeneration rather than fostering rejuvenation. In addition, the specificity of antibodies and the methods used to detect the protein in previous studies have been criticized. Therefore, further studies are needed to evaluate whether young and old individuals have a different GDF11 protein expression in tissues (e.g., skeletal muscle, hippocampus), and to clarify the actual role of GDF11 in the regulation of rejuvenation processes and longevity.

The increase of physical activity has been proposed as an effective therapeutic strategy to reduce the age-derived decline of muscular and cognitive functions although most of the molecular mechanisms underlying the benefit of exercise are still unknown. During the aging process exercise mediates beneficial effects on several brain functions by activating neurogenesis and delaying neurodegenerative processes. Recently, it has been reported that exercise mediates beneficial effects on brain plasticity and functions. Brain plasticity refers to the ability of the brain to modify its structure and function in response to maturation, learning, environmental stimuli, or pathological state. This activity-dependent phenomenon translates into a persistent boost in synaptic transmission, called long-term potentiation (LTP) that is considered the cellular and molecular substrate of learning and memory processes. Aging is a biological process associated with physiological cognitive decline; in particular, it can harm quality of life and result in deficits of declarative and working memory, spatial learning, and attention. Heterochronic parabiosis of young blood in old mice has been shown to enhance LTP and this effect has been attributed to the high GDF11 levels present in the blood of young mice.

The present study is an attempt to clarify, in a murine model, whether GDF11 expression in skeletal muscle and hippocampal tissues undergoes modulation during the aging process and whether training modulates GDF11 expression and LTP. Nowadays, it is still controversial whether tissue levels of GDF11 protein expression are age-related. In the current study we provide evidence, by using an antibody which specifically recognizes GDF11 and does not cross react with MSTN, that this protein is expressed at higher levels in the skeletal muscle tissue of old mice compared to young animals independently of sex and strain. The results were also confirmed by quantitative analysis of GDF11 mRNA. This observation is in sharp contrast with studies showing GDF11 decline in skeletal muscle with age, but in agreement with other studies in which GDF11 protein expression was found to increase with age.

The controversial results may reflect differences in experimental designs, strategies, detection reagents, specificity of GDF11 antibodies, sources of recombinant proteins used as controls. Our results, obtained with qRT-PCR using specific primers mapping in a GDF11 region which does not overlap with MSNT sequences and immunoblot analysis using an antibody specifically recognizing recombinant GDF11, indicate that skeletal muscles of old mice express higher GDF11 levels than young mice. The latter findings discourage the use of recombinant GDF11 to counteract age-related cardiac and skeletal muscle decline.

The age-dependent increase of GDF11 observed is limited to skeletal muscle; in fact, a wide variation of GDF11 protein expression was detected in the hippocampi of old animals. Actually, also in other tissues and in the serum the relationship between expression level and function of GDF11 is quite controversial. Recently GDF11 was reported to increase neurogenesis and to be involved in brain rejuvenation of aged mice. In the present study, we found variable levels of GDF11 in hippocampi of old mice with respect to those detected in young mice. Moreover, the GDF11 expression found in the hippocampi did not correlate with the impairment of synaptic plasticity in the hippocampal CA1 region, measured by LTP assay in old mice.

Physical exercise has been proposed as an effective strategy to reduce the detrimental influence of aging on muscle and cognitive function. We sought to investigate whether the beneficial effects of a forced long-term specific training program (i.e., continuous progressive protocol, which can be appropriate also for aged animals) may result in modulation of GDF11 expression. In our model, training slightly but significantly increased GDF11 levels in skeletal muscles of young animals, but it did not affect protein expression in the same tissues of old mice. In hippocampal tissues training did not substantially affect GDF11 protein levels of young mice, whereas it significantly decreased GDF11 protein expression in old mice. Based on these results, the beneficial effects of training on synaptic plasticity did not consistently correlate with modifications of GDF11 expression in hippocampi.

Autoimmune conditions such as multiple sclerosis can be cured by clearing the entire adult immune system and letting it reestablish itself. The misconfigurations of autoimmunity are carried by some immune cells, and removing all of them happens to be the easiest way to proceed in the absence of knowing exactly where the problem lies. This is currently a fairly risky and unpleasant procedure, akin to chemotherapy. Future improvement might involve less toxic means of removing immune cells, or a more targeted approach enabled by a greater understanding of exactly which immune cells cause autoimmunity. Given a good enough understanding of the mechanisms involved, it should be possible to solve the problem by changing cell state and behavior rather than destroying cells. The latter approach is in evidence here, in which researchers demonstrate reversal of autoimmunity in a mouse model of multiple sclerosis - though there remains a way to go in order to explain exactly what is going on under the hood.

While autoimmune diseases are largely not age-related, there is certainly a great deal of dysfunction in the aging immune system that might be eliminated by destroying all immune cells, or only some of the errant immune cells that cause such issues, or by altering their state and behavior. That list runs in order of difficulty: destroying all cells is a lot easier than the other options, especially given the gaps in knowledge that still exist when it comes to the immune system and aging. It nonetheless seems likely that the treatment of autoimmune conditions is where new technologies will emerge that can form the basis for therapies capable of turning back some of the aspects of age-related immune system failure. It is worth keeping an eye on this part of the field.

Multiple sclerosis can be inhibited or reversed using a novel gene therapy technique that stops the disease's immune response in mouse models. By combining a brain-protein gene and an existing medication, the researchers were able to prevent the mouse version of multiple sclerosis. Likewise, the treatments produced near-complete remission in the animal models. Multiple sclerosis starts when the immune system attacks the myelin sheath surrounding nerve fibers, making them misfire and leading to problems with muscle weakness, vision, speech and muscle coordination.

The researchers used a harmless virus, known as an adeno-associated virus, to deliver a gene responsible for a brain protein into the livers of the mouse models. The virus sparked production of so-called regulatory T cells, which suppress the immune system attack that defines multiple sclerosis. The gene was targeted to the liver because it has the ability to induce immune tolerance. "Using a clinically tested gene therapy platform, we are able to induce very specific regulatory cells that target the self-reactive cells that are responsible for causing multiple sclerosis."

The protein, myelin oligodendrocyte glycoprotein, was found to be effective in preventing and reversing muscular dystrophy on its own. A group of five mouse models that received the gene therapy did not develop experimental autoimmune encephalomyelitis, which is the mouse equivalent of multiple sclerosis in humans. In another experiment, all but one mouse model showed a significant reversal of the disease eight days after a single gene therapy treatment. After seven months, the mouse models that were treated with gene therapy showed no signs of disease, compared with a group of untreated mouse models that had neurological problems after 14 days.

When the protein was combined with rapamycin - a drug used to coat heart stents and prevent organ transplant rejection - its effectiveness was further improved, the researchers found. The drug was chosen because it allows helpful regulatory T-cells to proliferate while blocking undesirable effector T-cells. Among the mouse models that were given rapamycin and the gene therapy, 71 percent and 80 percent went into near-complete remission after having hind-limb paralysis. That shows the combination can be especially effective at stopping rapidly progressing paralysis. While researchers have established how gene therapy stimulates regulatory T cells in the liver, little else is known about the detailed mechanics of how that process works. Before the therapy can be tested in humans during a clinical trial, further research involving other preclinical models will be needed. Researchers also need to target the full suite of proteins that are implicated in multiple sclerosis.

Link: http://news.ufl.edu/articles/2017/09/unique-gene-therapy-prevents-reverses-multiple-sclerosis-in-animal-model.php

It seems to be a requirement that any review of what is known of the mechanisms of vascular aging must include a quote from Thomas Sydenham. You might compare the open access here with another noted earlier in the month, both of which feature that same quoted remark. Vascular aging is indeed an important component of age-related mortality, but we should expect two near future rejuvenation therapies to greatly improve matters, more so than has been possible through the medical advances of past decades, such as the introduction of statins.

Senescent cells and cross-links both contribute to vascular stiffness and chronic inflammation. Those two items drive much of the consequent dysfunction and progressive failure of the cardiovascular system. Fortunately, senolytic therapies are currently under development, involving numerous drug candidates and other approaches to clearance of senescent cells. In humans almost all of the persistent cross-links relevant to aging involve a single compound, glucosepane. Researchers are working on ways to break those links, with glucosepane as the target. Much of the research community continues to focus on aspects of vascular aging other than the root causes, however, focused on downstream changes. Progress will remain slower than it might be until that changes.

More than three centuries ago, a famous English physician and author, Thomas Sydenham, said "A man is as old as his arteries". This popular quote signifies a correlation between aging and the cardiovascular system including the susceptibility of this system to age-associated changes. Indeed, cardiovascular diseases such as atherosclerosis, hypertension, diabetes and heart attack are the leading causes of morbidity and mortality in the elderly population. In line with this, premature or normal aging is a major cardiovascular risk factor. About 40% of all deaths in the elderly (age 65 and older) are related to cardiovascular disease. The risk for cardiovascular morbidity between the ages of 50 and 80 increases by about 10-fold. Therefore, understanding the molecular and cell biological processes underlying age-associated structural and functional changes to the cardiovascular system including the heart and blood vessels is of significant importance.

The effect of aging on cardiovascular health is in part because aging perturbs a number of metabolic and hemodynamic mechanisms in the cardiovascular system in general and the vascular endothelium in particular. Some of these perturbations include increased oxidative stress and reduced telomere length resulting in DNA damage, impaired replicative capacity of cells and upregulated cardiovascular tissue senescence. These changes expose the heart and its vascular network to a series of risk factors that impair physiological repair mechanisms, and accelerate vascular dysfunction and cardiovascular disease.

Vascular endothelium, a diaphanous film of tissue, is the inner-most structure that coats the interior walls (tunica intima) of the cardiovascular and lymphatic systems. Endothelial dysfunction is one of the earliest indicators of cardiovascular disease. In line with this, the endothelium has emerged as one of the most important targets for the prevention and treatment of cardiovascular disease. Endothelial cells (ECs), mature or progenitor, are the building blocks of the vascular endothelium and are involved in active secretion of paracrine factors to modulate vascular homeostasis.

Unfortunately, aging exerts several pathological changes in the vascular system. The dysfunctional or aged endothelium is characterized by several phenotypic changes and molecular patterns that include impaired replicative capacity of cells, increased cellular senescence, reduced generation of anti-inflammatory molecules, antioxidants and other salutary mechanisms that are involved in vascular homeostasis. As a result, ECs lose their ability to proliferate and secrete vasoactive molecules. Several of the existing strategies attempt to restore key EC functions including production of nitric oxide (NO) - through exogenous supplementation or reactivation of cosubstrates and cofactors - and other vasodilators while decreasing inflammation, oxidative and nitrosative stress through antiinflammatory, antioxidants and restoration of eNOS coupling. However, these strategies have not been able to rejuvenate denuded or senescent endothelium in a meaningfully way.

In order to effectively overcome the exhausted number and function of mature ECs, endothelial lineage progenitors such as EPCs and endothelial colony-forming cells (ECFCs) may be isolated from circulation or from niches within the vascular wall and rejuvenated through ectopic expression of factors that halt senescence and other age-associated phenotypes. In this regard, transient extension of telomere length through non-viral and non-integrating approaches ex vivo is particularly appealing. This cell-based strategy may be combined with other mechanisms involved in the regulation of cellular senescence such as microRNA, senolytic drugs and/or new chemical entities that modulate DNA damage repair for preventative or therapeutic vascular rejuvenation.

Link: https://doi.org/10.4172/2161-1025.1000183

Some of the changes that occur in cells and tissues in heart failure center around a progressive loss of function in the ability of heart muscle to contract. Over the past decade or so, researchers have identified increased protein phosphatase-1 (PP1) as one of the regulatory mechanisms of interest in heart muscle contraction. The inhibitor-1 (I-1) protein acts to reduce levels of PP1 via a complicated network of interactions that researchers have mapped out piece by piece over the years, making it a potential target for interventions. There are a few good open access papers out there to provide an overview of this set of biochemical relationships and its relevance to heart failure.

Given a target, there are a number of ways in which the research community can proceed: manufacturing and delivering more of the protein, for example, or searching for a drug that has the effect of increasing gene expression of the desired protein. Both of these have their limitations. These days gene therapy is becoming an ever more viable option for the development of clinical therapies, as cost decreases and reliability improves in the technologies of delivery. In principle, gene therapy has the potential to be far more accurate and targeted than other approaches. In the research results noted here, a fairly well-proven method of gene therapy is applied to reduce PP1 levels in order to improve heart muscle function in pigs. This largely repeats work from three years ago - an example of the glacial pace at which research often progresses in the later stages of animal trials.

Many of the potential gene therapy approaches to the aging heart involve spurring greater stem cell activity: to in some way capture a part of the beneficial response to the signals delivered by transplanted stem cells, encouraging more regenerative activity. That isn't the case for PP1 reduction, which instead acts on the existing cell populations to make them work harder when it comes to driving muscle contraction. Near all of the present efforts to treat heart disease with gene therapy are essentially compensatory in nature. They are trying to improve the present situation in the aging heart without addressing root causes - putting a thumb on regulatory mechanisms that are reacting to the root causes of aging in ways that make things worse. Those causes are still there, however, the cell and tissue damage that accumulates with age. It is quite possible to improve on present day therapies by following this strategy of compensatory change, but radical degrees of improvement, turning back the condition entirely, is outside the bounds of the possible in this paradigm. For that, the causes of age-related decline must be addressed.

Gene Therapy Improved Left Ventricular and Atrial Function in Congestive Heart Failure by up to 25 percent

In heart failure, a weakened or damaged heart no longer pumps blood effectively. This potentially fatal disease is a major cause of morbidity and mortality, especially in elderly patients. Despite this toll, there has been little progress toward any kind of cure. Novel therapeutic approaches, such as gene therapy and cell therapy, hold the promise of complementing or replacing existing therapies for congestive heart failure.

This study featured two independent experiments. The first established the safety of administering a therapeutic gene delivery vector, BNP116, created from an inactivated virus over three months, into 48 pigs without heart failure through the coronary arteries via catheterization using echocardiography. The second experiment examined the efficacy of the treatment in 13 pigs with severe heart failure induced by mitral regurgitation. Six pigs received the gene and 7 received a saline solution.

The researchers determined that the gene therapy was safe and significantly reversed heart failure by 25 percent in the left ventricle and by 20 percent in the left atrium. Heart failure often results in enlarged hearts, and the team found a 10 percent reduction of heart size in the affected animals. Heart failure in the cohort of pigs treated with saline worsened. The research team plans to study the same gene therapy in a human trial starting next year.

Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure

Increased protein phosphatase-1 in heart failure (HF) induces molecular changes deleterious to the cardiac cell. Inhibiting protein phosphatase-1 through the overexpression of a constitutively active inhibitor-1 (I-1c) has been shown to reverse cardiac dysfunction in a model of ischemic HF. This study sought to determine the therapeutic efficacy of a re-engineered adeno-associated viral vector carrying I-1c (BNP116.I-1c) in a preclinical model of nonischemic HF, and to assess thoroughly the safety of BNP116.I-1c gene therapy.

Volume-overload HF was created in Yorkshire swine by inducing severe mitral regurgitation. One month after mitral regurgitation induction, pigs were randomized to intracoronary delivery of either BNP116.I-1c (n = 6) or saline (n = 7). Therapeutic efficacy and safety were evaluated 2 months after gene delivery. Additionally, 24 naive pigs received different doses of BNP116.I-1c for safety evaluation. At 1 month after mitral regurgitation induction, pigs developed HF as evidenced by increased left ventricular end-diastolic pressure and left ventricular volume indexes. Treatment with BNP116.I-1c resulted in improved left ventricular ejection fraction and adjusted dP/dt maximum. Moreover, BNP116.I-1c-treated pigs also exhibited a significant increase in left atrial ejection fraction at 2 months after gene delivery. We found no evidence of adverse electrical remodeling, arrhythmogenicity, activation of a cellular immune response, or off-target organ damage by BNP116.I-1c gene therapy in pigs.

Until September 30th, the World Health Organization (WHO) is accepting commentary on their position regarding aging research via an online form: anyone can participate, and those involved in research and development in the field are encouraged to do so. You might recall that their past positions on this topic have been almost comically terrible, omitting any mention of ongoing efforts to treat aging as a medical condition, either slowing it down or SENS-like approaches to repair the causes of aging. Their policy was stuck in the era of aging as an inevitable fact of like, written in stone and to be suffered rather than addressed.

Insofar as the WHO sets standards for medicine, such as via the Classification of Diseases, and influences the positions taken by government bodies, those in the research community who depend upon public funding have an incentive to try to shift the bounds of the system. That said, producing large degrees of change from within any large institution, playing by their rules in order to change those rules, is a long, painful, and expensive process in comparison to the efforts needed to become a successful revolutionary working outside the system, making the system irrelevant - which is why I've never favored the former of the two options. That is my opinion, and obviously others feel differently. For those wishing to help create change in the WHO, the Life Extension Advocacy Foundation (LEAF) volunteers have put together an article outlining how best to offer commentary:

Very recently, the World Health Organization, which is essentially the United Nations' agency for coordinating international health-related efforts, has launched The Global Online Consultation on Research Priority Setting for Healthy Aging. A corresponding survey is available on the WHO website and can be filled until September 30. As the WHO is the main source of policy recommendations for the UN member states, its position can significantly influence the allocation of state funding to different areas of scientific research. This is why we at LEAF urge you to step in and fill out the WHO survey; our community needs to demand more focused efforts to understand the basic mechanisms of aging, to develop innovative therapies to address these mechanisms, and to remove the barriers delaying the implementation of rejuvenation technologies into clinical practice.

While UN and WHO strategic documents, such as the world report on ageing and health (2015), the global strategy and action plan on ageing and health (2016) and the new set of Sustainable Development Goals include some provisions to encourage scientific research and development of new medicines, studies on biological aging and development of rejuvenation biotechnologies have never been made one of the main priorities. Furthermore, the application of medical technologies able to slow down, postpone and reverse the main mechanisms of aging has not been considered a viable approach to cope with the growing morbidity of age-related diseases provoked by rapid population aging. Instead, the main measures suggested to prepare our society to these demographic changes are to stimulate the birthrate while adapting healthcare systems and transforming living environments to become more age-friendly.

Even though studies on aging have a long history, there have been very recent breakthroughs, such as senolytics, Yamanaka factors, and gene therapies to extend telomeres. Due to remarkable progress in taming several hallmarks of aging, we might see the first powerful rejuvenation therapies enter the market in the next five years. The more prepared our society will be to support their development and implementation, the better. The most efficient way to accomplish this is to make an opinion leader like WHO accumulate the corresponding data faster and to form an official position that will be delivered right to the heads of the ministries of health and science around the globe.

We encourage every member of our community to fill out the form - you don't need a background in science for your response to be taken seriously. This is an open consultation, a disseminated "think tank" to provide the working group at WHO with a spectrum of ideas. If our opinion is represented in a significant share of surveys, we shall see it appear in the resulting WHO recommendations. The input of our community here could be vital, shifting the focus of research towards fundamental and translational gerontology and true control of the aging process for decades to come. LEAF volunteers have prepared a series of answers to inspire your own response to the different questions presented in the form.

Link: https://www.leafscience.org/open-consultation-of-the-who/

The proximate cause of osteoporosis, the age-related loss of bone strength, is a growing imbalance between the populations of osteoblasts responsible for creating bone and osteoclasts responsible for removing it. Bone tissue is in a constant state of active remodeling, so as the balance leans towards osteoclasts, bone becomes ever more fragile. Why does this balance shift? From the SENS rejuvenation research point of view, it is a downstream consequence of forms of fundamental cellular damage that accumulate over time, but as is the case for near all aspects of aging there is no complete and accurate map of the chain of causes and consequences leading from that damage to a loss of osteoblasts.

The majority of the research community works backwards from the other end of the chain, starting with the end stage of the condition, in search of the next most proximate cause. This is usually some form of change in the circulating levels of specific regulatory proteins, as is the case here. That in turn must be a reaction to an early form of change and damage - but this is usually where research teams stop, and hand off their work for an attempt at commercial development of therapies. This is precisely why most existing approaches to the treatment of age-related conditions are not all that effective in practice; they are tinkering with a comparatively late stage of the altered disease state rather than addressing root causes.

A major health problem in older people is age-associated osteoporosis - the thinning of bone and the loss of bone density that increases the risk of fractures. Often this is accompanied by an increase in fat cells in the bone marrow. Researchers have now detailed an underlying mechanism leading to that osteoporosis. When this mechanism malfunctions, progenitor cells stop creating bone-producing cells, and instead create fat cells. The researchers found that a protein called Cbf-beta, core-binding factor subunit beta, plays a critical role in maintaining the bone-producing cells. Furthermore, examination of aged mice showed dramatically reduced levels of Cbf-beta in bone marrow cells, as compared to younger mice. Thus, they propose, maintaining Cbf-beta may be essential to preventing human age-associated osteoporosis that is due to elevated creation of fat cells.

Bone is a living tissue that constantly rebuilds. Bones need a constant new creation of cells specific to their tissue, including the bone-producing cells called osteoblasts. Osteoblasts live only about three months and do not divide. The progenitor cells for osteoblasts are bone marrow mesenchymal stem cells. Besides osteoblasts, mesenchymal stem cells can also differentiate into the chondrocyte cells that make cartilage, the myocyte cells that help form muscles and the adipocytes, or fat cells. Thus, the same progenitor cell has four possible tracks of differentiation. The researchers focused on the molecular mechanism that controls the lineage commitment switch between the osteoblast and adipocyte tracks, and investigated the key role played by Cbf-beta.

The team generated three mouse models by deleting Cbf-beta at various stages of the osteoblast lineage. All three mouse models showed severe osteoporosis with accumulation of fat cells in the bone marrow, a pathology that resembles aged bone from enhanced adipocyte creation. Bone marrow mesenchymal stem cells and bone cells from the skulls of Cbf-beta-deficient mice showed increased expression of adipocyte genes. Looking at the mechanism downstream, the researchers found that the loss of Cbf-beta impeded the canonical Wnt signaling pathway, particularly through decreased Wnt10b expression. In addition, the researchers showed that Cbf-beta maintains the osteoblast lineage commitment in two ways - through the Wnt paracrine pathway to affect nearby cells and through endogenous signaling within the cell to suppress adipogenesis gene expression. Altogether, this knowledge of the mechanism driven by Cbf-beta can help explain the imbalance in bone maintenance seen in older people.

Link: http://www.uab.edu/news/innovation/item/8714

If you look at the media coverage of work on senolytic therapies, treatments that can clear out senescent cells and thus remove the contribution of these cells to the aging process, it is usually the case that there isn't much to distinguish it from the coverage of any random claim of progress towards anti-aging effects from either within or outside the scientific community: supplements, vitamins, diets, pharmaceuticals, and so forth. None of these other items work in the sense of repairing some of the cell and tissue damage that causes aging. The few that do slow aging do so marginally and in many cases unreliably. The output of the press is not the place one should be looking for accuracy or enlightenment, and it is futile to either demand or expect it to become any better than it is at the moment. Nonetheless, it is somewhat frustrating to see this in action now that the world is changing, and the first means of producing actual rejuvenation are almost upon us.

One could probably construct a metric of press quality that progresses in a spectrum from the worst tabloid to the best popular science effort, built on the basis of whether one can see any difference in the coverage of, say, the effects of senolytics on longevity (significant) and the effects of blueberry consumption on longevity (non-existent). Are objective measures offered? Is the tone exactly the same? Is the hypothetically entirely ignorant reader left thinking that senolytics and blueberries are in the same bucket of expected benefit? Or how about senolytics and antioxidant supplements? Or senolytics and whatever the diet of the month happens to be today? Or senolytics and metformin? Or senolytics and vitamin C? And so forth.

One of the problems here is that much of the press has a very limited number of buckets with which to categorize things, and an equally limited set of output formats. This is how they work cost-effectively when not being paid to propagate a specific viewpoint. So once a thing is tagged as "someone claims this can treat aging," into the same bucket as blueberries and metformin it goes, and the public at large is duly informed - with no attempt to draw any sort of distinction of truth, quality, or expected value to patients. Thus we live in a world in which everyone is told, repeatedly, that ways of turning back aging exist. Since we are in fact all aging to death, no-one believes this to be true. Or if they do, they know that the effects are obviously small and limited, or involve papering over aging in some way without much affecting the self-evident fact that people get old and die. Smoke and mirrors.

Now, I think that the public at large is generally smarter than most journalists credit. Media is primarily used as a way to note the advent of new things and changes in existing things, not as a resource for specific details. Even when the quality is terrible, it is better than trying to find out yourself, even if finding out for yourself was a practical possibility. However, this system breaks down in the scenario in which the media treats all new things in a category as being different shades of the same item. Blueberries and senolytics, just colors of blue or red on the same basic model. People then filter out these updates as being just background noise, and rationally so until now.

I have a vision of what will happen after the first human trials of senolytics demonstrate promise: much of the press will mangle this into something that looks exactly the same as a discussion of the alleged (and entirely non-existent) power of blueberries. It won't be the case that the populations of the world will suddenly awake to the possibilities. Only the parts of it that were already paying attention. Even after significant short-term benefits in human patients are demonstrated to result from the targeted removal of senescent cells, there will still be a need for advocacy and outreach to pull in significantly more funding to the field. That process of fundraising will certainly become easier, but it won't be the case that senolytics will the very next day be a word heard on every street corner.

There is a saying regarding the fact that every good idea needs to be forced upon people, following them to every venue, and waved under their noses until they have no choice but to consider it. It will be that way for the first rejuvenation therapies. It will probably be that way for the second, because they will be different, and work in different ways. Progress in creating the foundations of the future medical industry of rejuvenation becomes incrementally less challenging to engineer the more that the benefits are proven, but it will never become simply easy.

Of late, there has been some discussion in the research community on the role of alternative splicing in aging. Is it a relevant mechanism, and where does it fit in the chain of cause and consequence that leads to age-related disease? In the line of research noted here, the relevance of alternative splicing to cancer is considered - and of course cancer is certainly an age-related condition in the sense that the risk rises considerably with the years.

Alternative splicing refers to the fact that one stretch of DNA, one gene, can code for multiple different proteins. Just like epigenetic mechanisms such as DNA methylation, this is another way in which the balance of proteins produced from the genetic blueprint can change over time, in reaction to changing circumstances. So at first glance, age-related changes to alternative splicing look a lot like cellular reactions to rising levels of molecular damage, and are thus probably a secondary consequence of the causes of aging. Proving that beyond a doubt of course requires the implementation of therapies capable of repairing that damage, of which clearance of senescent cells is the closest to clinical availability.

Cancer, which is one of the leading causes of death worldwide, arises from the disruption of essential mechanisms of the normal cell life cycle, such as replication control, DNA repair and cell death. Thanks to the advances in genome sequencing techniques, biomedical researchers have been able to identify many of the genetic alterations that occur in patients and are common among and between tumor types. But until recently, only mutations in DNA were thought to cause cancer. In a new study, researchers show that alterations in a process known as alternative splicing may also trigger the disease.

Although DNA is the instruction manual for a cell growth, maturation, division, and even death, it's proteins that actually carry out the work. The production of proteins is a highly regulated and complex mechanism: cellular machinery reads the DNA fragment that makes up a gene, transcribes it into RNA and, from the RNA, makes proteins. However, each gene can lead to several RNA molecules through alternative splicing, an essential mechanism for multiple biological processes that can be altered in disease conditions.

Using data for more than 4,000 cancer patients from the Cancer Genome Atlas, a team has analyzed the changes in alternative splicing that occur in each tumor patient and studied how these changes could impact the function of genes. The results of the study show that alternative splicing changes lead to a general loss of functional protein domains, and particularly those domains related to functions that are also affected by genetic mutations in cancer patients. "Thanks to our previous research, we know that tumor type and stage can be predicted by observing alterations in alternative splicing. With this new study, we have discovered that changes in alternative splicing that occur in cancer impact protein functions in a way that is similar to that previously described for genetic mutations." All of these alterations in protein functions would cause changes in cells morphology and function, giving them the characteristics of tumor cells, such as a high proliferative potential or the ability to avoid programmed cell death.

Link: https://www.upf.edu/en/home/-/asset_publisher/UI8Z8VAxU47P/content/id/91248590/maximized

With the advent of low-cost accelerometers, epidemiological studies are beginning to show that even lower levels of sustained activity correlate with reduced mortality and improved health: walking, gardening, cleaning, and similar tasks that don't rise to the level of vigorous exercise. Animal studies of vigorous exercise show that this exercise causes gains in long-term health, and the consensus is that this is the direction of causation for correlations observed in human data. Should we expect the same to hold for lower levels of activity in humans, where there is no comparable animal data to support causation? This study does not make use of accelerometers, but does include populations that are not frequently assessed, and finds the same association between health and low levels of activity.

Physical activity of any kind can prevent heart disease and death, says a large international study involving more than 130,000 people from 17 countries. The Prospective Urban Rural Epidemiology (PURE) study shows any activity is good for people to meet the current guideline of 30 minutes of activity a day, or 150 minutes a week to raise the heart rate. Although previous research, from high income countries, shows leisure time activity helps prevent heart disease and death, the PURE study also includes people from low and middle-income countries where people don't generally don't participant in leisure-time physical activity. "By including low and middle-income countries in this study, we were able to determine the benefit of activities such as active commuting, having an active job or even doing housework." One in four people worldwide do not meet the current activity guideline and that number is nearly three of four in Canada.

The PURE study showed that by meeting the activity guidelines, the risk for death from any cause was reduced by 28%, while heart disease was reduced by 20%, and it didn't matter what type of physical activity the person did. The benefits also continued at very high levels with no indication of a ceiling effect; people getting more than 750 minutes of brisk walking per week had a 36% reduction in risk of death. However, less than 3% of participants achieved this level from leisure time activity while 38% of participants achieved this level from activities such as commuting, being active at work or doing household chores.

"Going to the gym is great, but we only have so much time we can spend there. If we can walk to work, or at lunch time, that will help too. For low and middle income countries where having heart disease can cause a severe financial burden, physical activity represents a low-cost approach that can be done throughout the world with potential large impact. If everyone was active for at least 150 minutes per week, over seven years a total of 8% of deaths could be prevented,"

Link: https://www.eurekalert.org/pub_releases/2017-09/mu-bas092017.php

Enough excess visceral fat tissue will kill you. It causes chronic inflammation that accelerates all of the common fatal age-related diseases, and further produces disarray in metabolism leading to metabolic syndrome and then type 2 diabetes. Considering that type 2 diabetes can, for the vast majority of patients, be turned back even in the later stages through a sustained low calorie diet, it is quite amazing the amount of funding present in the field chasing pharmaceutical solutions to this condition. A sizable fraction of medical researchers are working on this problem rather than others precisely because that is where the funding is. Like the rest of us, scientists need to earn a living. Looking at the situation from a glass half full perspective, this work should inform work on the interaction of aging with normal levels of fat tissue in later life, a point when fat starts to produce a number of similar problems to those exhibited by young, obese individuals.

In the recent past, researchers have made some progress on determining the mechanisms by which excess fat produces inflammation: fat cells can act in similar ways to infected cells, rousing the immune system; in addition, the debris from dying fat cells produces similar results. A sizable proportion of fat tissue in obese individuals is composed of the immune cells called macrophages, and in the research noted below, it is signaling by these immune cells that links the presence of excess fat tissue to some of the consequences of excess fat tissue. It is possible to envisage a chain of consequences involving fat dysfunction and the immune system that initially directly produces inflammation, and then the progressively larger number of immune cells that become involved in the tissue themselves cause further dysfunction in metabolic processes.

It is also worth considering the evidence for deposits of visceral fat tissue to produce harmful effects through the creation of a larger than usual level of cellular senescence. Senescent cells cause problems through altered signaling, the senescence-associated secretory phenotype. It will be interesting to see the degree to which the signaling mechanisms examined in the paper below are produced by senescent versus normal macrophage cells. This is all fairly speculative: researchers have found macrophages showing signs of senescence in older individuals, but there is currently some debate as to whether or not these are actually senescent cells. This part of the field is moving fairly rapidly, so answers may well emerge over the next few years, especially given the deployment of senolytic therapies to clear senescent cells into human trials.

Exosomes are the missing link to insulin resistance in diabetes

Chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance and type 2 diabetes. But the mechanism by which this occurs has remained cloaked. Researchers have now identified exosomes - extremely small vesicles or sacs secreted from most cell types - as the missing link. "The actions induced by exosomes as they move between tissues are likely to be an underlying cause of intercellular communication causing metabolic derangements of diabetes. By fluorescently labeling cells, we could see exosomes and the microRNA they carry moving from adipose tissue through the blood and infiltrating muscle and liver tissues."

During chronic inflammation, the primary tissue to become inflamed is adipose. Forty percent of adipose tissue in obesity is comprised of macrophages - specialized immune cells that promote tissue inflammation. Macrophages in turn create and secrete exosomes. When exosomes get into other tissues, they use the microRNA (miRNA) they carry to induce actions in the recipient cells. The macrophage-secreted miRNAs are on the hunt for messenger RNAs. When the miRNA finds a target in RNA, it binds to it, rendering the messenger RNA inactive. The protein that would have been encoded by the messenger RNA is no longer made. Thus, the miRNAs are a way to inhibit the production of key proteins.

Researchers took macrophages found in adipose tissue of obese mice and harvested their exosomes. Lean, healthy mouse models were treated with these "obese" exosomes and once-normal mice began exhibiting obesity-induced insulin resistance despite not being overweight. When reversing the process, the team found that they could restore insulin sensitivity to obese mice by treating them with exosomes from lean mice. The obese mice remained overweight, but were metabolically healthy. Similarly, during an in vitro study, when human liver and fat cells were treated with "obese" exosomes, these cells became insulin resistant. Conversely, when they were treated with "lean" macrophage exosomes, they became highly sensitive to insulin. "This is a key mechanism of how diabetes works. This is important because it pins the pathophysiology of the disease in inflamed adipose tissue macrophages which are making these exosomes. If we can find out which of the microRNAs in those exosomes cause the phenotype of diabetes, we can find drug targets."

Adipose Tissue Macrophage-Derived Exosomal miRNAs Can Modulate In Vivo and In Vitro Insulin Sensitivity

MiRNAs are regulatory molecules that can be packaged into exosomes and secreted from cells. Here, we show that adipose tissue macrophages (ATMs) in obese mice secrete miRNA-containing exosomes (Exos), which cause glucose intolerance and insulin resistance when administered to lean mice. Conversely, ATM Exos obtained from lean mice improve glucose tolerance and insulin sensitivity when administered to obese recipients.

miR-155 is one of the miRNAs overexpressed in obese ATM Exos, and earlier studies have shown that knock out animals are insulin sensitive and glucose tolerant compared to controls. Furthermore, transplantation of wild type bone marrow into miR-15 knock out mice mitigated this phenotype. Taken together, these studies show that ATMs secrete exosomes containing miRNA cargo. These miRNAs can be transferred to insulin target cell types through mechanisms of paracrine or endocrine regulation with robust effects on cellular insulin action, in vivo insulin sensitivity, and overall glucose homeostasis.

An emerging theme in regenerative research is the importance of the innate immune system to the mechanisms of tissue maintenance, and researchers have so far found a number of ways in which the behavior of these immune cells might potentially be adjusted in order to enhance healing. The scientific community has made initial strides with macrophages and microglia, shifting the balance of pro-inflammatory versus pro-regenerative cells, and here some of the same high level themes are observed in the response to injury of the innate immune cells known as neutrophils. It matters greatly as to whether these immune cells turn up at the point of injury in the mode of defending against intruding pathogens, or in the mode of assisting with repair; they are capable of both, but individual cells tend to be focused only on one of these at a given time.

White blood cells called neutrophils are like soldiers in your body that form in the bone marrow and at the first sign of microbial attack, head for the site of injury just as fast as they can to neutralize invading bacteria or fungi using an armament of chemical weapons. But when that injury is an intracerebral hemorrhage, which releases blood into the brain, neutrophils arrive at the point of battle only to discover that there's no infection to attack. Unless immediately removed from the brain by other immune cells, they actually cause damage and deploy an array of toxic chemicals into the brain that worsen injury.

Now researchers have discovered a way to temporarily suppress these soldiers' pro-killing effect and turn them into beneficial weapons that scavenge for toxins, potentially opening a door for a therapeutic approach to hemorrhagic stroke treatment. A hemorrhagic stroke occurs when an artery inside the brain leaks or ruptures. It is the second-most common form of stroke after ischemic stroke, has a 30 to 67 percent mortality rate and is the main cause of disabilities among adults. Because half of hemorrhagic stroke victims die within the first two days, researchers believe that deadly secondary damage, including through toxicity of iron from the breakdown of red blood cells, leads to an excess in free radicals and inflammation.

Along with carrying chemicals that could aggravate injury, neutrophils produce and release potentially beneficial molecules including lactoferrin, an iron-binding protein. At the same time the neutrophils are getting ready to attack inside the brain, the brain and spleen are releasing interleukin-27 molecules, which can signal to the neutrophils to produce more lactoferrin and thus benefit the brain as it recovers from the stroke injury. "This is one of the first discoveries showing that you can train neutrophils to act as friendly cells. We've adapted how the body already responds naturally, but it can take 12 to 18 hours for the signal to turn them from damaging neutrophils to the beneficial cells that release lactoferrin and by then, it can be too late. Treatment with lactoferrin in our models is effective in reducing brain damage after hemorrhage and we are working on a modified form of lactoferrin that could penetrate the brain better and quicker."

Link: https://www.uth.edu/media/story.htm?id=caf2ac24-bf5a-433e-aa00-e0d22ba0209b

The research materials here fit nicely with a recent post in which the degree to which frailty is self-inflicted was discussed. In this age of comfort and technology, people eat too much and exercise too little. The latter point is demonstrated in the numerous studies that show benefits in older individuals arising from structured exercise programs, a turning back of some of the advance of age-related disability. Thus the progression of frailty is not inexorable for those who choose to exercise more frequently in later years, a small example of the point that our choices do make a difference.

As we age, we may be less able to perform daily activities because we may feel frail, or weaker than we have in the past. Frailer older adults may walk more slowly and have less energy. Frailty also raises a person's risks for falling, breaking a bone, becoming hospitalized, developing delirium, and dying. No one knows exactly how many older adults are frail - estimates range from 4 percent to 59 percent of the older adult population. Researchers say that frailty seems to increase with age, and is more common among women than men and in people with lower education and income. Being in poorer health and having several chronic illnesses also have links to being frail.

Frailty also tends to worsen over time, but in at least two studies, a small number (9 percent to 14 percent) of frail older adults became stronger and less frail as they aged. The researchers examined information gathered from more than 5,000 men aged 65 or older (average age was about 73) who had volunteered for a study about bone fractures caused by osteoporosis. At the start of the study, between 2000 and 2002, the men all lived independently and could walk; none had had hip replacements. Most of the men participated in a second examination about four years after the study began.

At the start of the study, the researchers determined the participants' frailty status by measuring levels of weakness, exhaustion, lean muscle mass, walking speed, and physical activity. The men were categorized as frail, pre-frail (had one or more signs of frailty, such as low grip strength, low energy, slow walking speed, low activity level or unintentional weight loss), or robust (showing no signs of frailty). At the start of the study, nearly 8 percent of the men were frail and 46 percent were pre-frail. The most common problems for the frail men were weakness, slowness, and low activity.

Over four and a half years, the number of frail men increased while the proportion of robust men decreased. Among the men who were frail at both visits: 56 percent had no change in frailty status, 35 percent had become frailer or had died, 15 percent of pre-frail or frail men improved. Having greater leg power, being married, and reporting good or excellent health were linked to improvements in frailty status.

Link: http://www.healthinaging.org/blog/frailty-and-older-men-study-identifies-factors-that-speed-or-slow-progression/

The immune system participates in regeneration, particularly the innate immune cells called macrophages. The behavior of these cells also appears to be an important part of the differences between (a) proficient regeneration, exhibited by salamanders, zebrafish, and to a lesser degree by a few mammals such as spiny mice, and (b) the limited regenerative capacities of the rest of the vertebrate kingdom. Cut off a finger or an arm, and we do not regrow that limb. Our hearts do not regenerate well from damage. Our nerves do not restore themselves from injury. Salamanders accomplish all of these things, and a number of groups in the life science research community are working towards an explanation for that difference. The research results noted here represent the latest incremental gain in understanding, one of many such steps since the turn of the century.

The presently emerging picture of regeneration is one of a coordinated dance of biochemistry involving temporarily present senescent cells, macrophages, and the various populations of cells and stem cells resident in a tissue. Take away the macrophages and it all falls apart; that much has been demonstrated in the studies of recent years. When researchers look at aspects of this dance in salamanders, it appears to be a lot more efficient than is the case in most mammals - but still, as demonstrated in the research here, take away the macrophages and salamanders heal as poorly as we do. Further, spiny mice, that unlike other mammals can regenerate several tissue types without scarring, have salamander-like macrophage behavior during regeneration.

Despite the intriguing examples of tissue regeneration in spiny mice and engineered MRL mice, there is more going on in salamanders and zebrafish than just greater efficiency in the activities of senescent cells and macrophages in tissue regrowth. Salamander and zebrafish cells reprogram themselves into pluripotent states in response to injury, building a blastema, a mass of cells capable of generating all of the necessary replacement parts. Limb regeneration in those species bears a great deal of resemblance to embryonic development. Mammals do not do this, and it seems quite plausible that the reasons why mammals do not do this go far beyond macrophage behavior. One plausible theory is that most species lost the ability to regenerate in this way due to the evolution of cancer suppression mechanisms: inserting the human tumor suppressor gene ARF into zebrafish shuts down their ability to regrow fins and organs, for example.

So it seems very plausible at this point that adjusting macrophage activity is a path to some degree of enhanced human regeneration. Indeed, simple demonstrations in mammals have been carried out involving alterations of macrophage polarization, the balance between pro-inflammatory and pro-regeneration populations of these cells. However, the full salamander package with cellular reprogramming and blastemas recapitulating embryonic development seems likely to require an earnest reengineering of mammalian cellular biochemistry, and as such is probably not a near-term prospect. In the near term, the plausible goal is the enhanced regeneration of MRL and spiny mice, not the limb regrowth of salamanders and zebrafish. In the long term, of course, everything is possible, but we have other battles to fight before that comes to pass.

Study Finds Immune System is Critical to Regeneration

The answer to regenerative medicine's most compelling question - why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot - may lie with the body's innate immune system, according to a new study of heart regeneration in the axolotl, or Mexican salamander. Researchers found that the formation of new heart muscle tissue in the adult axolotl after an artificially induced heart attack is dependent on the presence of macrophages, a type of white blood cell. When macrophages were depleted, the salamanders formed permanent scar tissue that blocked regeneration.

The goal is to activate regeneration in humans through the use of drug therapies derived from macrophages that would promote scar-free healing directly, or those that would trigger the genetic programs controlling the formation of macrophages, which in turn could promote scar-free healing. The team is already looking at molecular targets for drug therapies to influence these genetic programs. "If humans could get over the fibrosis hurdle in the same way that salamanders do, the system that blocks regeneration in humans could potentially be broken. We don't know yet if it's only scarring that prevents regeneration or if other factors are involved. But if we're really lucky, we might find that the suppression of scarring is sufficient in and of itself to unlock our endogenous ability to regenerate."

The prevailing view in regenerative biology has been that the major obstacle to heart regeneration in mammals is insufficient proliferation of cardiomyocytes, or heart muscle cells. But researchers found that cardiomyocyte proliferation is not the only driver of effective heart regeneration. The findings suggest that research efforts should pay more attention to the genetic signals controlling scarring. When a human experiences a heart attack, scar tissue forms at the site of the injury. While the scar limits further tissue damage in the short term, over time its stiffness interferes with the heart's ability to pump, leading to disability and ultimately to terminal heart failure. The next step is to study the function of macrophages in salamanders and compare them with their human and mouse counterparts. Ultimately, researchers would like to understand why macrophages produced by adult mice and humans don't suppress scarring in the same way as in axolotls and then identify molecules and pathways that could be exploited for human therapies.

Heart regeneration in the salamander relies on macrophage-mediated control of fibroblast activation and the extracellular landscape

In dramatic contrast to the poor repair outcomes for humans and rodent models such as mice, salamanders, and some fish species are able to completely regenerate heart tissue following tissue injury, at any life stage. This capacity for complete cardiac repair provides a template for understanding the process of regeneration and for developing strategies to improve human cardiac repair outcomes. Using a cardiac cryo-injury model we show that heart regeneration is dependent on the innate immune system, as macrophage depletion during early time points post-injury results in regeneration failure.

In contrast to the transient extracellular matrix that normally accompanies regeneration, this intervention resulted in a permanent, highly cross-linked extracellular matrix scar derived from alternative fibroblast activation and lysyl-oxidase enzyme synthesis. The activation of cardiomyocyte proliferation was not affected by macrophage depletion, indicating that cardiomyocyte replacement is an independent feature of the regenerative process, and is not sufficient to prevent fibrotic progression. These findings highlight the interplay between macrophages and fibroblasts as an important component of cardiac regeneration, and the prevention of fibrosis as a key therapeutic target in the promotion of cardiac repair in mammals.

One component of most neurodegenerative diseases is that classes of immune cells resident in the brain adopt disruptive, inflammatory behaviors. This is a reaction in some way to growing levels of damage in the form of aggregated proteins, such as amyloid-β and tau in Alzheimer's disease, but it isn't a helpful reaction. It makes the overall situation worse, producing greater dysfunction in the necessary operations of brain cells. Reducing this immune failure should help to slow disease progression even in the absence of effective ways to remove the protein aggregates - though that will have to happen as well in order to produce some form of cure. The research here ties into SENS views of the causes of aging and age-related disease, in that failure of lysosomes in immune cells is implicated: lysosomes are responsible for recycling cellular waste and damaged components, but with age they become dysfunctional for various reasons. That is problematic in any cell, but particularly so in immune cells that are responsible for gathering and destroying metabolic waste materials from the cellular environment.

Microglia normally gobble up and break down amyloid-β (Aβ). However, in Alzheimer's disease (AD), an altered inflammatory state causes them to stop clearing the aggregated peptide. How does this happen, and can it be stopped? Researchers blame the microglial enzyme RIPK1, and believes that blocking it may help return microglia to their normal state. The kinase appears to set off transcriptional changes that cripple the microglial lysosome system. The cells start producing new gene products, some characteristic of the recently identified disease-associated microglia (DAM) surrounding plaques in AD model mice. Genetically deleting or pharmacologically inhibiting RIPK1 both sped up Aβ clearance and improved memory in an AD mouse model. The findings lay the groundwork for a new treatment for AD, and, since RIPK1 has been implicated in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), for those diseases as well.

"It's the first paper that shows blocking RIPK1 alleviates the inflammatory response, reduces plaque, and improves behavior in AD mice. It points out directly the beneficial effects of inhibiting RIPK1 for the treatment of multiple diseases characterized by inflammation and cell death. Microglial lysosome biology is poised to become the next hot topic in Alzheimer's research. A lot of recent data are pointing to failure of the lysosome in microglia and other innate immune cells as the problem in AD, and rebalancing that as the way forward."

RIPK1, short for Receptor-interacting protein 1 kinase, gets induced in response to the inflammatory signals tumor necrosis factor (TNFa) and ligands of the toll-like receptor (TLR) family. It causes an inflammatory response, controls inflammation-induced cell death (necroptosis), and leads to some forms of apoptosis. The researchers first peered into postmortem human brains and found more phosphorylated RIPK1 in slices from AD patients than controls. This implied that the kinase was activated in the disease. That RIPK1 co-localized with microglial markers suggested that it was expressed primarily in these cells.

What did the kinase do? The authors tested this in APP/PS1 mice by adding to their drinking water a RIPK1 inhibitor the group had previously developed called necrostatin-1 (Nec-1s). After a month, the treated mice had fewer plaques and less soluble and insoluble Aβ in the brain. What's more, whereas five-month-old APP/PS1 mice scurried around an open field in a hyperactive state, a month of Nec-1s treatment calmed them down. The researchers also examined spatial memory with a T-shaped water maze, where mice are trained to find a hidden platform at the end of one arm, then retrained to find it in another. At five months, APP/PS1 mice had trouble learning a new platform location, but a month of Nec-1s restored their performances to match those of wild-type mice.

How does a microglial kinase do this? The researchers added Aβ1-42 to microglia isolated from wild-type mice and mice lacking the kinase. Wild-type cells bumped up production of the inflammatory cytokines TNFa and IL6, mutant cells less so. Wild-type microglia pretreated with Nec-1s also produced less TNFα and IL6. Intriguingly, microglia lacking RIPK1 action better digested synthetic Aβ1-42 oligomers. What whetted their appetites? Analyzing the microglial transcriptomes, reserchers found that one of the proteins upregulated by RIPK1 was cystatin F. Encoded by the Cst7 gene, cystatin F inhibits the endosomal/lysosomal system responsible for breaking down unwanted proteins and other metabolic waste.

Link: http://www.alzforum.org/news/research-news/microglial-kinase-promotes-dam-blocks-lysosomal-av-digestion

Researchers here report on a cheaper implementation of encapsulation for transplanted stem cells, preventing the recipient's immune system from attacking cells originating from a different individual or even different species. Since the stem cells produce improvement in regeneration in heart tissue via signaling, there is no need to expose the cells themselves to the local environment - the cells are only needed at all because the signaling environment is not yet fully mapped and understood. Encapsulating transplanted cells in a nanogel extends their lifetime and thus the therapeutic effect.

As a promising approach to tissue repair, multiple types of stem cells have entered the stage of clinical testing. However, their efficacy is limited by low retention and engraftment of transplanted cells, together with the potential risk of inflammation and immunoreaction when allogeneic or xenogeneic cells are used. Heart diseases including myocardial infarction (MI) and heart failure remain the leading cause of death worldwide. Even with the most advanced pharmacological and medical device treatment methods, mortality and morbidity of heart disease stay high. Cardiac tissue engineering and stem cell transplantation approaches aim at de novo cardiac regeneration after injury. Clinical outcomes of cardiac stem cell (CSC) therapy are hampered by low cell retention rate and side effects associated with immune rejection if allogeneic cells are used.

Injectable hydrogels have been used to treat MI, and the studies have been demonstrated to improve cardiac function via increased heart wall thickness and reduced wall stress. Various natural polymers such as fibrin, collagen, Matrigel, chitosan, keratin, and hyaluronic acid have been investigated as injectable hydrogels to treat MI. They have excellent biocompatibility and can promote cell migration, proliferation, and/or differentiation, leading to ultimate heart regeneration/repair. However, the drawbacks of natural polymers hampering their clinical applications are their batch-to-batch variation and expensive cost.

Synthetic polymers hold the potential to replace natural polymers as injectable hydrogels to treat MI. One appealing regenerative medicine strategy for MI is encapsulating stem cells such as CSCs inside the hydrogels and deliver the cell-laden hydrogels into the damage tissues. Here, we propose the use of P(NIPAM-AA) nanogel, a synthetic injectable carrier to encapsulate human CSCs in mouse and pig models of MI. The nanogel serves as a scaffolding material to enhance cell retention and as a barrier to prevent T cells from entering and attacking the encapsulated CSCs. The treatment ultimately resulted in augmented cardiac function and stimulation of endogenous regeneration.

The mechanisms underlying the therapeutic benefits of nanogel-encapsulated CSC therapy are likely to be complicated. Our findings indicated that the P(NIPAM-AA) nanogel-encapsulated hCSCs promoted post-MI cardiac repair by the inhibition of apoptosis and promotion of angiomyogenesis. Collectively, these favorable actions lead to reduced fibrosis and improved cardiac function. Fast degrading natural polymers do not support long-term support to the heart. In contrast, synthetic polymers cannot be quickly removed by enzyme activities. In real scenarios, we expect the nanogel will provide a shield for allogeneic stem cells or induced pluripotent cells, which are likely to trigger immune reaction in the host tissue. In addition, the polymer carrier can drastically improve cell retention rate.

Link: https://doi.org/10.1021/acsnano.7b01008

In the early 1990s Cynthia Kenyon and others produced the first C. elegans nematode worms to exhibit significantly extended longevity through a single gene mutation, in daf-2, the nematode version of the insulin-like growth factor 1 (IGF-1) receptor, and went on to map the relevant nearby biochemical landscape of these mutants. It is perhaps overly simplistic to mark this as the dividing line between a research mainstream whose members believed aging to be an intractably complex process, and a research mainstream increasingly interested in slowing aging through adjustment of metabolism, but that is the story as it is commonly told these days.

The mechanisms of longevity enhancement in daf-2 mutants depend on daf-16, a FOXO family transcription factor. The roles of these and other related proteins have been studied intensively in nematodes and other species since the first discoveries. Insulin metabolism - involving insulin, IGF-1, growth hormone, and their cell surface receptors - has emerged as one of the more influential means by which cellular mechanisms determine variations in longevity, both in response to circumstances for individuals within the same species, and to some degree between species. The record for mouse longevity is still held by growth hormone receptor loss of function mutants, for example. These proteins and their relationships are tied to cell growth, nutrient sensing, the calorie restriction response, temperature regulation, autophagy, and many other fundamental aspects of biochemistry.

From a historical perspective, to understand how the research community came to its present distribution of attitudes and focus, it helps to know something about this body of research and its central position in the modern study of aging. It has progressed and grown alongside the slow awakening to view aging as a treatable medical condition. If reliable changes of any sort can be achieved, so the thinking goes, then in principle something can be done to reduce the terrible toll of suffering, pain, and death that accompanies aging. The ability make even small changes means that aging is not intractable. Manipulating insulin metabolism and its surrounding mechanisms, such as through the development of calorie restriction mimetic drugs, is not the future of longevity science, however. It is not a road to rejuvenation, because rejuvenation can only occur when the causes of aging are reversed. All that can be done with the manipulation of insulin metabolism is to modestly slow down aging.

Thus the future of the field, for the treatment of aging at least, will involve a transition away from the study of processes that explain natural variations in longevity between individuals, or due to environmental factors such as calorie intake. A transition away from the work that awoke the possibility of influencing aging, and towards effective means of turning back aging. Since tinkering with insulin metabolism, or any similar approach, cannot produce rejuvenation, other methods must be adopted. This future is best represented by the SENS portfolio, the strategies for engineered negligible senescence, and similar programs focused on repairing the cell and tissue damage that causes aging. This is an entirely distinct focus, orthogonal to topics such as the way in which insulin metabolism functions to adjust the pace of aging. Metabolism generates various forms of damage even when operating normally, and that damage accumulates over time to cause age-related dysfunction, disease, and death. Removing this damage will turn back the state of aging, and thus be a form of rejuvenation.

DAF-16/FOXO Transcription Factor in Aging and Longevity

The genetic pathways and biochemical processes that modulate aging and longevity are well conserved from budding yeast to the nematode worm Caenorhabditis elegans and mammals. The forkhead transcription factor FOXO as the key downstream regulator that integrates different signals from these pathways plays a crucial role in aging and longevity. The roundworm C. elegans has been considered to be an excellent system for studying molecular mechanisms in regulating animal aging and longevity. Here we discuss the evidence for the role of DAF-16/FOXO in aging and longevity, especially the data in C. elegans, which could give clues to the further studies for human aging and longevity.

FOXOs belong to the class O of the Forkhead transcription factors, which is featured by a conserved DNA-binding domain that participates a wide range of important cellular processes such as cell cycle arrest, apoptosis, and metabolism besides its function in stress resistance and longevity. There are four FOXO genes in mammals: FOXO1 (FKHR), FOXO3 (FKHRL1), FOXO4 (AFX), and FOXO6 sharing high similarity in their structure and function as well as regulation with each other, while invertebrates have only one FOXO gene, named daf-16 in C. elegans.

"Deregulated nutrient sensing" as one of the aging hallmarks to be firstly described to influence longevity, is mainly regulated by the insulin and IGF-1 signaling (IIS) pathway. And this pathway is so highly conserved to modulate aging and longevity across a great evolutionary distance from invertebrates to mammals that the components in every step found in C. elegans could be corresponded to the homologs in mice or human. Any conditions that cause inner stress to block the IIS pathway, like in the presence of food restriction or signals failing to be transduced to DAF-16/FOXO, would increase the transcriptional activity of DAF-16/FOXO by inducing the translocation of DAF-16/FOXO to the cell nucleus, which could subsequently promote or repress the expression of downstream targets to trigger the resistance to different kinds of stress and prolong the lifespan of the organisms.

Another pathway correlated with nutrition affecting longevity is the TOR (target of rapamycin) pathway, which was firstly described in C. elegans and was proved evolutionarily conserved later in other organisms. Various dietary interventions such as caloric restriction may inactivate TOR pathway to promote lifespan extension. The TOR kinase exists in two distinct complexes, TORC1 and TORC2. TORC1-mediated longevity is dependent on DAF-16/FOXO.

AMPK pathway as an energy-sensing signaling pathway responses to stimuli of decreased energy as well as reduced glucose or leptin levels, and it is the theoretical basis of dietary restriction regimen that is considered to extend both the mean and maximal lifespan in a wide range of species. DAF-16 is necessary for AMPK function in oxidative stress resistance and longevity, as the increased longevity caused by overexpression of AMPK was reverted when DAF-16 was inhibited.

The JNK (Jun N-terminal kinase) family, a subgroup of MAPK (mitogen-activated protein kinase) superfamily, as a part of a signal transduction cascade that is activated by cytokines such as TNF and IL-1, serves as a molecular sensor for various stresses including UV irradiation, ROS (reactive oxygen species), DNA damage, heat, and inflammatory cytokines. In C. elegans, overexpression of JNK showed extension lifespan and resistance to heavy metal toxicity, which may function through phosphorylation of DAF-16.

A reproductive system that may integrate nutrient signaling and communicate with other tissues through germline to affect aging has been observed in C. elegans, flies, and mice, indicating a conserved regulation mechanism across different organisms. And it has been reported that lifespan could be extended by 40-60% if the germline precursor cells were removed or the germline stem cell division were prevented in C. elegans. A steroid hormone pathway that includes the key components DAF-36/NVD, DAF-9/CYP27 as well as DAF-12/NHR is required for lifespan extension in response to germline loss, and DAF-12/NHR and DAF-9/CYP27 probably form a complex with DAF-16/FOXO to function, although the detailed mechanisms remain to be further determined.

Thus multiple signaling pathways such as the insulin/IGF-1 signaling pathway, TOR signaling, AMPK pathway, JNK pathway, and germline signaling have been found to be involved in aging and longevity. DAF-16/FOXO, as a key transcription factor, could integrate different signals from these pathways to modulate aging, and longevity via shuttling from cytoplasm to nucleus. Hence, understanding how DAF-16/FOXO functions will be pivotal to illustrate the processes of aging and longevity.

Funded by the SENS Research Foundation and allied philanthropists, the researchers at the Spiegel Lab are working on the tools needed to build the means to remove glucosepane cross-links from aged tissue. Like clearance of senescent cells, this is one of the more promising near-term approaches to rejuvenation therapies because it is just the single, narrow problem, rather an enormous range of compounds and mechanisms grouped into a category, as is the case for amyloids, lipofusin, and other forms of damaging metabolic waste. It should be possible to develop and deploy working approaches to glucosepane cross-link breaking in a much shorter period of time, once the initial hurdles are overcome.

Persistent sugary cross-links form in the extracellular matrix as a side-effect of the normal operation of cellular metabolism. In humans the vast majority of lasting, problematic cross-links involve glucospane. These cross-links alter and corrode the structural properties of tissue, making bone and cartilage fragile, and producing loss of elasticity in skin and blood vessels. While all of these are bad, the loss of blood vessel elasticity is probably the most important of these consequences, as increased vascular stiffness with advancing age drives the progression of hypertension, cardiac hypertrophy, and fatal cardiovascular disease. The sooner the research community makes the leap to far greater funding and interest in cross-link breaking, the better. This requires better tools, such as those planned in this new research project.

SENS Research Foundation (SRF) has launched a new research program focused on developing monoclonal antibodies against glucosepane. David A. Spiegel will be running the project in his laboratory, which focuses on developing new methods and molecules that will facilitate our understanding and treatment of human disease.

Glucosepane is the most prevalent crosslink found in collagen in people over 65 years of age, and its presence has been correlated to age-related tissue damage through various mechanisms. Understanding of glucosepane has been hampered by the molecule's complex and sensitive chemical structure; it can only be isolated from human samples in minute quantities and in an impure form. To enable these advances in both basic and therapeutic science, the Spiegel laboratory has recently accomplished the first total synthesis of glucosepane.

The lab is now utilizing its novel synthetic glucosepane derivatives to generate the first monoclonal anti-glucosepane antibodies. Access to these antibodies would profoundly accelerate the goal of developing the first discrete, specific reagents for labeling, studying, and perhaps also cleaving glucosepane in vivo. Such tools have tremendous potential to help illuminate, and reverse, age-related damage as it occurs in human tissues.

This research has been made possible through the generous support of Michael Antonov and the Forever Healthy Foundation and its founder Michael Greve. The Forever Healthy Foundation is a private nonprofit initiative whose mission is to enable people to vastly extend their healthy lifespans and be part of the first generation to cure aging. In order to accelerate the development of therapies to bring aging under full medical control, the Forever Healthy Foundation directly supports cutting-edge research aimed at the molecular and cellular repair of damage caused by the aging process.

Link: http://www.sens.org/outreach/press-releases/srf-and-spiegel-lab-to-collaborate-on-antibodies-to-glucosepane

When the population as a whole is aging because of historical changes in birth and mortality rates, meaning that an increasing percentage of people are older rather than younger with each passing year, it is perfectly possible to observe both a growth in the total number of cases of age-related disease and at the same time a reduction in the rate at which individuals develop age-related disease. Both of these trends are underway at the present time. In this context, the short article noted here reviews some of the epidemiological research that indicates the risk of suffering dementia is falling.

Numerous studies have reported a dip in dementia incidence in the developed world. When did this trend begin? Researchers analyzed birth cohort data from the Einstein Aging Study, which enrolls cognitively healthy older adults living in the Bronx. Surprisingly, people born after 1928 were 85 percent less likely to develop dementia than those born before that year. The reason for such a stark drop in incidence is unclear. Neither better education nor improved cardiovascular health accounted for the effect. "The birth cohort effect is intriguing but will need replication in other populations. This important insight compels us to search for novel social and environmental factors that may have impacted this birth cohort. Changes in nutrition, education, pollutants, and infections all occurred and would be worth examining."

A growing number of studies have reported a drop in dementia incidence in the U.S. and Europe over the last two or three decades. Researchers have speculated that this may be due to better public health, particularly cardiovascular health. The finding is not uniform, however, with a handful of studies reporting higher dementia incidence that may be due to greater recognition of the disease or a larger number of people reaching old age.

To try to clarify the picture, researchers examined data from participants who enrolled in the Einstein Aging Study between 1993 and 2015. The cohort comprised 1,348 participants who had completed at least one annual follow-up visit, with an average follow-up time of four years. All participants were older than 70, and about two-thirds were non-Hispanic white. The researchers diagnosed dementia by a clinical exam. A subset of participants donated their brains after death, and 96 percent of those with a dementia diagnosis had some type of extensive brain pathology. For example, in a subgroup diagnosed with Alzheimer's disease, 79 percent had plaques and tangles.

Within each age group, the researchers saw a steady drop in dementia incidence for those born in later years. Among people born before 1920 there were 5.09 cases per 100 person-years. This dropped to 3.11 for people born in the early 1920s, and 1.73 for those born in the late 1920s. The most dramatic shift occurred right at the turn of that decade, when the rate fell to 0.23. Mathematical modeling pegged the best estimate for the change point to July 1929. While the model suggests an abrupt change in dementia rates, the researchers noted that this might partly be the result of small sample size; the post-1929 cohorts totaled only 350 people, with just three cases of dementia among them. "If there were more people in the analysis, the trend might be smoother." Nonetheless, the findings were statistically significant, and the researchers believe the data are picking up a real decline in dementia risk at around this time point.

What might explain it? The researchers found marked decreases in the rates of heart attack and stroke in later birth cohorts, but after adjusting the model to account for this, the drop in dementia incidence in those born after 1929 remained unchanged. While previous epidemiological studies did not specifically examine birth years, those older findings are roughly congruent with the Einstein Aging Study data, reporting the greatest drop in dementia cases after 1990, the authors noted. People born after 1929 would have entered their 60s in that decade. Most cases of late-onset dementia occur after age 60. The Rotterdam Study found a 25 percent decrease in dementia incidence in the 1990s, while the Framingham Heart Study recently reported that incidence dropped starting in the late 1980s and continued to decline into the 2010s.

Link: http://www.alzforum.org/news/research-news/more-evidence-dementia-case-numbers-are-falling

The increasing number of senescent cells present in older tissues is one of the root causes of degenerative aging. It is also the closest to being effectively reversed. An open access paper describing the evidence for HSP90 inibitors to selectively destroy senescent cells was published earlier this month. I had half missed it in passing and half skipped over it in favor of a more general review of the current state of senolytic drug development, pharmaceuticals capable of clearing senescent cells, but on reflection I think it is worth pointing out. The number of senolytic drug candidates has not yet reached a count of twenty, and some of them are probably not all that great, such as quercetin and fisetin, while others are chemotherapeutics with enough in the way of ugly side-effects to be avoided if there is a choice in the matter. So new categories of potential senolytics are worth noting.

Like many classes of drug candidates, HSP90 inhibitors have been considered for use against cancer. There is a strong connection between the phenomenon of cellular senescence and cancer research, through scientists in that field have generally been interested in generating more senescent cells rather than fewer of them. They are trying to push tumor cells and potentially cancerous cells into becoming senescent rather than replicating rampantly, enhancing the natural function of of cellular senescence as a means to reduce cancer risk. Unfortunately, the fact that chemotherapeutics generate a high load of senescent cells in patients, either intentionally or because they are toxic to cells in general, is one of the reasons why chemotherapy is so damaging to long term health even when successful. There are other points of connection as well: cancer researchers are also interested in pushing abnormal cells into programmed cell death processes such as apoptosis, and selectively triggering apoptosis in senescent cells is the goal of all senolytic drug candidates to date. So we should certainly expect to see new senolytic pharmaceuticals to have been evaluated as cancer therapies at some point in the past.

Are HSP90 inhibitors any good in comparison to the other types of senolytic discovered to date? I'd say it is far too early to do any more than handwave this sort of comparison. The results from animal studies to date suggest that candidate senolytics fall into one of two broad categories: they either do little to senescent cells, or they clear up to 50% of these cells, that effectiveness varying by tissue type, drug candidate, and dosage. Different drugs in the same general category of senolytics can have very different outcomes. This sort of variation is in evidence in the data from progeroid mice in this study, which at least puts a few HSP90 inhibitors, geldanamycin and 17-AAG / tanespimycin, into the category of "clears senescent cells" rather than "does nothing" - the results in mice look something like 50% clearance in the kidney versus 25% in the liver, on a par with the best of the other present drug candidates with published animal data.

Identification of HSP90 inhibitors as a novel class of senolytics

Replicative senescence is a cellular program preventing further cell divisions once telomeres become critically short. Senescence also can be induced by cellular stress, including oxidative and genotoxic stresses, or by activation of certain oncogenes. Senescent cells secrete pro-inflammatory factors, metalloproteinases, and other proteins, collectively termed the senescence-associated secretory phenotype (SASP). With chronological aging, there is an accumulation of senescent cells in mammals. This is thought to drive senescence of neighboring cells via the SASP and the functional decline of tissues.

Clearance of senescent cells rodent models restored vascular reactivity, stabilized atherosclerotic plaques, improved pulmonary function, alleviated osteoarthritis, and improved fatty liver disease. Thus, the increase in cellular senescence that occurs with aging appears to play a major role in driving life-limiting age-related diseases. Therefore, therapeutic approaches to specifically kill senescent cells have the potential to extend healthspan and lifespan.

Using a bioinformatics approach, we recently identified several pro-survival pathways, including the Bcl-2/Bcl-XL, p53/p21, PI3K/AKT, and serpine anti-apoptotic pathways that, when inhibited, result in death of senescent murine and human cells. A combination of the drugs dasatinib and quercetin, which target several of these pro-survival pathways, induce death specifically in senescent murine and human cells. Similarly, we and others also demonstrated that several inhibitors of Bcl-2 family members like navitoclax (ABT263), A1331852 and A1155463 are senolytic in some, but not all cell types. In addition, a FOXO4-interacting peptide that blocks an association with p53 recently was demonstrated to induce apoptosis in senescent cells.

Here, we describe the development of a novel screening platform to identify senotherapeutics, drugs that either suppress senescence (senomorphics) or selectively kill senescent cells (senolytics). The screen utilizes DNA repair deficient Ercc1-/- primary murine embryonic fibroblasts (MEFs), which senesce rapidly when grown at atmospheric oxygen, and detection of senescence-associated β-galactosidase (SA-β-gal). Using this platform to screen a library of autophagy regulators, a process known to influence the senescence phenotype of different cell types, we identified HSP90 inhibitors as a novel class of senolytic agents, able to induce apoptosis of senescent cells specifically.

To validate the platform, HSP90 inhibitors were tested for senolytic activity in human cells in culture and in a progeroid mouse model of accelerated aging, where the intervention delayed multiple age-related comorbidities. These results demonstrate the utility of the screening platform for identifying novel classes of senotherapeutics. Furthermore, the results demonstrate that an HSP90 inhibitor used clinically is senolytic and could be potentially repurposed to extend healthspan.

Mitochondrial damage is important in aging, and many of the means shown to modestly slow aging in various species involve increased cellular maintenance activities directed towards mitochondria. One of these is mitophagy, a specialized form of autophagy that recycles damaged mitochondria. There is plenty of evidence to suggest that more efficient mitophagy is good for long-term health. There is also plenty of evidence for increased autophagy of all sorts to be one of the more important mediating mechanisms in many of the interventions shown to slow aging in laboratory species, including the long-studied and simple approaches of calorie restriction and exercise. In this paper, the authors review what is known of the effects of exercise on mitophagy and mitochondrial function in older individuals. We all know the rough boundaries of the benefits that can be produced by exercise; the open question for researchers is the degree to which various specific mechanisms contribute to those benefits.

The maintenance of mitochondrial structural integrity, biogenesis, and function is essential to cells, since mitochondrial dysfunction can induce disturbances in energy metabolism, increase reactive oxygen species (ROS) production and, consequently, trigger mechanisms of apoptotic cell death. Moreover, during the last decades, multiple lines of evidence in model organisms and humans have demonstrated that impaired mitochondrial function can contribute to the aging process, as well as age-associated diseases. In fact, it has been shown that decreased mitochondrial performance is a hallmark of aging possibly due to the central role of mitochondria in metabolism and cellular function. Thus, the potential toxicity of mitochondrial ROS (mtROS), originating from the mitochondrial respiratory chain, led to the formulation of the oxidative stress theory of aging, which suggested that the accumulation of oxidative damage to macromolecules is an important point in the aging process.

Mitochondrial DNA has two characteristics that make it a key target of mtROS: on the one hand, its proximity to the respiratory chain and, on the other, the lack of protective histones. Damaged mitochondrial DNA alters the respiratory chain, increasing the free radical generation and triggering a vicious cycle. These changes result in organic dysfunction and aging phenotype. Recently, however, in contrast to the original theory favoring oxidative damage as a cause for mtDNA mutations and corresponding declines in mitochondrial function, there are strong data arguing that most mammalian mtDNA mutations originate as replication errors made by the mitochondrial DNA polymerase.

Since mitochondria are involved in both adaptive metabolism and survival in response to cellular stress, it is necessary to maintain good mitochondrial functioning through a tight mitochondrial quality control. Recently, mitophagy has gained importance because the damage accumulated in the mitochondria may result in a large number of cell consequences. This process of dysfunctional mitochondria removal occurs by two major pathways, damage-induced mitophagy and developmental-induced mitophagy. Mitophagy not only clears dysfunctional mitochondria but also participates in adaptive response to nutrient deprivation, hypoxia, or developmental signals, promoting a reduction in the overall mitochondrial mass.

Physical exercise has been proposed as a nondrug treatment against different diseases for people of all ages. In addition, it is suggested that regular exercise could promote an increase in mitophagy capacity and produce effects on the mitochondrial life cycle. Theoretically, physical exercise could also have effects on the major signaling pathways that are involved in the quality and quantity control of mitochondria during the aging process, such as mitophagy. Mitochondria produce ROS that can act as signaling molecules, inducing a survival response or causing damage to cellular components. However, contraction of the skeletal muscle during physical exercise can activate a mitochondrial response that improves the quality of mitochondria in different ways: (1) increasing biogenesis; (2) enhancing the expression and action of the proteins involved in mitochondrial dynamics; (3) raising mitochondrial turnover by the action of mitophagy proteins; and (4) increasing the quality control of mitochondria through the degradation of damaged or dysfunctional mitochondria.

Although the studies analyzed do not exhibit a general consensus, it seems that aging impairs mitochondrial biogenesis and dynamics and decreases the mitophagic capacity of the organism. Several interventions, such as any type of physical exercise, are able to affect the activity and turnover of mitochondria by increasing biogenesis. In addition to the changes detected in the biogenesis, aerobic exercise or combined long-term training also seem to produce increases in several markers of mitochondrial dynamics and mitophagy.

Link: https://doi.org/10.1155/2017/2012798

The first, narrowly focused rejuvenation therapies based on repair of the cell and tissue damage that causes aging already exist. They are entering trials, they are under development in companies. Senolytic therapies to clear senescent cells will be a going concern in just a few years: the drug candidates are cheap, people are running small trials funded by philanthropists, and others are self-experimenting. The first forms of treatment capable of turning back numerous aspects of aging in humans to a large enough degree to be worth it are nearly here. Unless your remaining life expectancy is in fact only a few years, then you have every chance of being able to benefit from at least the first generation of these treatments. There is no excuse for turning away and shrugging, telling yourself that this is science fiction, the medicine of the next generation, out of reach and therefore not worth your support. That is all false.

Given that up to the beginning of the twentieth century many of us succumbed to disease at an early age, it should be no surprise that living a long life is still seen today as something akin to winning the lottery. Even when confronted with the galloping pace of scientific advances in human longevity, our historical sensibilities have led us to take a defeatist stance towards the subject: "Even if longevity interventions become available during my lifetime, I am already too late to take advantage of them, so why bother?" Indeed, for so long as tangible rejuvenation therapies do not become available, we will feel validated in our pragmatism.

Today, however, rejuvenation biotechnology is far from a fictional dream: it is a quickly growing field in which advances which may increase the lifespan of you and your children to well over a hundred years are already making their way to the clinic, and this is something we can no longer ignore. Every reality begins with a dream. Only 114 years ago, the Wright brothers made the first powered flight a reality, and since then we have taken to the skies, orbited the earth, and landed a man on the moon. Today, most of us will have flown in an airplane, and have ceased to see this as exceptional. It would be short-sighted to think that the same will not happen with new technologies such as cryonics or rejuvenation.

In the last year alone, we have seen a rapid rise in the number of senolytic drugs, that aim at clearing senescent cells, under development, with companies such as Unity Biotechnology recently raising more than 100 million dollars to push these therapies through the US regulatory process and into the clinic. Last year, scientists found a way to cheaply synthesize glucosepane, a key molecule thought to be a crucial factor in aging. A drug which clears glucosepane from the body is now being developed by the Spiegel Lab at Yale University, among others, and the first potential drug candidates are projected to be available within the next 10 years. And this is only the tip of the iceberg. At this point, it is indeed challenging to continue to pull the wool over our eyes. Not only are these therapies likely to become available in our lifetime, but it seems many of them will be reaching the market within the next decade.

However, reflecting on the feasibility and the desirability of bringing aging under comprehensive medical control inevitably demands us to question many of our preconceived assumptions regarding what is possible, what is or isn't good for us, and what is acceptable. Disputing what one had long thought to be true - or at least learned to accept - is never without effort or discomfort, and this is especially true when we consider that many of us still see aging as an inevitable, perhaps even necessary, fact of life. It should thus come as no surprise that one of the most common responses to the thought of robust rejuvenation is that of neglect; in other words: why concern ourselves with something that might come to pass only after we are long gone?

Yet our actions today have the possibility, for the first time in history, to bring a profound change to the number of people who may live long enough to benefit from rejuvenation. By acting to speed up the development of the first therapies in the coming years, we ensure that a large majority of people alive today are granted the opportunity to take advantage of them; conversely, our inaction will lead to a slowing down of the pace of progress, making the impossibility of robust rejuvenation a self-fulfilling prophecy.

Link: http://www.leafscience.org/not-in-my-lifetime/

Nothing in cellular biology is any way straightforward. All rules have exceptions, enormous complexity is the norm, and old understandings are consistently overturned with the arrival of new data: what was thought to be simple turns out to be anything but simple. Even something like the cellular maintenance processes of autophagy, universally demonstrated to be a good thing in laboratory species, to slow aging when more active, and to accelerate aging when disabled via genetic engineering, are no exception. As demonstrated here, researchers have found that selectively disabling autophagy can actually extend life in nematode worms, possibly because the operation of age-damaged autophagy in some important tissues is actually worse than the absence of running autophagy.

In the publicity materials, this is all wrapped in considerations of antagonistic pleiotropy in the evolution of aging, but I think the mechanics of the thing are more interesting in this case. In lower species like worms and flies there is a fair amount of evidence for some tissues to be especially influential over aging: the intestines, some groupings of neurons in the brain, for example. It is very unclear as to the degree to which this is still the case in mammals. Certainly most things demonstrated to slow aging in short-lived species have far less of an effect in long-lived species such as our own. Nonetheless, this research can be taken as an example of the importance of neurons in the pace of aging in nematodes.

Why we did not evolve to live forever: Unveiling the mystery of why we age

Natural selection results in the fittest individuals for a given environment surviving to breed and pass on their genes to the next generation. The more fruitful a trait is at promoting reproductive success, the stronger the selection for that trait will be. In theory, this should give rise to individuals with traits which prevent ageing as their genes could be passed on nearly continuously. Thus, despite the obvious facts to the contrary, from the point of evolution ageing should never have happened. This evolutionary contradiction has been debated and theorised on since the 1800s. It was only in 1953 with his hypothesis of antagonistic pleiotropy that George C. Williams gave us a rational explanation for how ageing can arise in a population through evolution.

Williams proposed that natural selection enriches genes promoting reproductive success but consequently ignores their negative effects on longevity. Importantly, this is only true when those negative effects occur after the onset of reproduction. Essentially, if a gene mutation results in more offspring but shortens life that's fine. This is because there can be more descendants carrying on the parent's genes in a shorter time to compensate. Accordingly, over time, these pro-fitness, pro-ageing mutations are actively selected for and the ageing process becomes hard-wired into our DNA. While this theory has been proven mathematically and its implications demonstrated in the real world, actual evidence for genes behaving in such as fashion has been lacking.

Now researchers have identified that genes belonging to a process called autophagy - one of the cells most critical survival processes - promote health and fitness in young worms but drive the process of ageing later in life. "These genes haven't been found before because it's incredibly difficult to work with already old animals, we were the first to figure out how to do this on a large scale. From a relatively small screen, we found a surprisingly large number of genes, 30, that seem to operate in an antagonistic fashion. Previous studies had found genes that encourage ageing while still being essential for development, but these 30 genes represent some of the first found promoting ageing specifically only in old worms. Considering we tested only 0.05% of all the genes in a worm this suggests there could be many more of these genes out there to find."

The researchers also found a series of genes involved in regulating autophagy which accelerate the ageing process. These results are surprising indeed, the process of autophagy is a critical recycling process in the cell, and is usually required to live a normal full lifetime. Autophagy is known to become slower with age and the authors of this paper show that it appears to completely deteriorate in older worms. They demonstrate that shutting down key genes in the initiation of the process allows the worms to live longer compared with leaving it running crippled. "Autophagy is nearly always thought of as beneficial even if it's barely working. We instead show that there are severe negative consequences when it breaks down and then you are better off bypassing it all together. It's classic antagonistic pleiotrophy. In young worms, autophagy is working properly and is essential to reach maturity but after reproduction, it starts to malfunction causing the worms to age."

In a final revelation, the team were able to track the source of the pro-longevity signals to a specific tissue, namely the neurons. By inactivating autophagy in the neurons of old worms they were not only able to prolong the worms life but they increased the total health of the worms dramatically. "We turn autophagy off only in one tissue and the whole animal gets a boost. The neurons are much healthier in the treated worms and we think this is what keeps the muscles and the rest of the body in good shape. The net result is a 50% extension of life."

Neuronal inhibition of the autophagy nucleation complex extends life span in post-reproductive C. elegans

Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen.

From this screen, we identified 30 novel regulators of post-reproductive longevity, including pha-4. Through downstream analysis of pha-4, we identified that the inactivation of genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as bec-1, strongly extend both life span and health span. Furthermore, our data demonstrate that the improvements in health and longevity are mediated through the neurons, resulting in reduced neurodegeneration and sarcopenia. We propose that autophagy switches from advantageous to harmful in the context of an age-associated dysfunction.

The way to avoid the harms done to long-term health and life expectancy by excess visceral fat tissue is not to gain that fat, or to lose it if you have it. This is not the path pursued by that part of the research community interested following the large-scale funding associated with the metabolic diseases of obesity, of course. There is comparatively little profit to be made in telling people to lose weight, versus selling them compensatory pharmaceuticals for a lifetime. However, even with normal, healthy levels of fat tissue, as aging progresses that tissue starts to cause similar issues to those produced by excess fat in earlier life: chronic inflammation, metabolic disruption leading to type 2 diabetes, and so forth. The changes of aging include processes that introduce dysfunction into the relationship between fat and the immune system, one of which is examined here.

Adipose tissue inflammation has become widely accepted as a major contributor to metabolic dysfunction and disorders. Previous studies on diet induced obesity mice have shown that adipose tissue is primed for inflammatory changes prior to other metabolic organs. There is a plethora of research investigating factors in obese adipose tissue inflammation to identify valuable therapeutic targets for metabolic dysfunction. However, much less is understood about age-related adipose tissue inflammation and dysfunction. A better understanding of the cellular and molecular mechanisms of adipose tissue inflammation in aging will be crucial in the development of therapeutics for metabolic diseases beyond cases of diet-induced adipose tissue inflammation and insulin resistance.

Both age-related adiposity and diet-induced obesity are characterized by immune cell infiltration and a sustained inflammatory cycle. Among these various immune cells, adipose tissue macrophage (ATM) accumulation, proliferation, and polarization are major contributors to adipose tissue inflammation and dysfunction. Interestingly, recent studies suggest that changes in preadipocyte function during aging also lead to dysfunctional adipose tissue, eventually progressing to chronic inflammation. Our group have recently shown that elevated endoplasmic reticulum (ER) stress response in aging contributes to greater inflammatory responses, in part due to compromised autophagy activity in the aging adipose tissue. Recent studies have also indicated that with aging there is increased accumulation of senescent cells in many organs including fat depots, which contributes to aging pathologies. However, the detailed molecular mechanisms that lead to increased inflammation in aging adipose tissue are poorly defined.

During the last decade, major advances were made in identifying the molecular mechanisms by which lipid-derived products promote inflammation in different cell types. One type of lipid-derived product, non-esterified fatty acids (NEFA), elevates tissue inflammation through interaction with the pattern recognition receptor Toll-like receptor 4 (TLR4) via its endogenous ligand Fetuin-A (Fet A), a liver derived glycoprotein. Fet A is considered a biomarker of chronic inflammation due to its ability to stimulate the production of inflammatory mediators from both adipocytes and macrophages. Interestingly, Fet-A null mice were protected against obesity and insulin resistance with aging.

The involvement of Fet A-mediated activation of TLR4 pathway in adipose tissue inflammation in diet-induced obesity is well explored. However, the role of this pathway in age-associated adipose tissue inflammation is unknown. We undertook this study to test the hypothesis that age-related adipose tissue inflammation is dependent on the Fet A-mediated TLR4 signaling pathway. We first evaluated the expression of Tlr4 and Fet A gene products in adipose tissue, liver, and plasma samples derived from young and old mice. We then exploited the TLR4-deficient mice to investigate the role of TLR4 in age-associated adipose tissue inflammation, ER stress response, autophagy activity, cellular senescence, and metabolic status (glucose tolerance).

We found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4-deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced adipose tissue inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished cellular senescence. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced adipose tissue inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated adipose tissue inflammation that is distinct from diet-induced adipose tissue inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation.

Link: https://doi.org/10.18632/aging.101288

This very readable review paper walks through what is known of modifications to proteins that occur after their creation, and the role these modifications play in aging. If you are familiar with the SENS view of aging as an accumulation of damage, you'll recall that this damage includes the buildup of numerous forms of metabolic waste, and many of these items are modified proteins. Equally, the vast majority of other age-related changes in modified proteins are downstream consequences of the damage of aging or reactions to the damage of aging, not root causes - the details matter on a case by case, per-protein and per-modification basis.

From a biodemographic point of view, aging is defined as an exponential increase in mortality with time, sometimes accompanied by a deceleration or plateau at later ages. Although the changes that underlie aging are complex, it is characterized by the gradual accumulation of a wide variety of molecular and cellular damage throughout the lifespan. The nine proposed hallmarks of aging in mammals are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. However, the connections between these hallmarks, their contributions to aging, and their links with frailty and disease remain incompletely understood. In fact, uncovering the biological basis of aging is one of the greatest contemporary challenges in science.

Interestingly, epigenetics plays a crucial role in aging. While there are several different types of epigenetic mechanisms, protein posttranslational modifications (PTM) are intriguing contributors in regulating aging. Proteins are the basis of cellular and physiological functioning in living organisms, and the physical and chemical properties of proteins dictate their activities and functions. The primary sequence of a protein is a main determinant of protein folding and final conformation as well as biochemical activity, stability, and half-life. However, at any given moment in the life of an individual, its proteome is up to two or three orders of magnitude more complex than the encoding genomes would predict. One of the main routes of proteome expansion is through posttranslational modifications (PTM) of proteins.

Protein PTM results from enzymatic or nonenzymatic attachment of specific chemical groups to amino acid side chains. Such modifications occur either following protein translation or concomitant with translation. PTM influences both protein structure and physiological and cellular functions. Examples of enzymatic PTMs include phosphorylation, glycosylation, acetylation, methylation, sumoylation, palmitoylation, biotinylation, ubiquitination, nitration, chlorination, and oxidation/reduction. Nonenzymatic PTMs include glycation, nitrosylation, oxidation/reduction, acetylation, and succination. Some rare and unconventional PTMs, such as glypiation, neddylation, siderophorylation, AMPylation, and cholesteroylation, are also known to influence protein structure and function.

Generally, protein PTMs occur as a result of either modifying enzymes related to posttranslational processing (such as glycosylation) or signaling pathway activation (such as phosphorylation). Moreover, PTM patterns are known to be affected by disease conditions. Similarly, the dysregulation of PTM is associated with the aging process. In this context, both enzymatic and nonenzymatic PTMs can undergo age-related alterations. Alteration in the pattern of nonenzymatic PTMs depends mainly on the nature of the modifying substances, such as metabolites and free radicals. For instance, reactive oxygen species can lead to oxidation of amino acid side chains (oxidation of thiols to different forms, oxidation of methionine, formation of carbonyl groups, etc.), modification by-products of glycoxidation and lipoxidation, and formation of protein-protein cross-links as well as oxidation of the protein backbone, resulting in protein fragmentation. In contrast, changes in the nature of enzymatic PTMs rely primarily on the activities of modifying enzymes.

As awareness of the role of PTMs in aging and aging-related diseases grows, there is an urgent need for the development of methods to detect protein PTMs more rapidly and accurately. Furthermore, the recent finding of rare and unconventional modifications in age-related pathologies calls for the development of more specific and sensitive methods to detect such modifications. The recent rapid progress in large-scale genomics and proteomics technologies is likely to be a catalyzing factor for such studies. Drugs that target PTMs, such as phosphorylation, acetylation, methylation, and ubiquitination, will serve as useful tools in exploring the basic mechanism of PTM modulation and provide a pharmacological platform to combat the detrimental effects of aging.

Link: https://doi.org/10.1155/2017/5716409

If you spend much time scanning through papers of interest to the field of aging research, one of the things that may strike you about the past few years of work on senescent cells is the way in which it dovetails so well with past research of all sorts. A great deal of life science work in many parts of the broader field makes a whole lot more sense given the context of senescent cell accumulation as both (a) an important contributing cause of aging, and (b) an important source of chronic inflammation.

Yet this context wasn't missing a decade go or more - there was more than enough evidence to place senescent cell clearance into the first SENS rejuvenation research proposals, for example. It was there for anyone to recognize. But it wasn't given the weight it deserved, and too many researchers let the biochemistry of cellular senescence fade into the background, failing to consider it as a matter of importance for the mechanisms they happened to be focused upon. This is a problem, because, put simply, any condition or change in aging with a strong inflammatory component is fundamentally linked to cellular senescence. It cannot be ignored.

The paper noted here is a good example of this snug fit between older research and modern, more widespread realizations of the importance of cellular senescence. Researchers have long investigated links between cancer cells, inflammation, and platelet regulation. Platelets are a form of small cell-like structure that are primarily responsible for clotting as a way to control bleeding. They are manufactured by a fascinating process of shedding from cells known as megakaryocytes. But in this context, you might think of platelets as an abstract bundle of mechanisms by which cells can amplify inflammatory signaling to generate much larger effects on surrounding tissues and bodily systems, though that is perhaps an oversimplification.

Like all systems in cellular metabolism, the behavior of platelets runs awry in older people. Blood clotting can run amok or proceed incorrectly and fail to resolve. It turns out that the inflammatory signals from tumor cells and their relationship with platelets, categorized by interested cancer researchers over the years without giving all that much thought to cellular senescence, are probably very relevant to the activities of senescent cells as well. Senescent cells are the missing third leg for the stool portrayed in this picture, and platelets may be an important part of the bigger picture for cellular senescence and cancer risk in aging.

The Potential Role of Senescence as a Modulator of Platelets and Tumorigenesis

The functional connection between cancer and platelets has been recognized since the late nineteenth century, when an association between the occurrence of certain solid tumors and the development of venous thrombosis and blood hypercoagulability was first described. Accordingly, defects in platelet function or reduced platelet counts have both been associated with a reduced ability of tumors to metastasize. We now know that platelets may contribute to the establishment of various hallmarks of cancer, including the ability of cancer cells to sustain proliferation, to resist apoptosis and to promote angiogenesis and metastasis. It is presently unclear, however, to what extent these contributions are the result of a direct action of platelets on tumor cells or, alternatively, may be part of an underlying inflammatory process inherent to many tumors. Inflammatory cells and soluble mediators of inflammation are important constituents of the tumor microenvironment.

Typical hallmarks of physiological aging include impaired tissue regeneration and repair, a functional impairment of progenitor cellsalterations of the immune system. While the specific cellular changes associated with each one of these hallmarks will vary depending on the tissue analyzed, cellular senescence is rapidly emerging as an underlying process that may help explain some of these changes. In keeping with this idea, senescent cells accumulate in several tissues derived from aged animals. In addition to cell cycle arrest, the establishment of a mature senescent phenotype involves extensive metabolic reprograming, as well as the implementation of complex traits such as the senescence-associated secretory phenotype (SASP). The SASP refers to the almost universal capacity of senescent cells to produce and secrete a variety of soluble and insoluble factors, including extracellular proteases, cytokines, chemokines, and growth factors.

A common feature of aging and age-related diseases is chronic inflammation. The term "inflammaging" has been coined to describe a low-grade, chronic, and systemic inflammation associated with aging and aging phenotypes in the absence of evidence of infection. In line with this concept, many of the factors secreted by senescent cells are also well-known pro-inflammatory molecules with the potential to induce chronic inflammation in certain biological contexts. More recently, a unique type of inflammation triggered by senescent cells, the senescence-inflammatory response, has been identified.

Based on the emerging physiological and pathological processes in which the SASP might be involved, it is conceivable that senescent cells may also affect hemostasis through mechanisms that include, but are not limited to, changes in the production and functional status of platelets. As mentioned elsewhere in this review, IL-6 is one of the most prominent pro-inflammatory cytokines present in the SASP. Moreover, IL-6 upregulates the synthesis of hemostatic factors, such as fibrinogen, and may also directly activate platelets.

Thus, it is tempting to speculate that the high levels of IL-6 (and other pro-inflammatory factors, such as IL-1β and TNF-α) detected in aged individuals could reflect, at least in part, an increased rate of secretion of this cytokine by senescent cells - or by other cells responding to senescent cells - in the context of a senescence-induced chronic inflammation. An age-dependent increase of pro-inflammatory factors would, in turn, contribute to platelet activation and a higher proclivity to thrombus formation. Therefore, we postulate that cellular senescence (as a result of physiological aging or secondary to therapeutic stress) might play an important role in the regulation of platelet function. By regulating the activation of platelets, senescent cells could provide yet another mechanism contributing to the higher prevalence of chronic inflammation (and cancer) in aged individuals.

The functional interaction between cancer cells and platelets has been well established. Most of the efforts aimed to clarify these interactions have been focused on the ability of tumor cells (or tumor-associated stromal cells) to produce and secrete pro-inflammatory factors that can result in the activation of platelets. Active platelets - acting synergistically with other components of the tumor stroma - can then promote or enhance tumor progression and metastasis. Paradoxically, many of the factors secreted by tumor cells or tumor-associated inflammatory cells with a known effect on platelet activity are also produced and secreted by cells undergoing senescence, a process originally regarded as tumor suppressive. Indeed, the evidence indicates that cellular senescence may also play an active role in driving, rather than suppressing, tumor formation, a non-cell autonomous role that seems to be largely dependent on the SASP. Accordingly, factors released by senescent cells may help create a pro-tumorigenic microenvironment that enhances proliferation and migration of neighbor cells. Although still controversial, this model would be in line with the observation that the prevalence of most cancers increases with age.

Alterations in hemostasis involving platelet dysfunction or alterations in the process of fibrinolysis are at the core of thrombogenesis. As with cancer, thrombogenesis is most commonly observed in older individuals, who presumably harbor a higher proportion of senescent cells in their tissues. We, therefore, postulate that cellular senescence, either as a result of normal aging or secondary to stress, could play an important role in the regulation of platelet function. According to this model, senescent cells have the ability to modify the microenvironment in ways that may enhance tumorigenesis. Similarly, senescent cells might also regulate the activity of platelets, the process of fibrinolysis, or both. By regulating the activation of platelets, senescent cells may provide yet another mechanism to enhance tumorigenesis. Whether or not these circuits are relevant to tumorigenesis and/or thrombogenesis remains to be fully elucidated.

Join the circulatory systems of two mice, one young and one old, a procedure known as heterochronic parabiosis, and the young one suffers some of the impact of aging while the old one loses some of that same impact. Regenerative capacity and stem cell activity are affected, for example. Researchers continue to search for factors in the blood that might explain this, but this work is still in its comparatively early stages. The question of the degree to which the mechanisms involve beneficial factors in young blood or harmful factors in old blood remains to be settled, with a range of interesting evidence on both sides. The "bad old blood" view seems to have the more compelling demonstration so far, I feel. If this is the case, benefits in the old mice are realized because the harmful factors in old blood are diluted by young blood, not because the young blood is providing beneficial signals.

Aging is a gradual biological process characterized by a decrease in cell and organism functions. Gingival wound healing is one of the impaired processes found in old rats. Here, we studied the in vivo wound healing process using a gingival repair rat model and an in vitro model using human gingival fibroblasts for cellular responses associated to wound healing. To do that, we evaluated cell proliferation of both epithelial and connective tissue cells in gingival wounds and found decreased of Ki67 nuclear staining in old rats when compared to their young counterparts.

We next evaluated cellular responses of primary gingival fibroblast obtained from young subjects in the presence of human blood serum of individuals of different ages. Eighteen to sixty five years old masculine donors were classified into 3 groups: "young" from 18 to 22 years old, "middle-aged" from 30 to 48 years old and "aged" over 50 years old. Cell proliferation, measured through immunofluorescence for Ki67 and flow cytometry for DNA content, was decreased when middle-aged and aged serum was added to gingival fibroblasts compared to young serum. Myofibroblastic differentiation, measured through alpha-smooth muscle actin (α-SMA), was stimulated with young but not middle-aged or aged serum both the protein levels and incorporation of α-SMA into actin stress fibers. High levels of PDGF, VEGF, IL-6R were detected in blood serum from young subjects when compared to middle-aged and aged donors. In addition, the pro-inflammatory cytokines MCP-1 and TNF were increased in the serum of aged donors.

In wounds in old rats there is an increased of staining for TNF compared to young rat wounds. Moreover, healthy gingiva (non injury) shows less staining compared to a wound site, suggesting a role in wound healing. Moreover, serum from middle-aged and aged donors was able to stimulate cellular senescence in young cells as determined by the expression of senescence associated beta-galactosidase and histone H2A.X phosphorylated at Ser139. Further, we detected an increased frequency of γ-H2A.X-positive cells in aged rat gingival tissues. The present study suggests that serum factors present in middle-aged and aged individuals may be responsible, at least in part, for the altered responses observed during wound healing in aging.

Link: https://doi.org/10.1371/journal.pone.0184189

The results noted here are unsurprising, a confirmation of what was expected by most in the field. The practice of calorie restriction has been shown to extend healthy life span and slow near all measures of aging in a range of species. Now that the research community has established a number of epigenetic clocks, characteristic patterns of DNA methylation that change in fairly predictable ways over the course of aging, it was only a matter of time before those too were shown to be slowed by calorie restriction. If, as is the consensus, calorie restriction does in fact slow the causes of aging, and slow aging as a process overall, then it should also slow all consequent measures of aging.

Where these publicity materials run awry is to paint epigenetic changes as a cause of aging. There is certainly a faction in the research community whose members consider aging to be a selected, evolved program, and place epigenetic changes as a root cause of aging. However I think they continue to have an uphill struggle to try to prove that case in the face of the overwhelming evidence for aging to be caused by accumulations of molecular damage, with epigenetic changes a downstream consequence of that damage: cells reacting to increased damage in the surrounding environment and themselves. The complexity of cellular biochemistry in a living individual means that this debate is unlikely be resolved through inspection before it is resolved by observing the results of different approaches to rejuvenation therapies. For example, clearance of senescent cells is a form of damage repair that extends life in mice: if that also turns back epigenetic changes of aging, something that has yet to be established in a published paper, then this would be strong evidence against epigenetic change as a cause of aging.

New research is the first to show that the speed at which the epigenome changes with age is associated with lifespan across species and that calorie restriction slows this process of change, potentially explaining its effects on longevity. "Our study shows that epigenetic drift, which is characterized by gains and losses in DNA methylation in the genome over time, occurs more rapidly in mice than in monkeys and more rapidly in monkeys than in humans." The findings help to explain why mice live only about two to three years on average, rhesus monkeys about 25 years, and humans 70 or 80 years.

Chemical modifications such as DNA methylation control mammalian genes, serving as bookmarks for when a gene should be used - a phenomenon known as epigenetics. Previous studies had shown that these changes occur with age, but whether they were also related to lifespan was unknown. The researchers made their discovery after first examining methylation patterns on DNA in blood collected from individuals of different ages for each of three species - mouse, monkey, and human. Mice ranged in age from a few months to almost three years, monkeys from less than one year to 30 years, and humans from age zero to 86 years (cord blood was used to represent age zero). Age-related variations in DNA methylation were analyzed by deep sequencing technology, which revealed distinct patterns, with gains in methylation in older individuals occurring at genomic sites that were unmethylated in young individuals, and vice versa.

In subsequent analyses, striking losses in gene expression were observed in genomic regions that had become increasingly methylated with age, whereas regions that had become less methylated showed increases in gene expression. Investigation of a subset of genes affected by age-related changes in methylation revealed an inverse relationship between methylation drift and longevity. In other words, the greater the amount of epigenetic change - and the more quickly it occurred - the shorter the species' lifespan.

One of the strongest factors known to increase lifespan in animals is calorie restriction, in which calories in the diet are reduced while still maintaining intake of essential nutrients. To examine its effects, the researchers cut calorie intake by 40 percent in young mice and by 30 percent in middle-aged monkeys. In both species, significant reductions in epigenetic drift were observed, such that age-related changes in methylation in old animals on the calorie-restricted diets were comparable to those of young animals. With the latest findings, the researchers were able to propose a new mechanism - the slowing of epigenetic drift - to explain how calorie restriction prolongs life in animals. "The impacts of calorie restriction on lifespan have been known for decades, but thanks to modern quantitative techniques, we are able to show for the first time a striking slowing down of epigenetic drift as lifespan increases."

Link: https://www.eurekalert.org/pub_releases/2017-09/tuhs-tru091317.php

Therapies such as statins, that aim to reduce circulating levels of low-density lipoprotein (LDL) cholesterol, are perhaps the most prevalent medical approach to cardiovascular disease. Indeed, when measured against the low bar set for past attempts to treat age-related conditions, they are one of the most successful forms of treatment to date. A sizable fraction of the reduction in cardiovascular mortality over the past few decades is attributed to the widespread use of statins and similar treatments. Still, this is only a delaying action, it is not a fix for the underlying problems.

How do reductions in LDL cholesterol slow the consequences of cardiovascular aging? The processes of interest involve damaged cholesterol molecules and cellular reactions to their presence. As the various causes of aging progress, there is ever greater inflammation and oxidative stress to produce damaged, oxidized cholesterols that find their way into the bloodstream. Once there, this mix of damaged molecules irritates blood vessel walls. In most cases unwanted metabolic waste of this sort is promptly cleaned up, consumed by the immune cells called macrophages, and disposed of. In some cases, however, there is an overreaction, or macrophages become overwhelmed by the damaged forms of cholesterol. A feedback loop is created in which the blood vessel wall becomes inflammatory, drawing in ever more macrophages that become dysfunction and die to add their mass to the creation of the characteristic fatty lesions of atherosclerosis. These masses narrow blood vessels and disrupt the structure of the blood vessel wall. They reduce critical blood flow, and eventually, as blood pressure rises due to other age-related issues, these fatty plaques rupture to kill or seriously injure the individual.

All of this can be slowed by interfering in any of the critical steps, even without preventing the underlying causes. It can't be reversed without forms of repair, however. So researchers could aim to make macrophages more resilient, could reduce the flux of damaged cholesterol by reducing the overall level of cholesterol, could dampen inflammation by attempting to adjust the regulation of the immune system, and so forth. All of these will slow down atherosclerosis to the degree that any particular implementation can produce change. But to turn it back, themedical community would need means of safely breaking down the problem compounds that irritate blood vessels and kill macrophages. Researchers associated with the SENS Research Foundation have investigated this class of treatment over the years, as their budget has permitted, and made some progress in targeting the problem compound of 7-ketocholesterol via adaptation of baterial enzymes.

Just how low can LDL cholesterol go, however? If less is consistently better, because it slows down atherosclerosis, does less ever stop being better? At some point, one has to presume that running out of LDL cholesterol has to be a bad thing, or else we wouldn't evolved to have it to begin with. With the advent of new and far more effective approaches such as PCSK9 inhibitors, a considerably more powerful intervention than statins, it is possible to reduce cholesterol levels to a fraction of what they would otherwise be. Normal healthy adults have LDL cholesterol measures somewhere below 100 mg/dL. The most severely impacted older people can be nearing or passing 200 mg/dL. The latest therapies can push LDL cholesterol in older people down below 10 mg/dL, far beneath that of normal, young, healthy individuals. The evidence suggests that this is beneficial, and for exactly the same reasons that smaller reductions are beneficial: it reduces the pace at which atherosclerosis progresses. This leads to a number of questions that researchers seem generally unwilling to state in print at this point in time, such as whether or not all adults should be lowering cholesterol throughout their lives, or whether to focus on gene therapies that can achieve this effect across the entire life span without the need for drugs.

How Low Should LDL Cholesterol Go?

A newer class of cholesterol lowering drugs known as PCSK9 inhibitors has emerged as an effective treatment for drastically lowering LDL cholesterol beyond current treatment targets. In a new analysis, researchers sought to explore whether there was "floor effect" in the lowering of LDL cholesterol - essentially, is there a threshold below which there would be no added clinical benefit? Additionally, researchers explored whether ultra-low LDL cholesterol levels would have any negative impact.

Using data from the FOURIER trial (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk), which found that patients treated with the PCSK9 inhibitor evolocumab and statin therapy had a 20 percent reduction in the risk of cardiovascular death, myocardial infarction, or stroke, researchers examined the efficacy and safety of very low levels of LDL cholesterol among 25,982 patients per the degree of LDL-C reduction following one month of treatment. Researchers found that the risk for cardiovascular events (including cardiovascular death, heart attack, and stroke) over 2.2 years progressively declined as LDL cholesterol levels decreased to below 20 mg/dL (0.5 mmol/L), and participants who achieved an LDL-C of less than 10 mg/dL (0.26 mmol/L) had a more than 40 percent lower risk of cardiovascular events than those with an LDL cholesterol equal to or greater than 100 mg/dL (2.6 mmol/L).

"Our findings demonstrate that there is essentially no floor effect, and that lower levels translated to a greater reduction in risk. Among high-risk patients, achieving a LDL cholesterol level far below the most common treatment target of 70 mg/dL (1.8 mmol/L) can further reduce the risk for an adverse cardiovascular event, with no major safety concerns."

Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial

27,564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25,982 patients (94% of those randomly assigned) 13,013 were assigned evolocumab and 12,969 were assigned placebo. 2,669 (10%) of 25,982 patients achieved LDL-cholesterol concentrations of less than 0.5 mmol/L, 8,003 (31%) patients achieved concentrations between 0.5 and less than 1.3 mmol/L, 3,444 (13%) patients achieved concentrations between 1.3 and less than 1.8 mmol/L, 7471 (29%) patients achieved concentrations between 1.8 to less than 2.6 mmol/L, and 4,395 (17%) patients achieved concentrations of 2.6 mmol/L or higher.

There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0.2 mmol/L). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations.

This is an interesting experiment, though note that the DOI link goes straight to a PDF at the time of writing. It is carried out in cell culture, so don't take the results too seriously: they would have to be replicated in at least an organoid tissue structure that better matched natural brain tissue. Nonetheless, the researchers show that brain cells in this more artificial environment are capable of recovering from some of the damage done by the presence of amyloid-β, the protein aggregate associated with Alzheimer's disease. The present consensus is that it isn't the amyloid itself that causes the harm, but rather the surrounding halo of related proteins and fragments. Still, get rid of the amyloid, and that halo vanishes as well.

Patients with Alzheimer's disease (AD) chiefly suffer from impairment of memory and other cognitive functions. AD is neuropathologically characterized by senile plaques and neurofibrillary tangles, which are composed of amyloid β-protein (Aβ) and phosphorylated tau proteins, respectively. Recently, a new concept has emerged: that soluble oligomeric forms of Aβ (Aβ oligomers), but not Aβ fibrils, play a primary pathogenic role in the pathological cascade of AD. This idea is based on findings that soluble forms of Aβ provoke neurotoxic effects, including tau abnormalities (especially hyperphosphorylation), functional and structural abnormalities of synapses, and induction of neuronal death. This concept is supported by numerous studies that have employed a variety of experimental systems, including cell culture, brain slices, and animal models, as well as the fact that Aβ oligomers are abundant in post-mortem AD brains. Thus, oligomeric Aβ is considered a major culprit in the molecular pathology of AD.

To investigate the pathological roles of Aβ oligomers, we have established a neuron culture model system, in which rat primary neurons are exposed to relatively low concentrations of Aβ42 oligomers (Aβ-O) for relatively long periods (2-3 days). We observed that Aβ-O induces neurotoxic insults with limited cell death under these conditions. Because these changes are reflective of characteristic pathological features of AD, this neuron model is considered a useful system for investigating the neurotoxic mechanisms triggered by Aβ oligomers.

We were interested in the question of whether the neurotoxicity of Aβ oligomers is reversible and abates upon their removal, an issue that has remained largely unexplored. To investigate this possibility, we designed the following experimental paradigm: Rat primary cultured neurons were treated with Aβ-O for 2 days, at which point cells were deprived of Aβ-O by replacing the medium with fresh medium lacking Aβ-O, or were re-provided Aβ-O and cultured for an additional 2 days; untreated neurons were used as controls. Neurons continuously treated with Aβ-O showed greater activation of caspase-3 and eIF2α, and exhibited persistent, abnormal alterations of tau and β-catenin. In contrast, upon Aβ deprivation, caspase-3 and eIF2α activation were considerably attenuated, aberrant phosphorylation and caspase-mediated cleavage of tau recovered for the most part, and abnormal alterations of β-catenin were partially reversed.

These results indicate that removal of extracellular Aβ-O can fully or partially reverse Aβ-O-induced neurotoxic and synaptotoxic alterations in our neuron model. Our findings suggest that Aβ oligomer-associated neurotoxicity is a reversible process in that neurons are capable of recovering from moderate neurotoxic insults. These data also support the idea that Aβ oligomers act on the cell surface of neurons to transmit aberrant signals, resulting in various abnormal cellular responses; upon Aβ oligomer removal, the aberrant signals subside, resulting in reversal of all abnormal responses.

Link: https://doi.org/10.18632/oncotarget.19083

The evidence has been in place for some years to show that low calorie diets can reverse type 2 diabetes even in comparatively late stages. For the vast majority of patients, this is a disease of choice: they chose to become fat enough to suffer sufficient metabolic disruption to produce the condition, as well as to accelerate the aging process, and they choose to remain fat enough to maintain this level of damage. Yes, eating less and exercising more is harder than it used to be, in this environment of low-cost calories, comfort, and convenience, but "harder" is not "I have no choice in this."

A body of research putting people with type 2 diabetes on a low calorie diet has confirmed the underlying causes of the condition and established that it is reversible. Research has revealed that for people with type 2 diabetes: (a) excess calories leads to excess fat in the liver; (b) as a result, the liver responds poorly to insulin and produces too much glucose; (c) excess fat in the liver is passed on to the pancreas, causing the insulin producing cells to fail; (d) losing less than 1 gram of fat from the pancreas through diet can re-start the normal production of insulin, reversing type 2 diabetes; (e) this reversal of diabetes remains possible for at least 10 years after the onset of the condition.

"I think the real importance of this work is for the patients themselves. Many have described to me how embarking on the low calorie diet has been the only option to prevent what they thought - or had been told - was an inevitable decline into further medication and further ill health because of their diabetes. By studying the underlying mechanisms we have been able to demonstrate the simplicity of type 2 diabetes." A body of research now confirms the Twin Cycle Hypothesis - that Type 2 diabetes is caused by excess fat actually within both liver and pancreas. This causes the liver to respond poorly to insulin. As insulin controls the normal process of making glucose, the liver then produces too much glucose. Simultaneously, excess fat in the liver increases the normal process of export of fat to all tissues. In the pancreas, this excess fat causes the insulin producing cells to fail.

The Counterpoint study, which was published in 2011, confirmed that if excess food intake was sharply decreased through a very low calorie diet, all these abnormal factors would be reversed. The study showed a profound fall in liver fat content resulting in normalisation of hepatic insulin sensitivity within 7 days of starting a very low calorie diet in people with type 2 diabetes. Fasting plasma glucose became normal in 7 days. Over 8 weeks, the raised pancreas fat content fell and normal first phase insulin secretion became re-established, with normal plasma glucose control. "The good news for people with Type 2 diabetes is that our work shows that even if you have had the condition for 10 years, you are likely to be able to reverse it by moving that all-important tiny amount of fat out of the pancreas. At present, this can only be done through substantial weight loss." The Counterbalance study published in 2016, demonstrated that type 2 diabetes remains reversible for up to 10 years in most people, and also that the normal metabolism persists long term, as long as the person doesn't regain the weight.

Link: http://www.ncl.ac.uk/press/news/2017/09/type2diabetesisreversible/

In the past few years, a number of epidemiological studies have suggested a correlation between more time spent sitting and a greater risk of mortality and age-related disease. Intriguingly, the claim is that this correlation persists even in people who do in fact exercise sufficiently. This should be considered in the context that statistical studies of human health and activities are notoriously challenging, given the degree to which data must be massaged into shape. Seemingly small differences in choice of metric can produce opposing outcomes: for example, differences in assessing the trajectory of weight over a lifetime, as well as whether to measure body mass index or waist circumference, have at times in the recent past produced quite distorted views of the degree to which excess fat tissue is harmful.

So the matter is far from settled as to whether lengthy periods of sedentary behavior - such as sitting - are a cause of harm even in people who meet guidelines for activity and exercise. There is no good mechanism, beyond that this might reflect an association with any number of other behaviors or conditions or choices or states of life that are themselves correlated with shorter life expectancy. Sitting time correlates with vascular calcification, for example, but that doesn't say anything about why this might be the case in people who do exercise in between their seated periods. The most obvious suggestion is that this is a question of overall activity levels in life, and length of time spent sitting is just a good proxy for overall activity levels. If the past fifty years are any guide, researchers will keep turning out this sort of study to argue subtle points of statistical interpretation well into the era of functional rejuvenation therapies - by which point the whole exercise becomes somewhat irrelevant.

Long Sitting Periods May Be Just as Harmful as Daily Total

A new study finds that it isn't just the amount of time spent sitting, but also the way in which sitting time is accumulated during the day that can affect risk of early death. Adults who sit for one to two hours at a time without moving have a higher mortality rate than adults who accrue the same amount of sedentary time in shorter bouts. "We tend to think of sedentary behavior as just the sheer volume of how much we sit around each day. But previous studies have suggested that sedentary patterns - whether an individual accrues sedentary time through several short stretches or fewer long stretches of time - may have an impact on health."

The researchers used hip-mounted activity monitors to objectively measure inactivity during waking time over a period of seven days in 7,985 black and white adults over age 45. (The participants were taking part in the REGARDS study, a national investigation of racial and regional disparities in stroke.) On average, sedentary behavior accounted for 77 percent of the participants' waking hours, equivalent to more than 12 hours per day. Over a median follow-up period of four years, 340 of the participants died. Mortality risk was calculated for those with various amounts of total sedentary time and various sedentary patterns. Those with the greatest amount of sedentary time - more than 13 hours per day - and who frequently had sedentary bouts of at least 60 to 90 consecutive minutes had a nearly two-fold increase in death risk compared with those who had the least total sedentary time and the shortest sedentary bouts.

Patterns of Sedentary Behavior and Mortality in U.S. Middle-Aged and Older Adults: A National Cohort Study

Excessive sedentary time is ubiquitous in Western societies. Previous studies have relied on self-reporting to evaluate the total volume of sedentary time as a prognostic risk factor for mortality and have not examined whether the manner in which sedentary time is accrued (in short or long bouts) carries prognostic relevance. Sedentary time was measured using a hip-mounted accelerometer. Prolonged, uninterrupted sedentariness was expressed as mean sedentary bout length. Hazard ratios (HRs) were calculated comparing quartiles 2 through 4 to quartile 1 for each exposure (quartile cut points: 689.7, 746.5, and 799.4 min/d for total sedentary time; 7.7, 9.6, and 12.4 min/bout for sedentary bout duration) in models that included moderate to vigorous physical activity.

Over a median follow-up of 4.0 years, 340 participants died. In multivariable-adjusted models, greater total sedentary time (HR, 1.22; HR, 1.61; and HR, 2.63) and longer sedentary bout duration (HR, 1.03; HR, 1.22; and HR, 1.96) were both associated with a higher risk for all-cause mortality. Evaluation of their joint association showed that participants classified as high for both sedentary characteristics (high sedentary time [≥12.5 h/d] and high bout duration [≥10 min/bout]) had the greatest risk for death.

These findings highlight the importance of the total volume of sedentary time and its accumulation in prolonged bouts as important health risk behaviors. Meta-analyses have shown that total sedentary time is associated with cardiovascular disease and mortality, independent of moderate physical exercise. However, these findings are largely based on self-reported sedentary time, data that may underestimate the magnitude of the relationship between sedentariness and health risk. Use of accelerometers reduces potential biases and measurement error inherent in self-reported data. To our knowledge, this is the largest study to date with objective measures of sedentary behavior and prospective health outcomes. The magnitude of the association between total sedentary time and all-cause mortality (2.6-fold greater risk for quartile 4 vs. quartile 1) is notably higher than that reported in meta-analyses (HR 1.22).

A key finding of our study, which we believe is the first to report, is that patterns of sedentary time accumulation are associated with mortality. Previous cross-sectional studies have reported associations between the total number of breaks in sedentary time per day (the reciprocal to mean sedentary bout length) and cardiometabolic biomarkers. These findings led to the "prolonger" versus "breaker" hypothesis, which postulates that it is not only the amount of sedentary time that is important to cardiometabolic health, but also the manner in which it is accumulated.

Areas of China can act as a laboratory for the impact of particulate air pollution on long-term health. There are good reasons to think that the established correlations between air pollution and life expectancy are due to physical and biochemical mechanisms such as increased chronic inflammation. It has been equally possible to argue that that the relationship has more to do with relative wealth of populations, however, as wealthier regions tend to have lower levels of pollution. In this study, researchers put some numbers to the correlation, and improve on previous attempts to rule out wealth and other effects as significant contributing causes.

A study finds that a Chinese policy is unintentionally causing people in northern China to live 3.1 years less than people in the south, due to air pollution concentrations that are 46 percent higher. These findings imply that every additional 10 micrograms per cubic meter of particulate matter pollution reduces life expectancy by 0.6 years. The elevated mortality is entirely due to an increase in cardiorespiratory deaths, indicating that air pollution is the cause of reduced life expectancies to the north. "These results greatly strengthen the case that long-term exposure to particulates air pollution causes substantial reductions in life expectancy."

The study exploits China's Huai River policy, which provided free coal to power boilers for winter heating to people living north of the river and provided almost no resources toward heating south of the river. The policy's partial provision of heating was implemented because China did not have enough resources to provide free coal nationwide. Additionally, since migration was greatly restricted, people exposed to pollution were generally not able to migrate to less polluted areas. Together, the discrete change in policy at the river's edge and the migration restrictions provide the basis for a powerful natural experiment that offers an opportunity to isolate the impact of sustained exposure to particulates air pollution from other factors that affect health.

Overall, the study provides solutions to several challenges that have plagued previous research. In particular, prior studies rely on research designs that may be unlikely to isolate the causal effects of air pollution; measure the effect of pollution exposure for relatively short periods of time (e.g., weekly or annually), failing to shed light on the effect of sustained exposure; examine settings with much lower pollution concentrations than those currently faced by billions of people in countries, including China and India, leaving questions about their applicability unanswered; measure effects on mortality rates but leave the full loss of life expectancy unanswered.

The study follows on an earlier study, conducted by some of the same researchers, which also utilized the unique Huai River design. Despite using data from two separate time periods, both studies revealed the same basic relationship between pollution and life expectancy. However, the new study's more recent data covers a population eight times greater than the previous one. It also provides direct evidence on smaller pollution particles that are more often the subject of environmental regulations.

Link: https://news.uchicago.edu/article/2017/09/11/air-pollution-cuts-three-years-lifespans-northern-china

Some of you may remember Betterhumans as one of a number of transhumanist community websites from years back, providing news and advocacy in service of efforts to improve the human condition. Extending healthy lifespan by engineering practical rejuvenation therapies has always been a core transhumanist goal. In one of the more interesting second acts in our community, the Betterhumans name is now hanging on the door of a medical research and development non-profit. This organization runs a supercentenarian study, and is now working on trials of senolytic therapies, starting with the dasatinib and quercetin combination that was first used in mice a few years ago. This is something that I would definitely like to see more of in our community. All of the pieces of the puzzle exist for people who want to work at assembling responsible, transparent, small human trials for the first candidate senolytic drugs. The drugs cost little, the animal studies are compelling, so why wait?

Betterhumans has a long history in the field of transhumanism. It was started as an educational website in mid-2001 and evolved to become a popular website presenting ideas and news about exponential technologies. It ceased operating as a website around late 2008, when h+ Magazine took over its functions. This new iteration of Betterhumans is the most aggressive yet. We will shortly be putting out new information about how ordinary people can modify their diet and lifestyle to take advantage of some of the latest findings in scientific research. Our research team is focused on bringing cutting-edge scientific discoveries from the lab to the clinic, so that humanity can take advantage of these breakthroughs in a safe and inexpensive manner, as quickly as possible.

Operating as a Florida non-profit corporation, the short-term goals of Betterhumans are extending healthy maximum human lifespan and greatly reducing the risk of disease. All discoveries will be offered under a Creative Commons Public Patent License, or equivalent. In 2015, Betterhumans received funding from the Methuselah Foundation to carry out stem cell research and gene-editing experiments, with the express intention of delaying aging and rejuvenating vital organs.

We intend to pursue many small scale human pilot studies to test the safety and efficacy of various FDA-approved drugs and therapies thought to have anti-aging effects. We will publish all results so that other researchers, physicians, and patients can have information which may aid their efforts. The question seeking to be answered by this Phase 0 pilot study is whether the senolytic compounds dasatinib and quercetin will significantly eliminate senescent cells contained in the muscle and fat tissue of elderly individuals who have metabolic syndrome and/or osteoarthritis, and will reduce levels of systemic inflammation, insulin resistance, improve their immunological responses, and in those having osteoarthritis, reverse the progression of this disease.

Link: http://www.betterhumans.org

Age-related diseases began as a matter of taxonomy. Presented with the immensely complex, mysterious, varied, and inscrutable happenings at the end of life, the first scientists, before science was even much defined, began by trying to categorize their observations. Categorization is the first step towards making sense out of the unknown. Some forms of decline are obviously similar. Some are much worse than others in characteristic ways. Common manifestations are bucketed and given names: dementia, apoplexy, dropsy. These named facets of aging then became diseases just about as soon as people started to think that they could be treated - rightly or wrongly, and largely wrongly. The slow carving away of slivers of the inscrutable core of aging, making them known, and attempting to treat them, naturally gave rise to the idea that there existed aging, and separately there existed diseases of aging, states that were somehow distinct.

This mistaken belief has persisted into our era, in which the classification of age-related disease has become highly formal, regulated, and detailed. Aging is still not considered a medical condition to be treated, though the battle to change this state of affairs is progressing, and it requires years to create a new formal definition of age-related disease. The mainstream still proceeds by carving diseases from the bulk of aging, one by one, just as soon as mechanisms are understood to the point at which forms of therapy can be proposed. Sarcopenia is one of the most recently named diseases of aging, and it is still undergoing formalization a decade after that process started. Without that formal, regulatory blessing, clinical development of therapies proceeds in only a limited fashion because it would be illegal to offer commercial therapies. There is so much inertia in this wasteful edifice of medical taxonomy that to break away to a better understanding and approach will require a major, long-running project of advocacy to reeducate the establishment.

There is such a thing as a wrong question: a question that arrives with a baggage of incorrect axioms, and to take it a face value is to be misdirected before even investigating a potential answer. To ask when the changes of aging become the pathology of disease is one such question. Yet that has been asked and answered for every formally defined age-related disease. It is built on a faulty view of aging, that the causative mechanisms of aging can be something other than pathological. But all aging is damage, even the damage that hasn't yet risen past minor inconvenience to the level of great pain, disability, and frailty. It is the same cell and tissue damage, and the current outcome is just a matter of degree. The most effective therapies will target that damage, but by drawing lines that don't exist between aging and disease, much of the research, medical, and regulatory communities have sabotaged and continue to sabotage their efforts to make a difference.

This paper is one example among many of researchers engaging with this model of thinking. It leads only to confusion - the inevitable destination for any attempt to split causation in aging into pathology and not-pathology, to find a definite transition from something innocuous to the malign cause of a disease state. At root it is all pathology: metabolism produces damage, damage produces aging, and the causes of aging start just as soon as metabolism starts. After that it is all just a matter of how damaged an individual happens to be. The more damage, the greater the disability, the higher the mortality rate. It is one unified, complex process, driven by the comparatively simple injection of molecular damage. Treating aging effectively can be as straightforward as working to address and reverse the damage, at any stage, however much of it there might be. The earlier the better.

Vascular aging and subclinical atherosclerosis: why such a "never ending" and challenging story in cardiology?

The true onset of atherosclerosis remains one of the biggest challenges for cardiologists. Is atheroma plaque development considered the earliest step of vascular aging? If so, when does it start? Before or after birth? If it starts before birth or early during childhood, it seems that Thomas Sydenham was right: "A man is as old as his arteries." Except disorganization of elastic fibers, less is known about the morphology of vascular aging and also about the molecular events influencing the age of arteries, arterial stiffness, and their role in the appearance of future complications. Cellular and molecular events responsible for the switch from physiologic to pathologic aging of human arteries are less known.

Vascular aging is described as a gradual process involving biochemical, enzymatic, and cellular events in vascular area combined with epigenetic and molecular alterations, and it is considered that arterial aging is a fundamental reflection of biological aging in general and a determinant of organ function. In the arterial wall, this is characterized by a decrease of elastin content, as well as by the production and accumulation of "bad" collagen and its cross-linkages, leading to increased arterial stiffness and elevated central blood pressure as well as brachial blood pressure, accompanied by increased variability in systolic blood pressure (SBP). A better understanding of these processes has led to the proposal of a condition named early vascular aging (EVA) in patients with increased arterial stiffness for their age and sex. This is a condition that could increase cardiovascular risk, and it is associated with various degrees of cognitive dysfunction, as well as other features of biological aging.

It is considered that vascular aging is found from several and sequential alterations that lead to the replacement of elastin fibers with collagen fibers in the vessel wall, which forms a less elastic structure due to the collagen bridges that prevent their elongation. This is the so-called physiological arterial stiffness. In time, there may be a pathological aging, consisting of various types of plaque deposition. There is no well-defined criteria that characterize EVA in this moment. What seems to be "early" for clinicians may be "too late" stages of vascular aging for vessel wall and also for the patient. "Early" microscopic changes in the structure of the arterial wall do not overlap with "early" vascular aging definition and assessment at all!

Data regarding the assessment of early steps of aortic wall changes and atheroma plaque formation are scattered for prenatal period, childhood, and teenage years. It is suggested that EVA starts in fetal life as stated by a few papers reporting perinatal atherosclerotic lesions in the fetal coronary arteries of babies of mothers who are smokers or by data suggesting the involvement of telomere length influencing arterial function and aging properties which could be programmed during fetal life or influenced by adverse growth patterns in early postnatal life.

The mechanism of vascular aging is associated with changes in the mechanical and structural properties of the arterial wall. These changes lead to the loss of arterial elasticity and reduced compliance because of the changes in the ratio between elastin and collagen fibers. Over time, destruction of elastin fibers with linear parallel structure takes place, due to the so-called fatigue phenomenon of the elastin. This leads to the breaking and fragmentation of elastin fibers which are replaced in a higher ratio with collagen fibers, resulting in a structure with increased rigidity.

The beginning of elastic fiber loss or damage remains a questionable issue for cardiologists. Our preliminary data showed that disorganization of elastic fibers appears early in human fetal aorta and continues during postnatal life, being extended immediately after birth. The process is not homogeneous along all length of the fetal or neonatal aorta, being mostly and easily detected on aortic arch level in prenatal life and immediately after birth. In this context, a big challenge is launched: how and when to define EVA related to detected microscopic changes which, for sure, anticipate the beginning of clinical vascular aging. Due to these facts, arterial stiffness may be seen as a complication of true, microscopic EVA.

If we would abruptly make a conclusion of the present review, we should go back to Thomas Sydenham who stated that "A man is as old as his arteries." This is definitely true but, unfortunately, it does not help patients to decrease vascular aging and to improve their life quality. Recently, it was suggested that the dissociation between chronologic and biologic age of large arteries represents the main reason for the failure of proper definition of EVA which overlaps clinical signs and patient prognosis. There are few studies regarding the molecular mechanisms of EVA with emphasis to the activation of pro-fibrotic, pro-inflammatory, redox-sensitive, and growth/apoptotic signaling pathways, but most of these studies were developed in mice and not yet validated in human subjects.

It has been quite a number of years since researchers first produced dwarf mice with disabled growth hormone or growth hormone receptors, some of which still hold the record for engineered mouse longevity. Using these mice as a point of comparison to further map metabolism and aging continues to be an ongoing process, as illustrated by this open access paper. In it, the authors discuss the role of just one of many regulatory genes that might be important in many of the methods that have been used to slow aging in mice.

Cellular biochemistry is enormously complex, and thus so are the details of the changes that occur with aging, even though the underlying root causes are comparatively simple. As an analogy, consider what happens when a complicated metal assembly rusts into structural failure: rust is very simple, and that the assembly can ultimately fall apart in any one of many different ways is a function of the complexity of the structure, not of the rust. This is why attempting to slow aging by altering metabolism is so very hard and expensive, while attempting to reverse aging by repairing the root causes is comparatively straightforward and cost-effective. You can see that dynamic at work by comparing the little that has been achieved in twenty years of attempts to replicate the metabolic response to calorie restriction versus the solid progress achieved over the past five years of work on clearance of senescent cells. The latter has required a fraction of the cost and far fewer researchers than the former, while the results are already far more impressive.

Recent evidence for extragonadal actions of follicle-stimulating hormone (FSH), including effects on the function of both brown and white adipose tissue, raises the intriguing possibility that FSH may be involved in the control of aging. If confirmed, this novel action of FSH would enhance our understanding of mechanisms and trade-offs involved in the control of healthspan and longevity of homeothermic organisms. Follicle-stimulating hormone is produced by the anterior pituitary gland and acts as one of the master regulators of reproductive functions in both females and males.

Recent work indicates that FSH also acts within nonreproductive tissues, including bone. Researchers provided elegant evidence that FSH also influences adipose tissue functions; specifically, blocking FSH actions with a specific antibody stimulated thermogenesis in both brown and white adipose tissues (BAT and WAT), reduced adiposity, and increased bone mass in laboratory mice. These findings imply that the well-documented postmenopausal increase in FSH secretion is likely among the causes for increased adiposity, reduction in bone mass, and alterations in energy metabolism at this stage of life history. One could also suspect that the gradual age-related increase in FSH levels in men has similar consequences.

We suggest that the physiological changes resembling the benefits of blocking FSH action may also occur in response to a modest reduction in FSH levels in animals genetically predisposed to extreme longevity. This would imply that FSH may have a role in the control of aging. Our hypothesis that FSH may have a role in the control of aging stems from observations in two types of mice in which reduction in FSH levels, activation of BAT, browning of WAT, and increased energy expenditure are associated with major extensions of healthspan and longevity.

In Prop1df (Ames dwarf) mutants with a genetic defect in the differentiation of somatotroph, lactotroph, and thyrotroph cell lineages in the anterior pituitary, the expression of the FSH-β subunit gene, the pituitary FSH content, and the plasma FSH levels are significantly reduced. A similar reduction in plasma FSH levels occurs in both sexes of mice with deletion of the growth hormone receptor (GHR) gene (Laron dwarf). In both Prop1df and GHR-/- mice, BAT is enlarged and highly active, subcutaneous WAT exhibits characteristics of 'beiging' and metabolic rate is increased. Moreover, their respiratory exchange ratio is reduced, implying a shift in mitochondrial function toward greater utilization of fatty acids as metabolic fuel. Both Ames dwarf and GHR-/- mice are remarkably long-lived, with increases in longevity ranging from some 20% to over 60% depending on the diet, gender, and genetic background of the animal.

We have previously proposed that the activation of BAT and increased metabolic rate in these long-lived mice represent responses to increased radiational heat loss in these diminutive animal. However, results of GH replacement therapy in Prop1df mice indicate that their metabolic characteristics and extended longevity can be at least partially uncoupled from body size. Extrapolating from the recent findings noted above, we now hypothesize that reduced FSH levels in these animals may produce (or contribute to) their unique metabolic profile, and also likely to their extended longevity.

If confirmed, the effects of reduced FSH levels in these animals would represent a novel mechanism of trade-offs between their fertility and longevity. Both sexes of GHR-/- mice and male Ames dwarfs are fertile, but their sexual maturation is delayed and fecundity is reduced. Important trade-offs between reproduction and aging have been studied and discussed for decades, but our understanding of the underlying mechanisms is very limited, and in mammals, virtually nonexistent. Thus, combining the results of FSH blockage with the available information on endocrine and metabolic characteristics of two types of long-lived mice produces a novel mechanistic insight into the complex interaction of sexual maturation, reproductive effort, fecundity, aging, and lifespan.

Link: https://doi.org/10.1111/acel.12663

Growth in the number of senescent cells that linger in tissues is one of the root causes of aging. In this context, the open access paper noted here illustrates a couple of points that are worth bearing in mind while thinking about the biochemistry of aging, the first of which is that aging is a feedback loop of damage. Cell and tissue damage generates more cell and tissue damage, which is why aging accelerates as it progresses. The same rough structure of events is found in the age-related failure of any complex machinery.

The second point is that many of the mechanisms and relationships established in past research now make a lot more sense in the context of senescent cells as a driver of aging. The relationship partially outlined by the authors of this paper is an unusually compact feedback loop: senescent cells contribute to kidney dysfunction, for example through a disruption of normal tissue maintenance that produces fibrosis. Scar tissue forms in place of necessary small-scale structures, and in organs like the kidneys those structures are needed for normal function. Kidney dysfunction can in turn lead to stressful metabolic states such as hyperphosphatemia that encourage more cells to become senescent - and not just in the kidneys. It is a downward spiral, one repeated in many different ways through the aged body.

Hyperphosphatemia is a pathological condition related to chronic kidney disease (CKD) and more recently found on premature aging syndromes. High concentration of serum phosphate has profound effects on vascular cell behavior and on vascular function, and has been associated with cardiovascular disease in patients with CKD. Phosphate toxicity has been related with many other organ dysfunctions. However, less is known about the effect of hyperphosphatemia on vascular endothelial cells. A few works have described that a high extracellular phosphate level induces endothelial dysfunction via various mechanisms, including a decline in nitric oxide (NO) release due to oxidative stress.

Endothelium exerts multiple functions to preserve vascular homeostasis. Vasoactive endothelial factors such as NO or ET-1 are involved in this regulation. An unbalanced production of these bioactive mediators results in endothelial dysfunction, a critical event in the development of renal and cardiovascular damage in some diseases such as diabetes, hypertension, or atherosclerosis. On the other hand, vascular dysfunction has been related to endothelial senescence. Cellular senescence is considered one of the hallmarks of aging, and the presence of senescent cells in the tissue can induce or increase some pathologies. Senescent cells are not able to proliferate and present some morphological and biochemical changes, such as increased senescent activity of β-galactosidase (SA-β-GAL) and increased expression of cell cycle inhibitors such as p16 or p53 tumor suppressor genes.

Senescence can be promoted by the replicative life of cells, due to the progressive telomere shortening or prematurely in response to stressful stimuli, which result in DNA damage or oncogene activation. Recent studies from our group have demonstrated that hyperphosphatemia could be one of these stressful stimuli, as it induced cellular senescence in human aortic smooth muscle cells through the activation of IGF-1 receptor and integrin-linked kinase overexpression. The present work shows, for the first time, the key role of ET-1 in the senescence process induced by hyperphosphatemia. We show that a high extracellular phosphate concentration up-regulates the synthesis of ET-1 in endothelial cells, inducing cellular senescence through the modulation of ECE-1 via oxidative stress and AP-1 activation. Thus the hyperphosphatemia related to aging or aged diseases could increase senescent cells, which could be involved in the development of other pathologies.

Link: https://doi.org/10.1111/acel.12664

Regeneration and tissue maintenance are highly complex, regulated processes. Unfortunately, these processes run awry as the low-level molecular damage of aging increases over the years. Cells change their behavior, change the signals they produce, and one of the detrimental outcomes of these changes is fibrosis. This is the creation of scar-like collagen structures in place of the expected arrangement of cells and extracellular matrix. Since the fine details of that arrangement matter greatly to the correct function of organs, fibrosis is very harmful. It features prominently in the most common age-related diseases of the lungs, kidneys, liver, and heart, but can be found in other tissues as well.

With the explosion of interest in senescent cells as a cause of aging over the past few years, and a matching increase in funding for studies, research groups have been able to prove that the presence of lingering senescent cells is a significant cause of fibrosis. Senescent cells have an important transient role to play in wound healing and regeneration in general: in a perfect world some cells become senescent, their signals and their interaction with the immune system directs rapid and accurate reconstruction of tissue, and all of these temporary senescent cells then promptly self-destruct or are consumed by the immune cells called macrophages. Unfortunately this system starts to head downhill into disarray given a growing population of senescent cells that stick around for the long term. Their signals produce chronic inflammation, confuse the regulation of regeneration, and make matters worse in numerous other ways as well.

The open access paper noted here doesn't mention senescent cells at all, but it does focus on one of the proteins that both causes cells to become senescent and is also secreted by cells that have become senescent. The protein is called TGF-β1 and is one small part of the senescence-associated secretory phenotype, SASP, a range of molecules important to the short-term tasks carried out by senescent cells, but that cause disruption, damage, and ultimately organ failure when the number of lingering senescent cells grows large over the years. The authors of this paper show that TGF-β1 inhibition reduces fibrosis, a result that dovetails well with studies from the past few years that have demonstrated targeted removal of senescent cells to reduce fibrosis. All things consider, I think it should be taken as more evidence for the potential benefits of senolytic therapies that clear senescent cells from old tissues.

As a further matter of interest, note the comments on tissue stiffness in the paper. Where it occurs in blood vessels, this age-related change is a very important component of vascular aging and heart disease. Solid evidence for senescent cell removal to affect elasticity of tissues has so far only arrived for the lungs, and in mice, but the relevant mechanisms here are much the same in most tissue types. It is reasonable to be cautiously optimistic. If clearance of senescent cells does produce a significant reduction of vascular stiffening in humans, then that outcome is a very big deal. In that scenario, we should expect cardiovascular mortality to fall dramatically as senolytic therapies are deployed to the clinic.

Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis

Tissue fibrosis is a major cause of human morbidity and mortality worldwide. TGF-β1 signaling is a well-known driver of collagen expression and tissue accumulation important to wound repair. Exaggerated TGF-β1 signaling is also strongly implicated in numerous fibrotic diseases, including those involving liver, heart, and lung. For example, approximately 80% of the upregulated genes in lungs of patients with idiopathic pulmonary fibrosis are reported to be direct or indirect TGF-β1 target genes. Pathological collagen accumulation, and its promoting effects on tissue stiffness, are also strongly implicated in cancer progression. TGF-β1 signaling is both an initiator and a driver of tissue stiffness because accumulation of collagen and other matrix proteins promotes integrin-dependent latent TGF-β1 activation and further extracellular matrix deposition. Enhanced stiffness is thought to promote tumor cell β1 integrin activation, leading to more invasive tumor phenotypes and metastasis, consistent with the strong correlation of TGF-β1 signaling with poor cancer prognosis. For these and other reasons there has been much interest in TGF-β1 signaling as a therapeutic target.

Although attractive as a target, the critical roles of TGF-β1 in suppressing inflammation and epithelial proliferation give pause to the idea of global inhibition of TGF-β1 signaling. Indeed, systemic inhibition of TGF-β1 can lead to the development of squamous skin tumors and autoreactive immunity. In addition, chronic administration of several small-molecule inhibitors of TGF-β1 receptor (TβR) kinases has led to enhanced skin and colonic inflammation and abnormalities in cardiac valves. To minimize adverse consequences, an approach of blocking TGF-β1 activation in specific cell types using the unique pathway of αvβ6-dependent latent TGF-β1 activation has developed and is currently in clinical trial. But this integrin is primarily expressed in epithelia of lung, kidney, and skin. In an attempt to develop a more circumscribed inhibitor of TGF-β1 signaling centered on suppression of collagen accumulation, we undertook a high-throughput, image-based phenotypic screen of small molecules that could block TGF-β1-induced epithelial-mesenchymal transition (EMT) in vitro but not directly inhibit TβRI kinase itself.

We identified trihydroxyphenolic compounds as potent blockers of TGF-β1 responses. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. This selectivity likely avoids the toxicities of long term general TGF-β1 inhibition in chronic disease processes such as fibrosis and cancer progression. Indeed, we have observed no adverse events in mice on the trihydroxyphenolic-rich diet for at least 6 months, including the absence of skin inflammation and discernible lesions in cardiac valves.

Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TβRI kinase. Combined inhibition of LOXL2 and TβRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TβRI kinase in LOXL2-expressing cells.

The lack of concrete progress in the amyloid clearance approach to Alzheimer's disease, despite significant investment and many clinical trials over the past decade, has led to a great deal of theorizing in the research community. Is it that the dominant anti-amyloid strategy of immunotherapy is intrinsically challenging when applied to the brain at this point in the progress of medical biotechnology, or is it that amyloid is not the best target? In the SENS view of aging, amyloid accumulation is a primary difference between old and young tissue, and it should be removed. But Alzheimer's is a very complicated condition, involving multiple forms of altered protein aggregation, immune system issues, and other changes in cellular activity. There is plenty of room to advance novel interpretations of the order of causation, or the identification of new agents of causation, without denying that the presence of amyloid is a problem. Ultimately, the proof will lie in the effectiveness of therapies; those based on a correct model of the disease and targeted at the true root cause should in principle produce better outcomes for patients.

Researchers have recently proposed a novel role for biofilms - colonies of bacteria that adhere to surfaces and are largely resistant to immune attack or antibiotics - in eczema. It was suggested that because biofilms block skin ducts and trigger innate immune responses, they may cause the stubborn skin condition. Other recent work shows that Lyme spirochetes form biofilms, which led the researchers to wonder if biofilms might also play a role in Alzheimer's disease. When they stained for biofilms in brains from deceased Alzheimer's patients, he found them in the same hippocampal locations as amyloid plaques.

Spirochetes, common members of the oral microbiome, belong to a small set of microbes that cross the blood-brain barrier when they're circulating in the blood, as they are during active Lyme infections or after oral surgery. However, the bacteria are so slow to divide that it can take decades to grow a biofilm. This time line is consistent with Alzheimer's being a disease of old age, researchers reasons, and is corroborated by syphilis cases in which the neuroinvasive effects of spirochetes might appear as long as 50 years after primary infection.

Work on biofilms contributes to the revival of a long-standing hypothesis concerning the development of Alzheimer's. For 30 years, a handful of researchers have been pursuing the idea that pathogenic microbes may serve as triggers for the disease's neuropathology. Most came across the connection serendipitously, and some have made it their life's work, in spite of scathing criticism and related challenges in attracting funding and publishing results.

The Alzheimer's field seems primed for a fresh look at a theory that might account for the disease's pathogenesis. Researchers still cannot say with confidence which features of the disease, such as neuroinflammation, tau tangles, and amyloid plaques, are involved in disease progression and thus would make effective targets for treatment. So far, most drugs that have made it to clinical testing have targeted the amyloid-β peptide, the main component of the amyloid plaques that characterize Alzheimer's brains. The idea is that a build-up of amyloid-β causes the neuropathology and that removing amyloid-β - by decreasing its production, impeding aggregation, or aiding removal of the molecule from the brain - will improve, or at least stall, symptoms of dementia. But so far, researchers have come up empty-handed.

In light of continued failures to develop effective drugs, some researchers think it's high time that more effort and funding go into alternative theories of the disease. "Any hypothesis about Alzheimer's disease must include amyloid plaques, tangles, inflammation - and, I believe, infection." And, slowly but surely, Alzheimer's researchers finally seem to be giving the pathogen hypothesis a good, hard look. There remain more questions than answers at this point in terms of the causative factors in Alzheimer's, however. "The pathology is a mess. The brain has been diseased for a long time by the time we see it. We're looking at the end product and trying to determine how it got that way. Most of the resources in this field are spent on a few biomarkers. All the evidence shows that amyloid is important. But causality and centrality are two different things."

Link: http://www.the-scientist.com/?articles.view/articleNo/50208/title/Do-Microbes-Trigger-Alzheimer-s-Disease-/

This research improves on the established links between a few of the forms of molecular damage and cellular dysfunction that central to the SENS view of aging, at least in the case of Parkinson's disease. These are lysosomal failure, mitochondrial dysfunction, and the accumulation of damaged proteins that form solid deposits, alpha-synuclein in this case. All age-related diseases emerge from the various typs of root cause damage that causes aging, some more directly, some with more intervening layers of secondary failure and damage.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, primarily caused by the death of dopamine-containing neurons in the substantia nigra, a region of the brain involved in motor control. While people naturally lose dopamine neurons as they age, patients with PD lose a much larger number of these neurons and the remaining cells are no longer able to compensate. Understanding how and why these neurons die is an important step in identifying treatments. While previous research indicated that the cellular mechanism behind the cell death involved the mitochondria and lysosomes, how these two pathways converge in dopamine neurons to cause cell death remained unknown up until now.

Using human neurons from Parkinson's patients, researchers identified a toxic cascade of mitochondrial and lysosomal dysfunction initiated by an accumulation of oxidized dopamine and a protein called alpha-synuclein. Specifically, the current study demonstrated that an accumulation of oxidized dopamine depressed the activity of lysosomal glucocerebrosidase (GCase), an enzyme implicated in PD. That depression in turn weakened overall lysosomal function and contributed to degeneration of neurons. The accretion of oxidized dopamine didn't just interfere with lysosomes, however. Researchers discovered that the dopamine also damaged the neurons' mitochondria by increasing mitochondrial oxidative stress. These dysfunctional mitochondria led to increased oxidized dopamine levels, creating a vicious cycle.

"The mitochondrial and lysosomal pathways are two critical pathways in disease development. Combined with the alpha-synuclein accumulation, this study links the major pathological features of PD. One of the key strategies that worked in our experiments is to treat dopamine neurons early in the toxic cascade with specific antioxidants that improve mitochondrial oxidative stress and lower oxidized dopamine. With this approach, we found that we can attenuate or prevent the downstream toxic effects in human dopaminergic neurons." Interestingly, when compared to human cellular models, mouse models of PD did not demonstrate the same toxic cascade. The researchers showed this is due to differences in metabolism of dopamine between species, and underscored the importance of studying human neurons to discover new targets for drug development.

Link: https://news.northwestern.edu/stories/2017/september/interrupting-parkinsons-disease/

Calorie restriction slows aging in most species and lineages tested to date, though the size of the effect on life span diminishes as species life span increases. Calorie restriction produces very similar short-term health benefits in humans and mice, but mice live as much as 40% longer as a result. We certainly do not. The necessary human studies have yet to run, but the consensus in the research community is that five years of additional life expectancy for calorie restricted humans is about as much as could be expected. The beneficial response to calorie restriction isn't just one mechanism under the hood, though increased autophagy appears to be an outsized contribution. Calorie restriction changes just about everything there is to be measured in cellular metabolism, shifting the behavior of many networks of linked genes and protein interactions. Given these networks, there are a range of other means of provoking some of the same effects. This is true for most aspects of cellular biochemistry: there is never only one way to produce change.

Among the alternative means to touch on some of the changes involved in calorie restriction are intermittent fasting without calorie deficit, protein restriction, such as low methionine diets, and carbohydrate restriction - the much-hyped ketogenic diet, which is the topic for today. All structured popular diets are much-hyped, of course, surrounded by a moat of nonsense and borderline fraudulent commerce. It has to be said that if people spent one hundredth of the effort they put into considerations of diet into useful medical research, we'd be a lot closer to solving the problem of degenerative aging and age-related disease. So much light and noise for so little gain. No alteration you can make to your eating habits will reliably let you live to see a century of life, and even those people with the best, most optimal diets are still decrepit and much harmed by age in later life. The degree of difference that can be made just isn't large enough to justify the investment.

I point out this sort of research because it is interesting, not because it is the road to large increases in healthy human longevity. Researchers are progressively uncovering the details of shared mechanisms touched upon by a wide variety of dietary interventions, exercise, and other environmental factors known to influence health. Under the hood just a few core clusters of cellular behaviors are responsible for steering the bulk of natural variations in the pace of aging within a given species. These natural variations in aging and in health are tools that can be used to learn more about the intricacies of mammalian biochemistry. That is the primary output of these research efforts: knowledge, not practical therapies. You, I, and anyone else can set forth today to obtain all of the potential benefits under examination here: just choose to exercise regularly and eat less, and while doing it give some thought to the myriad fascinating biochemical changes taking place throughout the body and brain. I think we all understand the scope of what is possible via these methods, and just how limited they are in comparison to the potential of the nascent industry of rejuvenation therapies, treatments such as senolytics that are based on damage repair rather than tinkering with the recreation of calorie restricted metabolic states.

Ketogenic diet improves healthspan and memory in aging mice

Eating a ketogenic diet - which is high fat, low protein, and low carbohydrates - ramps up the production of the ketone body beta-hydroxybutyrate acid (BHB). While small studies in humans with cognitive impairment have suggested that BHB could improve memory, this is the first study in aging mammals which details the positive effects of BHB on memory and lifespan. "We're looking for drug targets. The ultimate goal is to find a way for humans to benefit from BHBs without having to go on a restrictive diet."

Reserchers carefully designed three diets that were matched in every way except fat and carbohydrate content: a normal high-carbohydrate diet, a zero-carbohydrate ketogenic diet, and a high-fat, low-carbohydrate diet that was not ketogenic. Mice were fed the ketogenic diet intermittently to prevent them from becoming obese, starting at one year old - middle age for mice. The ketogenic diet-fed mice had a lower risk of dying as they aged from one to two years old, although their maximum lifespan was unchanged. Another group of mice underwent memory testing at both middle age (one year old) and old age (two years old). Mice that had been eating a ketogenic diet performed at least as well on memory tests at old age as they did at middle age, while mice eating the normal diet showed an expected age-associated decline. Mice who ate the ketogenic diet also explored more, and their improved memory was confirmed with another test a few months later.

"We were careful to have all of the mice eating a normal diet during the actual memory testing which suggests the effects of the ketogenic diet were lasting. Something changed in the brains of these mice to make them more resilient to the effects of age. Determining what this is, is the next step in the work. Looking at gene expression, the ketogenic diet suppressed the longevity-related TOR pathway and insulin signaling and up-regulated the fasting-related transcription factor PPAR-alpha, a master regulator that helps the body more efficiently metabolize fat. Exercise also creates ketone bodies - that may be one of the mechanisms why it shows such protective effects on brain function and on healthspan and lifespan."

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

BHB is a normal human metabolite that is synthesized in the liver from fat, and then circulates throughout the body as a glucose-sparing energy source. It is intrinsically produced during states such as intermittent fasting and dietary restriction (DR) that result in extended longevity, cognitive protection, cancer reduction, and immune rejuvenation. Recent work has elucidated an array of signaling functions of BHB that suggest that BHB might itself regulate inflammation and gene expression, with implications for health and longevity.

A ketogenic diet is one means to deliver high levels of BHB for a prolonged time outside of a fasting or exercise context. Ketogenic diets generally contain little or no carbohydrate and stimulate endogenous ketogenesis. We sought to test whether a ketogenic diet carefully matched to comparison diets could enhance the longevity and healthspan of normal mice, and to elucidate potential molecular mechanisms of such effects.

We show that long-term exposure to a ketogenic diet, fed every other week starting in middle age, reduces midlife mortality and preserves memory in aging C57BL/6 male mice. Similar feeding of a high-fat, low-carbohydrate non-ketogenic diet appeared to have an intermediate effect on mortality, but survival of this group could not be definitely distinguished from either the control or ketogenic diet groups. These results might be interpreted in the broader context of the health effects of DR and of segmental DR mimetics such as metformin and rapamycin, and suggest that one or more aspects of a ketogenic diet may similarly act as a segmental DR mimetic.

Many methods of modestly slowing aging in laboratory species are accompanied by reduced rates of protein synthesis and higher levels of activity by cellular maintenance processes such as autophagy. The research noted here is one of a number of examples from recent years in which an intervention lowers the rate of protein synthesis and slows aging as a result. This is much more a tool to assist in mapping the details of metabolism and aging than it is the basis for any sort of practical therapy, however. The practice of calorie restriction lowers protein synthesis rates, and no attempt to mimic that has yet produced a practical treatment that is as reliably, effective, and free from side-effects as simply eating less. The scope of the possible results should also be apparent: no-one can reliably live to 100 just by eating less, and even if they make that far, they are still greatly impacted by the aging process. This is not the road to rejuvenation. Only repair of the forms of cell and tissue damage that cause aging, such as that addressed by the SENS research portfolio, can in principle achieve reversal of aging.

For about one hundred years it has been known that nutrient restriction and moderate stress can significantly prolong life. Researchers have now discovered how the transcription factor Gcn4, a protein that regulates the expression of many genes, extends the life of baker's yeast Saccharomyces cerevisiae. In various stress situations, the cells stimulate Gcn4 production which leads to reduced biosynthesis of new proteins and increased yeast lifespan.

It has long been known that protein synthesis - also known as translation - plays an important role in aging. Inhibition of protein synthesis, caused for example by reduced nutrient intake, can have a positive effect on the life expectancy of diverse organisms such as yeast, flies, worms, or fish. Reducing the ribosomes, the protein factories of the cell, can also considerably extend the lifespan of yeast cells. What these cellular stresses have in common is that they activate the production of Gcn4. However, how this protein promotes longevity has remained unclear.

The team exposed yeast cells to different stress conditions, measured their lifespan, protein synthesis rates and Gcn4 expression. "We observed that the level of the Gcn4 protein was positively correlated with the longevity of yeast cells. However, we wanted to understand why. We have now shown for the first time that it is the transcriptional suppression of genes that are important for cellular protein synthesis by Gcn4 that seems to account for its lifespan extension effect. As the translation machinery is limiting, the energy-intensive production of new proteins is overall dampened." From the yeast cell's point of view, this is an advantage: This enables them to live about 40 percent longer than usual.

The transcription factor Gcn4 is conserved in over 50 different organisms, including mammals, and it likely play a significant role in the aging of these organisms as well. The researchers will now investigate whether the mammalian homolog similarly slows aging and extends lifespan by regulating protein synthesis genes in response to nutrients and stress.

Link: https://www.unibas.ch/en/News-Events/News/Uni-Research/A-Protein-that-Extends-Life-of-Yeast-Cells.html

Statins work to reduce cardiovascular disease risk by reducing blood lipid levels. In the research here, the authors quantify the benefits that have been obtained through the use of this class of drug over the past few decades. This class of drug is broadly considered to be one of the more important contributions to the reduced rate of cardiovascular mortality over that span of time. The data here suggests that statins should be even more widely used than they are at present: there are incrementally greater gains that might be obtained.

The mechanism of cardiovascular damage influenced by statins is one in which lipids oxidized due to other mechanisms of aging drive the pace at which atherosclerosis progresses. Lowering overall lipid levels in the bloodstream also lowers the level of these problem damaged molecules, and so atherosclerosis is slowed. The logical step beyond this in order to produce much better classes of therapy, treatments capable of reversing this condition, is to remove the damaged lipids and their byproducts rather than just slow their impact. The SENS Research Foundation, for example, ran a program to uncover bacterial enzymes that might be modified to accomplish this task for 7-ketocholesterol. For now, however, the only available approaches involve improved ways to lower blood lipids, such as PCSK9 inhibitors. These should be better than statins, but still not as good as repairing the situation by specifically clearing damaged lipids.

Previous research has shown the benefit of statins for reducing high cholesterol and coronary heart disease risk amongst different patient populations. However, until now there has been no conclusive evidence from trials for current guidelines on statin usage for people with very high levels of low density lipoprotein (LDL) cholesterol (above 190mg/dL) and no established heart disease. After studying mortality over a 20-year period, researchers showed that 40mg daily of pravastatin, a relatively weak type of statin, reduced deaths from heart disease in participants by more than a quarter.

"For the first time, we show that statins reduce the risk of death in this specific group of people who appear largely healthy except for very high LDL levels. This legitimises current guidelines which recommend treating this population with statins." In addition, the findings challenge current approaches on treating younger patients with LDL elevations with a 'watch and wait' approach. Instead, even those with slightly elevated cholesterol are at higher long term risk of heart disease, and that the accumulation of modest LDL reductions over time will translate into large mortality benefits. "Our findings suggest that we should consider prescribing statins more readily for those with elevated cholesterol levels above 155 mg/dl and who also appear otherwise healthy."

This research follows on from a five-year 1995 study in which researchers observed the long-term effects of statins on patients involved in the West of Scotland Coronary Prevention Study (WOSCOPS) trial. The researchers took into account the original five-year study and followed the patients for a further 15 years. The WOSCOPS study provided the first conclusive evidence that treating high LDL in men with pravastatin for five years significantly reduces the risk of heart attack or death from heart disease compared with placebo. Statins were subsequently established as the standard treatment for primary prevention in people with elevated cholesterol levels.

Now, researchers have completed analyses of the 15-year follow up of 5,529 men, including 2,560 with LDL cholesterol above 190 mg/dL of the original 6,595, chosen because they had no evidence of heart disease at the beginning of the present study. Participants were aged 45-64 years. During the five-year initial trial they were given pravastatin or placebo. Once the trial ended the participants returned to their primary care physicians, and an additional 15-year period of follow-up ensued. The 5,529 men were split into two groups: those with 'elevated' LDL (between 155 and 190mg/dL) and those with 'very high' LDL (above 190mg/dL). The standard 'ideal' level of LDL for high risk patients is below 100mg/dL, but this varies depending on individual risk factors.

The researchers found that giving pravastatin to men with 'very high' LDL reduced twenty year mortality rates by 18 per cent. Statins also reduced the overall risk of death by coronary heart disease by 28 per cent, and reduced the risk of death by other cardiovascular disease by 25 per cent among those with very high LDL cholesterol. The 15-year follow up also meant the researchers could compare patients' original predicted risk of heart disease with actual observed risk. According to the risk equations for cardiovascular disease, 67 per cent of patients included in the WOSCOPS trial with LDL above 190mg/dL would have less than a 7.5 per cent risk of heart disease by year ten, and thus would not have been treated with statins based on that risk. However, the present study shows that in fact, this group actually had a 7.5 per cent risk by year five, meaning their ten year risk was 15 per cent. Following statin therapy, this group's ten year risk was reduced compared with those that were given placebo during the trial.

Link: http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_6-9-2017-18-48-55

Researchers have demonstrated that shifting the balance between mitochondrial fusion and fission towards fission increases the life span of flies. The authors provide evidence to suggest that this is because greater fission enhances the operation of the quality control mechanisms of autophagy that clear away damaged mitochondria. This fits in with the wealth of studies that demonstrate modest increases in life span in a variety of species through enhanced autophagy, both of mitochondria and other damaged proteins and structures - better cellular repair and maintenance, in other words. Aging is a process of damage accumulation, and the more aggressively that cells clean up primary damage, the less of a chance that damage has to cause an accumulation of secondary and later effects.

Mitochondria are the evolved descendants of symbiotic bacteria, their presence an ancient and early development in the evolutionary tree of life. Every cell has a herd of hundreds of these structures, stripped of most of their original DNA, and integrated into the cell's quality control systems. Mitochondria divide like bacteria to make up their numbers, and when damaged are, in theory, destroyed by the processes of autophagy: tagged, wrapped, and dismantled by specialized machinery in the cell. Also like bacteria, mitochondria constantly split apart, fuse together, and promiscuously pass around copies of their molecular machinery.

Mitochondria are power plants, the last stage in the conversion of food into energy store molecules that a cell uses to power its operations. They are also generators of potentially damaging oxidative molecules, molecules that are also vital signals that trigger cell housekeeping and maintenance activities. Further, mitochondria play vital roles in a range of other portions of the cell life cycle, from replication to programmed cell death. All of this activity makes it hard to model or visualize in detail the progression of age-related damage in mitochondria, despite the overwhelming evidence for their importance in aging.

What little DNA mitochondria have left over is prone to damage, either because it has poor repair machinery in comparison to the cell nucleus, because it is right next door to the energy store creation mechanisms that produce damaging oxidative molecules as a byproduct, or because mitochondria replicate their DNA a lot more often than occurs for nuclear DNA. More dramatic forms of damage can block access to necessary proteins, turning off the most efficient energy store creation method, producing a mitochondrion that is both malfunctioning and more resistant to quality control efforts. Its descendants will very quickly take over the entire cell population, and the whole cell falls into a state of senescence or other dysfunction, exporting damaging molecules into the surrounding tissue. This is one of the root causes of aging. Researchers can see these cells after the fact, but observing and mapping the details of the process by which damaged mitochondria take over a cell in this way is yet to be achieved.

Fortunately, understanding exactly how this happens is not necessary in order to prevent it from happening. It doesn't matter how mitochondrial DNA is damaged or how damaged mitochondria overtake a cell if a supply missing proteins can be provided. Having a backup supply of the proteins encoded in mitochondria DNA bypasses all of the thorny questions and big unknowns, which is why it is the chosen strategy for the SENS rejuvenation research programs. The specific implementation involves allotopic expression, a gene therapy to place a mitochondrial gene into the cell nucleus, suitably adjusted such that the resulting protein is shipped back to mitochondria to be used. This has been demonstrated for three of the thirteen genes in recent years, one of which is the center of a commercial effort to repair inherited mitochondrial disease.

In this context, adjustments to mitochondrial dynamics of the sort demonstrated here look a lot like the quest for ways to mimic the response to exercise, the response to calorie restriction, or other favorable altered metabolic states. It is a shift of proportions and relative effectiveness of mechanisms, not a fix to the underlying problem. The potential upside of this sort of approach is typically not large - look at the survival curves in the paper here. This is noteworthy for producing those curves after a short treatment in middle age, rather than a life-long intervention, but it is still the case that it is a small effect in the grand scheme of things. Short-lived species such as flies have much greater plasticity of life span than long-lived species such as our own. In the few cases where effects can be compared fairly directly, adjustments of metabolic state that extend life significantly in worms, flies, and mice only add a few years at most to human life span.

Biologists slow aging, extend lifespan of fruit flies

In a study on middle-aged fruit flies, researchers substantially improved the animals' health while significantly slowing their aging. They believe the technique could eventually lead to a way to delay the onset of age-related diseases in humans. The approach focuses on mitochondria, the tiny power generators within cells that control the cells' growth and determine when they live and die. Mitochondria often become damaged with age, and as people grow older, those damaged mitochondria tend to accumulate in the brain, muscles and other organs. When cells can't eliminate the damaged mitochondria, those mitochondria can become toxic and contribute to a wide range of age-related diseases. Researchers found that as fruit flies reach middle age - about one month into their two-month lifespan - their mitochondria change from their original small, round shape. "We think the fact that the mitochondria become larger and elongated impairs the cell's ability to clear the damaged mitochondria. And our research suggests dysfunctional mitochondria accumulate with age, rather than being discarded."

The scientists removed the damaged mitochondria by breaking up enlarged mitochondria into smaller pieces - and that when they did, the flies became more active and more energetic and had more endurance. Following the treatment, female flies lived 20 percent longer than their typical lifespan, while males lived 12 percent longer, on average. The research highlights the importance of a protein called Drp1 in aging. At least in flies and mice, levels of Drp1 decline with age. To break apart the flies' mitochondria, researchers increased their levels of Drp1. This enabled the flies to discard the smaller, damaged mitochondria, leaving only healthy mitochondria. Drp1 levels were increased for one week starting when the flies were 30 days old.

Researchers further showed that the autophagy-related gene Atg1 also plays an essential role in turning back the clock on cellular aging. They did this by "turning off" the gene, rendering the flies' cells unable to eliminate the damaged mitochondria via autophagy. This proved that Atg1 is required to reap the procedure's anti-aging effects: While Drp1 breaks up enlarged mitochondria, the Atg1 gene is needed to dispose of the damaged ones. "We actually delayed age-related health decline. And seven days of intervention was sufficient to prolong their lives and enhance their health." One specific health problem the treatment addressed was the onset of leaky intestines, which previous research found commonly occurs about a week before fruit flies die. Subsequent research in other laboratories has determined that an increase in intestines' permeability is a hallmark of aging in worms, mice and monkeys. In this study, the condition was delayed after flies were given more Drp1.

In another part of the experiment, also involving middle-aged fruit flies, the scientists turned off a protein called Mfn that enables mitochondria to fuse together into larger pieces. Doing so also extended the flies' lives and improved their health. "You can either break up the mitochondria with Drp1 or prevent them from fusing by inactivating Mfn. Both have the same effect: making the mitochondria smaller and extending lifespan."

Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster

Mitochondrial dysfunction is a key hallmark of aging and has been linked to numerous age-onset pathologies. Therefore, identifying interventions that could improve mitochondrial homeostasis when targeted to aged animals would be highly desirable toward the goal of prolonging healthspan. A growing body of data support the idea that autophagy has an important anti-aging role. However, the relevant autophagic cargo in the context of aging remains elusive. Mitochondrial autophagy (mitophagy) is a type of cargo-specific autophagy, which mediates the removal of dysfunctional mitochondria. Recent studies in mammals, including humans, have reported an age-related decline in mitophagy. Moreover, impairment of mitophagy recapitulates the age-related accumulation of mitochondria in Caenorhabditis elegans. These findings suggest that the mitophagy pathway may represent a therapeutic target to counteract aging. However, a major unanswered question remains: why does mitophagy decline in aged animals?

Mitochondrial dynamics (fission and fusion) and mitophagy are closely related. Mitofusin (Mfn) proteins mediate fusion of the mitochondrial outer membrane, while mitochondrial fission, conversely, requires Dynamin-related protein 1 (Drp1). Several studies indicate that an important event preceding mitophagy is the Parkin-mediated turnover of Mfn leading to a shift in the balance of mitochondrial dynamics toward decreased fusion/increased fission. In yeast, the mitochondrial fission protein, Dnm1, homologous to Drp1, is required for certain forms of mitophagy. Together, these findings support the model that mitochondrial fission can promote the segregation of damaged mitochondria and facilitate their clearance by mitophagy. Critically, however, the interplay between mitochondrial dynamics and mitophagy during aging remains poorly understood, and the question of whether an increase in mitochondrial fission alone is sufficient to prolong lifespan and/or improve mitochondrial function in an aged animal has not been addressed.

Here, we show that inducing Drp1-mediated mitochondrial fission, in midlife, increases lifespan and improves multiple markers of health in aged Drosophila. Remarkably, we show that a transient induction of Drp1, for 7 days, in midlife is sufficient to prolong lifespan. Studying aging flight muscle, we find that a midlife shift toward a more elongated, less circular mitochondrial morphology is linked to the accumulation of dysfunctional mitochondria. Short-term, midlife Drp1 induction restores mitochondrial morphology to a youthful state, improves mitochondrial respiratory function and reduces mitochondrial reactive oxygen species (ROS) levels. Importantly, midlife Drp1 induction facilitates mitophagy and improves proteostasis in aged flies. Finally, we show that disruption of Atg1, a core autophagy gene, inhibits the anti-aging, prolongevity effects of midlife Drp1 induction. Our findings indicate that transient, midlife interventions that promote mitochondrial fission could delay the onset of frailty and mortality in aging mammals.

The SENS Research Foundation and the Forever Healthy Foundation will be running a new conference on rejuvenation biotechnology in March 2018 in Berlin. This is good news; over the long term, conference series have a high return on investment when it comes to expanding the scope and influence of a field of scientific endeavor. Networking makes the world turn. Over the past few years, the SENS Research Foundation ran the Rejuvenation Biotechnology conferences in the US, bringing together academia and industry to help smooth the path for the transition of rejuvenation therapies from the laboratory to clinical development. Now that same approach will be applied to the European research and development communities.

Given the rapid growth in development of senolytic therapies to clear senescent cells, this is the time to point out that SENS advocates and organizations have been calling for more work on exactly this type of treatment for the past fifteen years - long before the current explosion of interest. It isn't an accident that senolytics are proving effective and very promising in animal studies: it is expected and rational based on (a) the view of aging as an accumulation of molecular damage, and (b) scientific evidence gathered in recent decades. It is of particular importance to broaden the realization that senolytics are not a single fortunate discovery, but one part of a larger scheme, one of numerous potential rejuvenation therapies that are all based on the same concept of damage repair as the best way to treat aging as a medical condition.

Senescent cells are a form of damage, present only in old tissues in any significant number, and removing them is a form of restoration. But beyond that there are a number of other therapies that will be just as important and just as beneficial once developed: cross-link clearance, preventing the consequences of mitochondrial DNA damage, clearance of amyloids and lipofuscin, and so forth. We have the opportunity to educate those newly arriving in our community because they have learned of senescent cell clearance, and show them that this is just one portion of a larger, logical plan for the reversal of aging, most of which still needs greater support and funding in order to progress.

Undoing Aging 2018 is focused on the cellular and molecular repair of age-related damage as the basis of therapies to bring aging under full medical control. The conference, a joint effort of SENS Research Foundation and Forever Healthy Foundation, provides a platform for the existing scientific community that already works on damage repair and, at the same time, offers interested scientists and students a first-hand understanding of the current state of this exciting new field of biomedical research.

Speakers will include leading researchers from around the world focused on topics including stem cells, senescent cells, immunotherapies, biomarkers and drug discovery. Aubrey de Grey, Chief Science Officer of the SENS Research Foundation, will be the scientific organizer for the conference. Undoing Aging 2018 is not only open to the scientific community but also welcomes all interested members of the broader Life Extension movement. The conference will also feature a student poster session showing the work of innovative undergraduate and graduate students in the field of damage repair.

"With the 2018 Undoing Aging Conference, SENS Research Foundation (SRF) resumes its series of conferences previously based in Cambridge. As we did from 2003 to 2013, we will host a scientific conference that will demonstrate the enormous strides currently being made in genuine rejuvenation biotechnologies. The lesson will be clear - the community is broad and deep, and its members see the potential for genuinely comprehensive approaches to the prevention of age-related disease. We're especially pleased that our partnership with Forever Healthy will bring this conference to the heart of the Berlin life sciences community for the first time."

"Forever Healthy is already a vanguard supporter of SRF research programs and rejuvenation biotechnology start-ups. We are now very excited to work with SRF on Undoing Aging 2018, the first conference for our organization. Forever Healthy has two key goals for this conference: To support the remarkable scientific community already working on repair of age related damage and to create an unique opportunity for the broader scientific world to experience that the possibility of bringing aging under complete, genuine medical control is realistic, achievable, and, indeed, beginning to happen."

Link: https://www.undoing-aging.org/news/sens-research-foundation-and-forever-healthy-foundation-announce-2018-undoing-aging-conference

Genetically engineered loss of ANGPTL2 has been shown to slow the progression of heart disease in mice. Lower levels of ANGPTL2 result from exercise, and higher levels are associated with greater age, greater amounts of visceral fat, and the presence of senescent cells, among other factors - all of which fits well with the range of known risk factors for heart disease. The more ANGPTL2 in circulation, the worse the outcome. This open access review paper covers what is presently known of ANGPTL2 and its role in metabolism and age-related cardiovascular disease: of interest given the past few years of research is that ANGPTL2 may be generated by senescent cells as a part of their harmful senescence-associated secretory phenotype.

Worldwide, the number of patients with heart disease is increasing as populations of elderly people expand. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are associated with adverse health outcomes that decrease a patient's well-being and productivity. Prevention of these conditions is desirable to promote healthy aging and improve patients' lifestyle. The pathologic basis of CVD is atherosclerosis caused by ectopic accumulation of cholesterol in vessel walls; thus advent of therapies aimed at reducing low-density lipoprotein (LDL)-cholesterol levels has succeeded in decreasing the number of CVD events. However, these events continue to occur, even in patients whose LDL-cholesterol levels have been lowered, indicating that the pathologies underlying CVD are highly complex.

Many of our previous studies have revealed that the expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiologic stimuli such as hypoxia, reactive oxidative species, and pressure overload. ANGPTL2 expression also increases in cells undergoing senescence, suggesting that ANGPTL2 is a SASP factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathologic states and contributes to the development of aging-associated diseases such as CVD. Thus, to understand the mechanisms underlying these conditions, we focus our discussion here on the role of ANGPTL2 in CVD.

Obesity and associated metabolic diseases predispose individuals to coronary artery disease (CAD), the major common form of CVD. In terms of the mechanisms linking these conditions, accumulating evidence suggests that inflammatory changes in perivascular fat, which is distributed ubiquitously around arteries throughout the body, may have a direct role in promoting the pathogenesis of vascular diseases accelerated by obesity. Interestingly, in obesity, chronic inflammation occurs in both visceral and perivascular adipose tissues. In obese mice, the expression of ANGPTL2 is increased in perivascular adipose tissues surrounding the femoral artery at levels equivalent to those seen in visceral adipose tissues. In mice, we have undertaken adipose tissue transplantation experiments that show that adipose tissue-secreted ANGPTL2 accelerates vascular inflammation, pathologic vascular tissue remodeling and subsequent CVD development.

Moreover, atherosclerosis progression, including plaque instability, is associated with chronic vessel wall inflammation and is a risk factor for major CAD events. Therefore, therapies designed to inhibit chronic inflammation in vessel walls should slow atherosclerosis progression. Relevant to this, ANGPTL2 is abundantly expressed in vascular endothelial cells of CAD patients. ANGPTL2 expression in endothelial cells also significantly increases in subjects predisposed to atherosclerotic disease brought on by obesity or metabolic disturbances. As expected, increases in endothelial cell-derived ANGPTL2 expression in mice promote vascular inflammation and subsequent endothelial cell dysfunction and atherosclerosis development. Vascular inflammation, which underlies atherosclerotic disease, emerges from the interplay of different cell types, including endothelial cells, smooth muscle cells, and perivascular adipocytes as resident cells, and macrophages as infiltrating cells. Macrophage-secreted ANGPTL2 also accelerates atherosclerotic disease in mice. Thus, ANGPTL2-induced chronic inflammation predisposes individuals to atherosclerotic disease and to CAD development.

Cellular senescence is defined as cell cycle arrest as a means to counteract DNA damage induced by aging and various stressors. Accumulation of senescent cells in various tissues accelerates aging and disease development. A recent report using a transgenic approach in mice demonstrated that clearance of senescent cells delays several age-associated disorders, suggesting that senescent cells promote these conditions. Interestingly, it has been reported that endothelial cells derived from smokers and exhibiting oxidative stress-induced premature senescence show significantly increased ANGPTL2 expression. Moreover, senescent fibroblasts from patients with Werner syndrome (adult progeria) show abundant ANGPTL2 expression and increased expression of other SASP factors. We have also reported that ANGPTL2 expression significantly increases in the hearts of aged compared with young mice. Thus, ANGPTL2 may function as a senescence-associated secretory phenotype in several senescent cell types. If so, markedly increased circulating ANGPTL2 levels seen in patients with chronic aging-related diseases may reflect the accumulation of senescent cells in their organs.

Link: https://doi.org/10.1253/circj.CJ-17-0854

A new paper published yesterday is perhaps the fourth in a recent series of similar commentaries and reviews from a variety of research groups involved in the study of senescent cells. Each declares in its own way that senolytic therapies, approaches capable of selectively destroying senescent cells in old tissues, are a development of great importance in aging research. Senolytics have the near-future potential to produce sweeping change and improvement in the treatment of age-related conditions. The degree to which removal of senescent cells is better than the vast majority of present day medicine is hard to overstate. Accumulation of senescent cells is one of the root causes of aging, and removing these cells is a form of rejuvenation, capable of partially turning back the progression of most of the common age-related medical conditions.

Senescent cells well illustrate the SENS view of aging as an accumulation of unrepaired damage, generated as a side-effect of the normal operation of metabolism. Senescent cells are generated in large numbers in our tissues, day in and day out, but near all are destroyed, either by their own programmed cell death mechanisms or by the immune system. A tiny, tiny fraction of these cells evade this fate, however, and linger. Senescent cells generate a range of signals - the senescence-associated secretory phenotype, SASP - that corrode nearby tissue structures, change surrounding cell behavior, and generate an inflammatory response in the immune system. This is all beneficial in the short term and in small numbers, and senescent cells play a temporary role in steering embryonic development, or in regeneration of wounds, or in suppression of potentially cancerous cells. The problem arises in the long term, as growing numbers of lingering senescent cells continually run their program of inflammation and corrosion.

In recent years, studies have definitively linked senescent cells to age-related fibrosis, a major cause of organ dysfunction, to the progression of inflammatory conditions such as osteoarthritis and atherosclerosis, to the failing function of lungs, and to a range of other measures of age-related decline. Removing senescent cells from old mice has been shown to partially reverse the progression of many of these conditions. Since the mechanisms of cellular senescence are very similar in mice and humans, the hope is that the benefits of senolytics in old people will be significant. Since human studies have commenced in a variety of venues, we will find out in the next few years just how transformative this new approach to the treatment of aging might be.

Researchers review the clinical potential of senolytic drugs on aging

Researchers are moving closer to realizing the clinical potential of drugs that have previously been shown to support healthy aging in animals. In a review article aging experts say that, if proven to be effective and safe in humans, these drugs could be "transformative" by preventing or delaying chronic conditions as a group instead of one at a time. The drugs being tested are called senolytic agents, because they target senescent cells. These are cells that have stopped dividing and secrete toxic chemicals that damage adjacent cells. Accumulation of senescent cells, which increases with age, is associated with chronic conditions, including diabetes, cardiovascular disease, most cancers, dementia, arthritis, osteoporosis, and frailty.

In a recent study researchers confirmed that the first senolytic drugs to be discovered effectively clear senescent cells while leaving normal cells unaffected. The study also describes a new screening platform for finding additional senolytic drugs that will more optimally target senescent cells. The platform, together with additional human cell assays, identified and confirmed a new category of senolytic drugs, which are called HSP90 inhibitors. The platform will help researchers quickly identify additional drugs that target aging processes, which he says will be useful as they move closer to clinical intervention. "We've moved rapidly in the last few years, and it's increasingly looking like senolytic drugs, including the recently discovered HSP90 inhibitors, are having an impact on a huge range of diseases. We will need to continue to test whether there are more optimal drugs or drug combinations to broaden the range of senescent cell types targeted."

As senolytic drugs and drug combinations are discovered, researchers then will need to test them in clinical trials. The review article, "The Clinical Potential of Senolytic Drugs," acknowledges the unique challenges of these trials in the field of aging, including the difficulty of testing long-term end points, such as life span and health span - the healthy, productive years of life. Outcomes such as effects on median or maximum lifespan cannot be tested feasibly in humans. That's why researchers are using new clinical trial paradigms, which include testing the effects of senolytic drugs on co-morbidity, accelerated aging like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age-related loss of physiological resilience, and frailty. The authors also call out a need for additional geriatricians with research training to lead future clinical trials.

The Clinical Potential of Senolytic Drugs

Chronological aging is the leading predictor of the major chronic diseases that account for the bulk of morbidity, mortality, and health costs worldwide. Furthermore, age-related chronic diseases, geriatric syndromes, and disabilities tend to cluster within individuals, leading to multimorbidity. These observations support the concept that fundamental aging processes not only cause aging phenotypes, but also predispose to chronic diseases and the geriatric syndromes. Thus, it has been predicted that therapeutically targeting these processes can delay, prevent, or alleviate age-related chronic diseases and disabilities as a group, instead of one at a time-the "geroscience hypothesis."

The biological processes that underlie aging phenotypes and are active at the nidus of most chronic diseases include chronic, low-grade, "sterile" (absence of known pathogens) inflammation; macromolecular and organelle dysfunction (e.g., changes in DNA, such as telomere erosion, unrepaired damage, mutations, polyploidy, proteins - e.g., aggregation, misfolding, autophagy - carbohydrates, lipids, or mitochondria); stem and progenitor cell dysfunction; and accumulation of senescent cells. These four processes are linked; that is, in general, interventions that target one process also attenuate the others. For example, DNA damage causes increased senescent cell burden and mitochondrial and stem or progenitor cell dysfunction. Conversely, reducing senescent cell burden can lead to less inflammation, less macromolecular dysregulation, and enhanced function of stem and progenitor cells.

To remove senescent cells pharmacologically from wild type animals, "senolytic" agents, including small molecules, peptides, and antibodies, are being developed. Since the article describing the first senolytic agents was published in 2015, progress in identifying additional senolytic agents and their effects has been rapid. In that first article, a hypothesis-driven senolytic agent discovery paradigm was implemented. Senescent cells are resistant to apoptosis, despite the SASP factors they release, which should trigger apoptosis. Indeed, pro-apoptotic pathways are up-regulated in senescent cells, yet these cells resist apoptosis. The hypothesis was therefore tested that senescent cells depend on pro-survival pathways to defend against their own pro-apoptotic signaling.

Using bioinformatic approaches based on the ribonucleic acid (RNA) and protein expression profiles of senescent cells, five senescent-cell anti-apoptotic pathways (SCAPs) were identified. That SCAPs are required for senescent cell viability was verified in RNA interference studies, in which levels of key proteins in these pathways were reduced. Through this approach, survival proteins were identified as the Achilles' heel of senescent cells. Knocking down expression of these proteins causes death of senescent but not nonsenescent cells. The SCAPs discovered so far have been used to identify putative senolytic targets.

The first senolytic agents discovered using this hypothesis-driven approach were dasatinib and quercetin. Ten months later, the third senolytic drug, navitoclax, a BCL-2 pro-survival pathway inhibitor, was reported. Since then, a growing number of senolytics have been reported. Yet more senolytics are in development, and additional potential SCAPs are being identified. The SCAPs required for senescent cell resistance to apoptosis vary according to cell type. The Achilles' heels, for example, of senescent human primary adipose progenitors differ from those of a senescent human endothelial cell strain, indicating that agents targeting a single SCAP may not eliminate all types of senescent cells. The senolytics that have been tested across a wide range of senescent cell types have all exhibited a degree of cell type specificity. For example, navitoclax is senolytic in a cell culture-acclimated human umbilical vein endothelial cell strain but is not effective against senescent primary human fat cell progenitors.

Senolytics do not have to be continuously present to exert their effect. Brief disruption of pro-survival pathways is adequate to kill senescent cells. Thus, senolytics can be effective when administered intermittently. For example, dasatinib and quercetin have an elimination half-life of a few hours, yet a single short course alleviates effects of radiation-induced senescent cell creation in vivo for at least 7 months. The frequency of senolytic treatment will depend on rates of senescent cell re-accumulation, which probably varies according to conditions that induce cellular senescence. Advantages of intermittent administration include less opportunity to develop side effects, the feasibility of administering senolytic drugs during periods of relatively good health, and less risk of off-target effects caused by continuous exposure to drugs. Another advantage of senolytics is that cell division-dependent drug resistance is unlikely to occur, because senescent cells do not divide and therefore cannot acquire advantageous mutations, unlike the situation in treating cancers or infectious agents.

The introduction of effective senolytics or other agents that target fundamental aging processes into clinical practice could be transformative. These drugs may be critical to increasing healthspan and delaying, preventing, or alleviating the multiple chronic diseases that account for the bulk of morbidity, mortality, and health costs in developed and developing societies. They could also delay or treat the geriatric syndromes, including sarcopenia, frailty, immobility, and cognitive impairment, as well as age-related loss of physiological resilience, in a way not imaginable until recently. These agents could transform geriatric medicine from being a discipline focused mainly on tertiary or quaternary prevention into one with important primary preventive options centered on a solid science foundation equivalent to, or even better than, that of other medical specialties.

Senolytics might prevent or delay chronic diseases as a group, instead of one at a time in presymptomatic or at-risk individuals. Furthermore, if what can be achieved in preclinical aging animal models can be achieved in humans, it may be feasible to alleviate dysfunction even in frail individuals with multiple comorbidities, a group that until recently was felt to be beyond the point of treatment other than palliative and supportive measures. Although considerable care must be taken, particularly until clinical trials are completed and the potential adverse effects of senolytic drugs are understood fully, it is conceivable that the rapidly emerging repertoire of senolytic agents might transform medicine as we know it.

Naked mole-rats live something like nine times longer than similarly-sized rodent species, and appear near immune to cancer. As such they are one of the most studied species among researchers who investigate the comparative biology of aging. Finding the underlying reasons for such large differences may inform human medicine, particularly when it comes to cancer, though in the matter of aging in general there is every chance that this sort of research will be overtaken in relevance in the near term by efforts such as clearance of senescent cells that directly address the root causes of aging. In recent years, it has become clear that gut bacteria have a fair degree of influence over natural variations in longevity in any given mammalian species. It is thus reasonable to ask whether they play a role in naked mole-rat longevity, though it is hard to imagine that this could be a significant contribution in comparison to the cellular differences, which include resilient mitochondrial membrane composition, efficient ribosomes, and overpowered anti-cancer mechanisms.

The composition and functionality of complex and rich community of microbes living on the surfaces and cavities of the mammal's body, i.e. microbiota, is well known to be crucial for the health maintenance of the host. An extremely rich and diverse microbial ecosystem inhabits the gastrointestinal tract collectively named as gut microbiota. Studies on humans have demonstrated that the gut microbiota strongly impacts on the prevention of disorders and pathologies, such as obesity and metabolic syndrome, cardiovascular diseases, inflammatory bowel diseases, as well as several types of cancer. The gut microbiota can indeed influence the education and homeostasis of the immune system and metabolism, as well as brain functionality, with as yet unknown long-term effects on human health and lifespan.

The impact of the gut microbiota on human health is a topic of huge interest for the scientific community, as demonstrated by the ever-increasing amount of studies on the microbiological peculiarities of the human gut ecosystem within the context of different lifestyles, genetic backgrounds, or pathologies. It is a matter of fact that, by preserving the biological homeostasis of the human host, the gut microbiota has a role of primary importance in supporting human longevity. However, only few hypotheses on the mechanisms involved have been advanced. Longevity is a tricky trait to be studied in humans, because it is a rare event, with an incredible amount of confounding genetic, lifestyle, and clinical variables, both past and present. Still, the microbiota of human populations with extraordinary longevity rate is being investigated across geographical zones and interesting hypotheses on the role of the microbiome in health-maintenance during aging are being advanced.

In this scenario, the naked mole-rat might represent an extremely interesting model to study health and longevity, since, like for human beings, in naked mole rat the selection against aging is strongly reduced. This eusocial, subterranean mouse-sized mammal occupies underground mazes of sealed tunnels and lives a very long life in large colonies with only one breeding queen and few breeding males. The naked mole-rat shows few age-related degenerative changes, displays an elevated tolerance to oxidative stress, and its fibroblasts have shown resistance to heavy metals, DNA damaging agents, chemotherapeutics and other poisonous chemicals. Moreover, this mammals show remarkably small susceptibility to both spontaneous cancer and induced tumorigenesis. These features of the naked mole-rat are maintained throughout their long lifespan, making this rodent a putative animal example of impressively prolonged "healthspan".

Moreover, the within-colony low genetic diversity (possibly due to the high inbreeding rate), the climatologically stable underground habitats, and the constant diet (mainly tubers and other underground plant storage organs), make the naked mole-rat a unique model for studying the microbiota-host interaction, focusing on the ability of the gut microbes to contribute to health maintenance during aging. Here, we characterized the gut microbiota of the naked mole-rat by next generation sequencing, aiming at understanding of how the rodent´s gut microbiota profile aligns with human microbiome and that of other mammals.

We found that the naked mole-rat possesses a unique gut microbiome composition, which is the result of the host phylogeny and its peculiar ecology. This microbiome layout has many compositional and functional peculiarities - such as the propensity for an oxidative metabolism, an enhanced capacity to produce short-chain fatty acids and mono- and disaccharides, as well as the peculiar structure within Bacteroidetes, the high load and diversity of Spirochetaceae and the presence of Mogibacteriaceae - some of which are shared with gut microbial ecosystems considered as models of healthy aging, as well as metabolic and immune homeostasis. This might suggest a possible role of the gut microbiota as a universal contributor to mammalian health, which goes beyond the host phylogeny and ecology constrains, supporting health and longevity of the mammalian host.

Link: https://doi.org/10.1038/s41598-017-10287-0

Progress towards the construction of entire organs is gated by the lack of a reliable way to produce sufficient vascular networks. Natural tissue comes equipped with hundreds of tiny capillaries passing through every cubic millimeter, and lacking this network means that engineered tissue can only be a few millimeters in thickness. One way to work around this problem in the near term is to use a donor organ, stripping it of all its cells in the process known as decellularization, leaving the extracellular matrix and its chemical cues to guide replacement cells. Even this isn't enough in cases where a suitable recipe for rebuilding the necessary structures with patient-matched cells has yet to be established. So here, researchers suggest an approach of partial decellularization: only remove the cells and structures that can presently be replaced, and go forward on that basis. Intriguingly, this might even be made to work in a living patient, replacing some types of tissue section by section in damaged or diseased lungs.

Lung transplantation - the only definitive treatment for patients with end-stage lung disease - remains limited by a severe shortage of donor organs such that only 20% of patients waiting for a donor lung undergo transplantation. Strategies aimed at increasing the number of transplantable lungs would have an immediate and profound impact. Tissue engineering strategies are currently under development to regenerate or replace injured lungs. Because of the extreme complexity of the lung, with its hierarchical three-dimensional architecture, diverse cellular composition, highly specialized extracellular matrix (ECM), and region-specific structure and function, bioengineering a functional lung is still an elusive goal. The lungs bioengineered by full decellularization and recellularization have shown a limited and temporary function, largely due to blood clotting and pulmonary edema, which have led to lung failure within a few hours following transplantation. To date, whole-organ engineering methods using lung grafts with denuded vascular networks have failed to produce functional grafts.

Given the essential need for intact and functional pulmonary vasculature, we developed an airway-specific approach to removing the pulmonary epithelium while preserving the surrounding cells, matrix, basement membrane, and vasculature. Previously established methods for decellularization of the entire organ were designed to remove both the epithelium and endothelium and could only be applied ex vivo. This study developed the first procedure for the removal of epithelium from the lung airway with the full preservation of vascular epithelium, which could be applied in vivo to treat diseases of lung epithelium. Whole lung scaffolds with an intact vascular network may also allow for recellularization using patient-specific cells and bioengineering of chimeric lungs for transplantation. In addition to the clinical potential, lung scaffolds lacking an intact epithelial layer but with functional vascular and interstitial compartments may also serve as a valuable physiological model for investigating (i) lung development, (ii) the etiology and pathogenesis of lung diseases involving pulmonary epithelium, (iii) acute lung injury and repair, and (iv) stem cell therapies.

Lung decellularization has resulted in substantial advances in lung bioengineering and the ability to create scaffolds for tissue engineering applications. We believe that our methodology can address some of the challenges that have slowed the progress in lung bioengineering by (i) preserving the vascular endothelium throughout the lung (from large vessels to capillaries) and (ii) targeting the removal of airway epithelium while maintaining structural and cellular components essential for lung repair. In summary, the creation of de-epithelialized whole lungs with functional vasculature may open new frontiers in lung bioengineering and regenerative medicine. Additionally, de-epithelialization could be applied to other organs with dual flow, such as the liver or kidney.

Link: https://doi.org/10.1126/sciadv.1700521

The Open Longevity group is a Russian non-profit volunteer organization that emerged from the Science for Life Extension Foundation community, and is working to organize responsible, open trials of potential therapies to address aspects of aging. They are a little too focused on tinkering with metabolism rather than repair of the damage that causes aging for my tastes, but each to their own. Based on recent news it seems they are going to try the Initial Coin Offering (ICO) path of fundraising for their ongoing efforts. It will be interesting to see how this goes, as just about anyone who has watched the frenzy over ICOs this past year has probably at some point wondered how to tap this flow of funding.

A few months ago I asked whether or not ICOs are a viable approach to pull funding into the field of longevity science. Here I mean in any capacity, whether that is running patient-paid clinical trials, conducting fundamental research, commercializing a senolytic drug candidate, and so forth. You should probably look back at that prior post for a brief overview of what an ICO is, how it relates to blockchain technologies such as Bitcoin and Ethereum, and why ICOs presently look like magical money fountains from some angles. Groups with very little credibility are raising tens of millions of dollars via this mechanism, bypassing traditional venture funding mechanisms. If they can do it, why not credible efforts in the field of rejuvenation research?

Following that post, a small group of us set up a mailing list to talk about the prospect (if you are knowledgeable regarding blockchain matters and have an interest in longevity science, let me know if you'd like an invite). We fairly quickly came to the conclusion that, magical money fountain or not, the only viable ICOs are those that promise some sort of network effect that, at least in theory, could increase coin value enormously given enough participation in that network. While it is entirely possible to run a Kickstarter-like project through an ICO, using a blockchain to track obligations, and allowing those obligations to be transferred, any sort of token that is at the end of the day exchanged for a product or service has a upper limit to its value. It is rather like a futures contract in nature. This is not interesting to the people pushing funds through the ICO ecosystem. They are looking for unlimited upside, in the same mindset as startup investors: this is true whether or not the ICOs in question are pump and dump schemes, failures waiting to happen in some other way, or actually legitimate ventures taking advantage of the opportunity to obtain funding without having to give up equity.

At this point we found ourselves a little stuck; if the goal is pull in some of the funds flowing through the ICO marketplace, then there must be a suitably attractive coin mechanism, one with network effects and upside. Yet there doesn't seem a good way to attach a suitably attractive coin mechanism to any of the potential near term ventures that our community might undertake. They all look, at best, like Kickstarter projects, or like equity fundraising, and at worst like traditional non-profit fundraising with no return on investment. Without that mechanism, the ICO marketplace will ignore any use of blockchain technologies, and so there is little point in trying to use them. It just complicates the usual process of fundraising, and that is not even to talk about the regulatory issues, which are evolving rapidly now that the SEC has taken an interest.

Has Open Longevity found a viable way forward by tying tokens to a voting mechanism in addition to Kickstarter-like forms of redemption? That is an open question, but we'll see how it goes. I'd suggest reading their white paper. Certainly, I wish them the best of luck in exploring this avenue: any group that pioneers a useful means of bringing more funding into our community has performed a useful service.

Open Longevity Project: a Scientific Approach to Conquer Aging

Open Longevity is organizing research of anti-aging therapies in humans by providing online advisory services. Their ultimate goal is to find and introduce effective methods of radical life extension into clinical practice. Therefore, the tokens are called YEAR. Mikhail Batin, the CEO of Open Longevity, states he is sure that effective ways to delay the onset of aging will be found - it is only a matter of time. He and his colleagues just want to accelerate the research.

The project consists of two parts: clinical trials and online service. Part of the funds raised through ICO will be spent on the first three studies: Longevity Diet-1 (a variant of a fasting mimicking diet); Alzheimer's disease therapy (vitamin B12) and atherosclerosis therapy (sartans + statins). One can even find documents for the first trial in progress, though just in Russian yet. As the trial is planned to be submitted to the NIH's Clinical Trials registry, the documents will be translated into English at some point. All the subsequent studies will later be also funded: life extension projects are expected to be submitted for voting on a general basis, voting will be conducted among all the YEAR token holders.

All clinical trials will be carried out in strict accordance with existing norms. Thus CROs (contract research organizations), laboratories, and clinical institutions that traditionally carry out similar research, will be involved. But the OL team is already talking about making all paperwork more automated. Another part of the funds will be spent on creating an online platform. By uploading biomedical data, users will be able to monitor their health and aging status in dynamics; receive recommendations from specialists and expert system based on AI; and also become volunteers in trials. The service will be accessible to everyone. But payment with YEAR tokens is promised to be more favorable than paying with fiat currencies due to 50% discount.

Open Longevity ICO

Open Longevity is a project that initiates, organizes, and guarantees openness of clinical trials of antiaging therapies. Two important components of our project are an online expert system, which interprets users' biomedical information in terms of aging biology, and new infrastructure for antiaging clinical trials. They are closely connected: the data obtained through trials is taken into account in the operations of the expert system, and the funds raised from users are spent on antiaging research.

At the first stage, the aim of which is the development of the platform and launching of the first trials, we will raise funds through our ICO. Our task is to build a self-sufficient system that will provide paid services to individuals but at the same time solve important problems for humanity on a noncommercial basis. We do not plan to protect our therapies with patents - our research results will be publicly available. We endeavor to direct patients' energy toward the fight against aging, and in our experience, our policy of openness attracts projects, funding, scientists, and volunteers to us.

One of the common concerns in the industry is that, once on the market, antiaging medicine will become available only to the elite. The openness of our project is a possible solution to this potential problem. Moreover, publishing final and intermediate results, as well as research protocols and all related materials, will give us the highest level of expertise. All clinical trials will be carried out in strict accordance with existing norms. We will prepare questionnaires, informed-consent forms, permissions of ethical committees, and brochures describing the design of our experiments. We will involve a CRO (contract research organization), laboratories, and clinical institutions that traditionally carry out similar research. We will include patients in a global movement to seek and test potential antiaging therapies that, once proven effective, will immediately become part of their own lives.

In this open access paper, evidence is presented for neuroimaging to be the basis for a biomarker of aging that is as good as the best of present candidate DNA methylation biomarkers. This is most interesting, though I suspect that there might be a higher chance that it will prove unhelpful as a way to assess the quality and effectiveness of potential rejuvenation therapies. That process of assessment is the reason why there is at present a considerable interest in the development of biomarkers that reflect chronological or biological age. Today the only practical approach to assessing candidate rejuvenation therapies is to provide the treatment and then wait and see: this is prohibitively expensive in humans, and too expensive for most research groups even in mice. That expense - and the time required to run life span studies - is holding the field back. If potential approaches to rejuvenation could be assessed quickly, that new capability would considerably speed up the pace of progress.

Why do I think that there is a great risk that neuroimaging might fail to be helpful in assessing rejuvenation therapies? Because most of the present proposed candidate treatments will change cellular biochemistry, remove problem cells, or repair forms of cellular damage, but will not repair the secondary outcomes of aging in the brain, such as white matter hyperintensities and other outcomes of the structural failure of blood vessels. These therapies would be expected to alter DNA methylation patterns, however, which are most likely more a reaction to cellular dysfunction and low-level molecular damage than a reaction to larger-scale structural changes. Still, this is an opinion offered in absence of evidence; we shall see how things turn out.

The search for robust, reliable and valid biomarkers of the ageing process is a key goal for gerontological science. Such tools should enable the quantification of individual differences in underlying biological ageing. This could have great utility for mapping personalised ageing trajectories, for predicting risk of future age-related deterioration and disease and for evaluating potential treatments aimed at improving healthspan or even slowing ageing itself. Given the multi-faceted nature of biological ageing, numerous potential candidate biomarkers have been proposed. These can be anthropometric, physiological or blood-based; indexing immune function, epigenetic signatures, gene expression profiles, physical capacity or body composition. To improve on individual predictors of biological age, panels combining multiple markers have also been proposed. While many of these approaches are highly promising, the results have yet to be translated into clinical practice.

The criteria most commonly used for assessing the appropriateness of ageing biomarkers is how strongly they correlate with chronological age in healthy people. In addition, thanks to the increasing use of machine learning, the accuracy with which chronological age can be predicted using multivariate biological data is also a useful indicator of potential biomarker value. Aligned with this, an independent line of research has emerged from the field of neuroscience. Using neuroimaging data, principally magnetic resonance imaging (MRI) brain scans, chronological age can be predicted accurately in a machine-learning framework. This neuroimaging-derived brain-age model is based on data from over 2000 healthy adults and shows excellent test-retest reliability. This presents the intriguing possibility that in-vivo measurements of brain volume could be used as an alternative ageing biomarker.

It is well-known that ageing affects the brain, both in terms of outward behavioural changes and cognitive decline, alongside alterations to the brain's biophysical structure and cellular and molecular functioning. Using measures of brain volume derived from T1-weighted structural MRI, assumed to reflect grey and white matter atrophy, high levels of age prediction accuracy have been consistently achieved. For example, our work found a mean/median absolute error of age prediction of 4.2/3.4 years, with a correlation between age and brain-predicted age of r = 0.96. This is comparable to or better than leading biological age prediction models, for example using DNA methylation status (r = 0.96, median absolute error = 3.6 years) or a panel of blood chemistry markers (r = 0.91, mean absolute error = 5.6 years).

Given the published data on neuroimaging-derived brain-age, it is worth considering its qualification against a set of consensus ageing biomarker criteria. Paraphrasing from the American Federation for Aging Research recommendations, an ageing biomarker must: 1) Predict the rate of ageing (i.e., estimate where a person is in their total life span); 2) Measure a basic process that underlies ageing, not the effects of disease; 3) Be able to be tested repeatedly without causing harm; 4) Work in humans and laboratory animals. Based on the above evidence regarding prediction of survival, neuroimaging-derived brain-age meets criteria #1. Given the accuracy of age prediction and the fact that brain atrophy occurs in the context of non-pathological ageing, this satisfies criteria #2. As a non-invasive imaging technique, T1-weighted MRI meets criteria #3. Finally, the accuracy of this technique in non-human primates has been recently reported, suggesting that it appropriately meets criteria #4.

While perhaps the major caveat regarding the use of neuroimaging in this context is the cost and potential logistics, projects like the UK Biobank imaging study show that collecting neuroimaging data on an extremely large scale are becoming increasingly feasible. It is timely for a marriage of neuroscience and biogerontology, and approaches that combine the most complementary information on the ageing human body will have the greatest utility in developing effective ageing biomarkers.

Link: https://doi.org/10.18632/aging.101286

Researchers have recently published an online database of biomarkers of human mortality, covering all such measures published and replicated to date. Many of these are not much more than background noise for ongoing efforts to establish a biomarker of biological age that is accurate and reliable enough to be used to assess candidate rejuvenation therapies. For example, excess fat tissue correlates very well with mortality over even fairly small study populations, but this isn't useful if the goal is to measure degree of rejuvenation following treatment. Other biomarkers might be more helpful, and taken as a whole, a database of measures of this nature allows for an easier synthesis of what is presently known about aging and mortality. Here the link points to an open access paper rather than the database itself, but you should take a look at both.

Ultimately, I think that the forms of damage outlined in the SENS vision for rejuvenation therapies will become important biomarkers. For example, senescent cell presence. As therapies for clearance of senescent cells are still in the process of clinical development, it isn't yet possible to use senescent cell counts as a biomarker of aging. Nonetheless, starting with cellular senescence, the next decade or so will see a circular process of verifying various candidate rejuvenation therapies and candidate biomarkers of biological age against one another, step by step. At the end of the day, each type of damage repaired by an effective rejuvenation therapy must be accepted as a valid biomarker of aging in and of itself. That the treatment works is proof of relevance.

Mortality biomarkers are of great clinical and research interest. General clinical applications include identifying high-risk patient groups, prognosticating for individual patients, and helping healthcare providers decide among treatment options. Examples of very well-studied mortality biomarkers include blood pressure, cholesterol, and waist circumference, which have well-established relationships with mortality in various populations documented in dozens of studies, some with thousands or millions of participants. These traditional biomarkers have been joined in more recent years by many biomarkers utilizing modern assays, for example genome-wide methylation levels, cell-free DNA concentration, and leukocyte telomere length.

Biomarkers of human mortality are also centrally important to research on human aging, due largely to the long potential duration of prospective studies on human lifespan. This can be a tremendous obstacle both in terms of resources (i.e. money to support such lengthy trials) and delayed progress (i.e. each research result could take decades to obtain). Mortality biomarkers have solved similar problems in the past by providing surrogate endpoints for crucial clinical outcomes, facilitating studies that might otherwise have been prohibitively expensive or time consuming. Blood pressure and cholesterol are two of many markers that have played this role in the past, by facilitating cardiovascular research aimed at reducing morbidity and mortality. Such biomarkers have also gained clinical importance as surrogate markers in clinical practice, where treatments are often initiated with the explicit goal of changing a patient's biomarker value. While this approach has important potential drawbacks, it is certainly more practical for a patient to track how a new intervention affects her blood pressure or serum cholesterol, rather than how it affects her lifespan, which is unknown until death.

Abundant research on mortality biomarkers has resulted in numerous associations documented across hundreds of publications, generating an unwieldy collection of data that can be difficult for researchers or clinicians to interpret or use effectively. There have been no recent attempts to collate this data nor, to our knowledge, to provide tools for locating, organizing, or comparing data from relevant studies. In the present article, we describe an effort to facilitate a more comprehensive and effective approach to evaluating the literature in this area. We present MortalityPredictors.org, a manually curated, publicly accessible database housing published, statistically-significant relationships in humans between biomarkers and all-cause mortality in population-based or generally healthy samples. To our knowledge, this is the first publicly available resource to collect such information, and we hope it will encourage: 1) the allocation of resources to mortality biomarkers with the greatest potential for accurately predicting human all-cause mortality, 2) efforts to construct multi-biomarker models to further improve such accuracy, and 3) research on human aging and therapies that aim to slow aging or otherwise reduce mortality.

Link: https://doi.org/10.18632/aging.101280

Nearly a decade ago ago I hopefully envisaged the Vegas Group as a fictional, near-future, informal association of like-minded people coming together to organize and fund trials of early rejuvenation therapies, a natural outgrowth of longevity-focused conferences and progress in the underlying science. I put the founding date for the Vegas Group as 2016. That might be close, as it turns out. On balance, I think that the Society for the Rescue of our Elders, established this year in the wake of the Revolution Against Aging and Death (RAAD) Festival, has a shot at becoming this association in reality. A number of quite sensible people in our community are apparently involved, and the Society for the Rescue of our Elders is in a position to harness the raw enthusiasm of two generations of longevity advocates and potential trial participants: those who started in the 1970s, tried and failed to make anti-aging medicine work, but who still have the enthusiasm for the cause, and those of today who are focused on senolytics, gene therapies, and other modern techniques that may well produce actual, functional, first generation rejuvenation therapies. The evidence to date looks good.

Individuals associated with the Society for the Rescue of our Elders are coordinating and organizing a small variety of human trials at this point, covering a number of approaches to treating aging as a medical condition. I think some of these are worth the effort and we should be cautiously enthused: primarily senolytics to remove the contribution of senescent cells to the aging process, but also other items with varying degrees of support. The important point here is that this is happening at all, that our broader community has generated an association that can potentially act as a seed, a nucleus, a rallying point for all additional efforts. Many hands can make light work, and once there exists an informal network with experience in running the trials that we want to see take place, then future trials and larger trials and clinical availability all become that much easier to organize. Once the relationships with laboratories and university groups and all the other important groups are there - well, that is the hurdle that would stop most people from proceeding, not the funds. What use money when you are corroding?

I have in the past suggested that at some point the "anti-aging" marketplace, whose participants have built an industry and pipeline and customer base on the basis of selling things that don't work, will gravitate to the first potential approaches that do in fact work. A significant fraction of those involved are still believers in the original goal - to meaningfully turn back aging. The Society for the Rescue of our Elders, like the RAAD Festival, emerges from the Life Extension Foundation crowd. They have always had the burden of being supplement and "anti-aging" focused, but their initiatives have been incrementally stepping towards engagement with the most promising new medical technology, and I suppose that the current explosion of interest in senolytics has finally tipped things over the edge. Rejuvenation therapies are almost here, cheap candidate drugs exist, and it would be foolish to think that the "anti-aging" community would ignore this development. In the present environment, an alliance between those who can bring funding and a broad base of interested participants and those who know the presently most promising science and medical initiatives could go a long way. That is exactly what may be happening here.

I can say that had I the funds to pay for organizing a trial of one of the more promising senolytic drug candidates, I'd certainly be interested in coordinating with the people who are already running a small senolytic trial with the Society for the Rescue of our Elders. There are, I think, any number of individuals ten or twenty years my senior with the resources to do just that, were they aware of the opportunity. One of them already has. In my hypothetical had-I-the-funds trial, I'd collar a dozen volunteers in their late 40s, a selection of the assays I suggested would be good for a single-person experiment, and look for significant effects in the demographic who are just starting to see the first declines of aging. It would be an interesting counterpoint to the current - and quite sensible - strategy of restricting trials to people in their late 60s and older, possessed obvious manifestations of aging. Larger and more pressing problems make it easier to quantify the results of treatments like clearance of senescent cells. But aging doesn't start at 60, and the ideal time to begin rejuvenation therapies is earlier in life. Therefore we want to be able to prove that the first senolytic drugs are or are not capable of producing meaningful outcomes at those earlier ages.

The Society for the Rescue of our Elders is still at the stage of understanding how to best manage the self-assembly of a community, and how to channel help. But they have a contact form, they have an email address. If you can help to make things happen, given a network of connections to laboratories, clinics, and research groups, let them know. Tell them what you can bring to the table and ask for their contacts, then see what can be made to happen. It is a much better path that sitting around waiting for someone else to do the work of bringing therapies to the clinic.

The proximate cause of age-related osteoporosis is a growing imbalance between the distinct mechanisms and cell populations that are responsible for creating and breaking down bone tissue. It is plausible that delivering more cells capable of building bone may usefully patch over the situation to some degree - but it is only a patch, and it does only address this one majority cause of weakened bone in old people, and it does so without addressing the underlying causes, such as presence of senescent cells. Further, there are other unrelated causes of weakened bone in older individuals, including the persistent cross-linking of molecules in the bone extracellular matrix that makes bone less resilient. Nonetheless, as the authors here point out, a great many stem cell trials that might produce effects on the progression of osteoporosis are already taking place, without recording that data because they are focused on the treatment of other conditions. There is an opportunity to learn more about the utility of stem cell therapies for this condition with comparatively little additional effort.

Osteoporosis is caused by an imbalance between the tightly regulated process of bone formation by osteoblasts and resorption by osteoclasts. Primary osteoporosis is defined as bone loss attributed to aging or a decline in sex hormones associated with aging. This age-related osteoporosis involves the gradual loss of bone caused by insufficient bone formation.

The lack of an overall mechanistic understanding of what drives age-related osteoporosis has hindered the development of anabolic therapy appropriately targeting the etiology of the disease. It is hypothesized that decrease in the number and function of bone and bone marrow (BM)-derived mesenchymal stromal cells (MSCs) - a heterogeneous population comprising skeletal stem cells (SSCs), osteoblastic cells, and fibroblasts - lies at the root of age-related bone loss. Specifically, age-related changes in the proliferative and differentiation capacity of BM-MSCs are suspected, and recent evidence suggests that the loss of SSCs, which are a rare subset of MSCs, could be the most relevant event in the progression of senile bone loss. Thus, treatment strategies aimed at replenishing the MSCs compartment - and by extension SSCs - or augmenting endogenous populations of these cells, could result in bone growth and combat age-related osteoporosis.

A number of preclinical studies have been undertaken to determine whether MSC-based cell transplantation can induce bone formation. We have recently reported that transplantation of unmodified, low-passage MSCs prevents age-related osteoporosis in a mouse model. At the 6-month time point, we showed that transplanted animals displayed markedly increased bone formation, as well as higher osteoclast numbers. This led to improved bone quality and turnover, and importantly, sustained microarchitectural competence. Complementary to our work, studies documenting proof of principal that MSC transplantation can prevent senile osteoporosis in mouse models of accelerated aging present consistent findings.

Before the full benefit of SSC therapy can be leveraged toward bone regeneration, certain basic, translational, and clinical scientific questions will need to be answered. First, SSCs have only recently been characterized in murine models, and aside from one study documenting a BM stromal cell possessing some properties of SSCs (the generation of the hematopoietic microenvironment), this cell remains unidentified. As such, the human SSC still needs to be located, and fully characterized for phenotypic characteristics and cell surface antigen profile. Second, once identified, methods need to be developed to ensure the cell can be harvested and expanded to clinically relevant quantities. Stem cells often lose their multipotent, and self-renewal capabilities soon after removal from their native environment, therefore techniques will need to be optimized to enable large scale culture. Finally, although the safety and tumorigenic profile of MSCs has been fully evaluated and deemed safe, necessary due diligence will need to be performed on SSCs.

With over 500 clinical trials using MSCs registered with clinicaltrials.gov and numerous others being conceived, there presents a tremendous opportunity to maximize the scientific value of these expensive, laborious studies. The ability to co-operate, and leverage the availability of large, well-characterized cohorts of patients receiving MSCs (or other cell therapy/regenerative medicine agents) will maximize resource utilization. The ubiquitous nature of age-related bone loss in humans makes it an ideal candidate for regenerative medicine. Thus, we propose an ancillary study for osteoporosis to assess bone formation gains after systemic MSC transplant. By teaming up with other, even multiple, clinical trials the necessary number of patients could be more readily reached. This innovative model could be used to assess stem cell effects on various diseases in patients with existing comorbidities and chronic disease from trials that would normally only focus on one of the patient disease states. Significant savings can be achieved using an ancillary model in cell therapy due to cost sharing of expensive cell isolation, manipulation, and patient delivery.

Link: https://doi.org/10.1002/sctm.17-0054

Researchers have found hundreds of genes that can be manipulated to at least modestly extend longevity in various laboratory species, though the size of the effects diminish as species life span increases. Short-lived species have life spans that are far more plastic in response to environmental and genetic changes. Since proteins group into interaction networks, most of these genetic manipulations are different ways to adjust the same few core underlying processes. Mapping metabolism sufficiently to understand all of this is an ongoing process, but one that seems unlikely to contribute greatly the near future of human longevity. Unfortunately, adjusting the operation of metabolism is a poor path to the treatment of aging in comparison to repair of the molecular damage that causes aging: it can only slow aging, not reverse it; the past fifteen years have demonstrated that it is expensive and produces few useful therapies; the potential for additional years of healthy life is low. Nonetheless, it remains the primary focus of the research community.

Hundreds of genes, when manipulated, have been shown to affect the lifespan of model organisms (yeast, worm, fruit fly, and mouse). These genes, further denoted as longevity-associated genes, LAGs, could be defined as those whose modulation of function or expression results in noticeable changes in longevity - lifespan extension or accelerated aging. We have previously investigated the characteristic features of LAGs and found that (i) they display a marked diversity in their basic function and primary cellular location of the encoded proteins; and (ii) LAG-encoded proteins display a high connectivity and interconnectivity. As a result, they form a scale-free protein-protein interaction network ('longevity network'), indicating that LAGs could act in a cooperative manner.

Many LAGs, particularly those that are hubs in the 'longevity network', are involved in age-related diseases, including atherosclerosis, type 2 diabetes, cancer, and Alzheimer's disease, and in aging-associated conditions such as oxidative stress, chronic inflammation, and cellular senescence. The majority of LAGs established in yeast, worms, flies, and mice have human orthologs, indicating their conservation 'from yeast to humans'. This assumption was also supported by studies on specific LAGs or pathways such as Foxo, insulin/IGF1/mTOR signaling, Gadd45, and cell-cell and cell-extracellular matrix interaction proteins.

Now, the existing databases on orthologs allow for an essential extension of the analysis of LAG orthology, far beyond the traditional model organisms and humans. In particular, the data deposited in the InParanoid database Eukaryotic Ortholog Groups include orthologs for the complete proteomes of 273 species. Here, we report the results of an unprecedentedly wide-scale analysis of 1805 LAGs established in model organisms, available at Human Ageing Genomic Resources (HAGR) GenAge database, with regard to their putative relevance to public and private mechanisms of aging.

Our wide-scale analysis of longevity-associated genes (LAGs) shows that their orthologs are consistently overrepresented across diverse taxa, compared with the orthologs of other genes, and this conservation was relatively independent of evolutionary distance. Moreover, many worm LAGs were discovered by postdevelopmental RNA interefence on genes essential for growth and development, and this predominantly resulted in lifespan extension. That is, postdevelopmental suppression of genes that are vital early in life but are detrimental later in life, can be beneficial for longevity. The orthologs of these LAGs are also highly overrepresented across diverse taxa. Altogether, the C. elegans analysis suggests that antagonistic pleiotropy might be a highly conserved principle of aging.

An important observation in our study was that the majority of manipulations on LAG orthologs in more than one model animal resulted in concordant effects on longevity. This strengthens the paradigm of 'public' longevity pathways and of using model animals to study longevity, even across a large evolutionary distance. This notion is further strengthened when combined with the observation that the existence of an ortholog is probably accompanied by a preserved role in longevity. Yet, we also observed LAGs with ortholog presence only in a limited number of taxa, or that displayed discordant effects when tested in more than one species, which could, at least in part, be attributed to 'private' mechanisms of aging. Definitely, more comparative studies are warranted to better discriminate between private and public mechanisms, with unified methods of intervention and evaluation in mind.

Link: https://doi.org/10.1111/acel.12659