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- Reviewing Juvenescence: Investing in the Age of Longevity
- Gene Therapy Improves Heart Muscle Function to Compensate for Heart Failure
- The Biochemistry of GDF11 is Complex, and Whether or Not it Has a Significant Role in Aging Remains a "Matter of Lively Debate"
- Suppressing Wnt/β-catenin Signaling to Reduce Cardiac Fibrosis after Injury
- Additional Evidence for Transthyretin Amyloid to Contribute to Osteoarthritis
- CBFB is Involved in the Loss of Osteoblasts with Advancing Age
- Participate in the WHO's Open Consultation on Research Priorities for Healthy Aging
- A Review of Vascular Aging, with Thoughts on Reversing It
- Adjusting the Behavior of Specific Immune Cells to Reverse Autoimmunity
- More Data on the Direct Financial Costs of Excess Fat Tissue
- The Degeneration of Axons in Aging
- Inflammatory Immune Cells Make Fat Harder to Lose as Well as Worse for Health
- Immune Cell Telomere Length Correlates with a Blended DNA Methylation and Immune System Biomarker of Aging
- Lipid Peroxidation and APOE Variants in Alzheimer's Disease
- FOXO Genes and Human Longevity
Reviewing Juvenescence: Investing in the Age of Longevity
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.
Gene Therapy Improves Heart Muscle Function to Compensate for Heart Failure
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.
The Biochemistry of GDF11 is Complex, and Whether or Not it Has a Significant Role in Aging Remains a "Matter of Lively Debate"
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.
Suppressing Wnt/β-catenin Signaling to Reduce Cardiac Fibrosis after Injury
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.
Additional Evidence for Transthyretin Amyloid to Contribute to Osteoarthritis
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.
CBFB is Involved in the Loss of Osteoblasts with Advancing Age
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.
Participate in the WHO's Open Consultation on Research Priorities for Healthy Aging
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.
A Review of Vascular Aging, with Thoughts on Reversing It
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.
Adjusting the Behavior of Specific Immune Cells to Reverse Autoimmunity
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.
More Data on the Direct Financial Costs of Excess Fat Tissue
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."
The Degeneration of Axons in Aging
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.
Inflammatory Immune Cells Make Fat Harder to Lose as Well as Worse for Health
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.
Immune Cell Telomere Length Correlates with a Blended DNA Methylation and Immune System Biomarker of Aging
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.
Lipid Peroxidation and APOE Variants in Alzheimer's Disease
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."
FOXO Genes and Human Longevity
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.