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- A Nuanced Opposition to the FDA and Similar Regulatory Agencies
- Fibrosis is Harmful, and Varied Approaches to Suppress it are Under Development
- Genetic Manipulation to Increase the Proportion of Brown Fat Tissue is Shown to Modestly Extend Mouse Life Span
- Continuing the Debate Over the Heart of the Mitochondrial Theory of Aging
- As Cicero Said, We Must Fight Against Aging as We Would Against a Disease
- Delivery of Exosomes Improves Recovery from Stroke in Pigs
- Calorie Restriction as the "Most Reasonable Anti-Aging Intervention"
- The Fight Against Aging and the Fight Against Ageism
- Regenerative Medicine as an Approach to Treat Alzheimer's Disease
- Inflammatory Signaling Reduces Pancreatic Islet Cell Replication in Aging
- An Interview with a Programmed Aging Theorist
- CXCR4 as an Indicator of Microglial Involvement in Neurodegenerative Diseases
- Cells in High Risk, Unstable Atherosclerotic Plaque Exhibit a Cancer-Like Metabolism
- Results from a Human Trial of Mitochondrially Targeted Antioxidant MitoQ
- SPATA31 Gene Family Copy Numbers as a Human Example of Antagonistic Pleiotropy
A Nuanced Opposition to the FDA and Similar Regulatory Agencies
As regular readers will know, I am no great admirer of medical regulation as it presently exists in the wealthier parts of the world. It is a burdensome system, in which whatever power good intentions have to make the world a better place has long been eroded away by the short-term human incentives present in any large bureaucratic organization. What is left is a system in which it costs multiples of what it should cost to bring medicine into the clinic at an appropriate level of risk, a system that acts primarily to suppress rather than encourage development of new medical technology, and a system that tramples upon the rights of patients to make their own informed choices.
In the past my prescription for a better future has been one in which medical tourism flourishes: the use of regulatory arbitrage to bring medicine to the clinic in a responsible way in places outside the US. The eminently dysfunction US medical system, in which no party is incentivized to control costs, the most influential parties collude to prevent cost discovery, and quoted costs have little relation to actual costs, leads to a situation in which it is cheaper to fly halfway around the world to another country to receive even modest procedures. So let medical tourism grow as a form of pressure upon the existing regulatory system, because competition from outside is the only thing that has a hope of resulting in significant reform.
Any number of people work within the system on initiatives to make it better. There are non-profits and high net worth individuals and patient advocates all calling for reform of the FDA in one way or another. All are distinguished by having had very little positive effect over the years of their efforts. Indeed, over the last decade the cost of FDA approval has doubled, the time lengthened, and the rate at which new medical technologies are approved is stagnating. This has happened over the course of a period of enormous, staggering progress in biotechnology, in which costs of the underlying technologies have fallen dramatically. How can this be the case? Cynically, I would say this was also a period of great progress in connectivity and media exposure. Thus the tendency of bureaucrats to prioritize the minimization of bad press and accountability leads to ever greater demands, costs, and delays placed on regulatory applications, in search of a mythical, non-existent minimum level of risk that can only really be obtained by preventing new technologies from arriving at all.
Medical tourism, however, has challenges, primarily that it remains a highly disorganized market. Few of the people who might benefit significantly in fact do so. It requires a fair amount of research and determination; there is no easy on-ramp. I think that it will require universally desired enhancement therapies, such as follistatin or myostatin gene therapies for muscle growth, to obtain a large enough number of potential customers to generate sufficient organization in this marketplace to build that on-ramp. The number of people with severe illnesses is simply too small for the self-organization of entrepreneurship and venture funding to snowball in medical tourism - if it was going to happen, it would have happened already.
Here is another question: how do new therapies become available via medical tourism? Just as medical tourism is disorganized, so too there are large challenges facing company founders who want to responsibly develop and offer a therapy outside the established mainstream regulatory systems. A clear path forward to this goal has not been built; there is no roadmap. It is the jungle of uncertainty, and investors fear uncertainty. The founders of a company heading in this direction, such as BioViva Sciences and a few others, are faced with not just the challenging of building a therapy that is safe and reliable, but also building the entire infrastructure - the relationships, the legal understandings, the third party validation of safety and effectiveness - to bring that therapy into a clinic. Then they must also survive the bombardment of negative press from organizations invested in the status quo, hostile to the idea that proving safety and responsibility really doesn't require more than a fraction of the costs that the FDA imposes. Further, the founders must successfully woo investors who are very used to the present beaten path and nervous regarding anything new.
Taken together, this is a tall order. It is a task suited to a non-profit, or more accurately a dedicated organization, or a distributed bootstrapping process of cultural change driven by many such groups. The prize is well worth it, in terms of an acceleration of progress towards many new classes of therapy, a removal of the dead weight cost that slows and suppresses advances in medicine. As is so often the case, it is far easier to articulate the change we'd like to see than to make it happen, however.
So if I started a medical biotech company, I'd have to say that I would take it through the current regulatory system, while (a) being an honest player by the rules of that system, because that is the best way through the gauntlet, and (b) continuing to hold the view that the whole thing should be replaced with a far less self-serving, onerous, expensive, and terrible option. Unfortunately, the standard regulatory path is the only fairly reliable way to put a therapy in the hands of large numbers of patients. The other, ethically far better paths, such as that pursued by BioViva, have the unfortunate outcome of great uncertainty in whether patients will ever be able to use the treatment in large numbers. I'm sure I'm not alone in having come to this position.
The change the world needs here is clear: a far more organized industry of medical tourism, and an infrastructure for responsible medical development and validation of therapies, outside the established regulatory systems, that is generally accepted by investors. These challenges are easy to state, but resistant to any sort of easy solution that can do better than reaching a fraction of the patients who might benefit. At present any one company might succeed against the odds in obtaining enough funding and support to set up an offshore clinic - but how many patients can they reach? Small heroic battles, one company at a time, will not be enough. Until greater change is achieved, near everyone who starts the process of medical development will likely look at the landscape and make the rational short-term choice to pass through the existing regulatory gauntlet.
Fibrosis is Harmful, and Varied Approaches to Suppress it are Under Development
Fibrosis is one of the major age-related failures of mammalian regenerative processes. Instead of reconstructing or maintaining the correct form of tissue, scar-like structures are deposited, disrupting organ function. Enough of this is fatal in organs such as the heart, liver, kidney, or lungs. Rising levels of fibrosis, and particularly following trauma such as infection or structural failure of aged blood vessels, are a significant component of loss of organ function and mortality in the old. Worse, the medical community has little in the way of therapies that can treat fibrosis; those that do exist are marginal in their benefits.
The causes of fibrosis are thought to be complex and tissue specific because regeneration is complex and tissue specific. Considered at the high level, it is a coordinated dance carried out between stem and progenitor cells of various types, the somatic cells already present in the tissue to be worked on, and immune cells, with many and varied signals passing back and forth between all of these types. The lower level details vary considerably by tissue type and structure.
In recent years, however, investigation of senescent cells - and the ability to slow aging by targeted removal of those cells - has revealed that a fair amount of fibrosis appears secondary to cellular senescence. Senescent cells generate chronic inflammation, as well as signals related to construction and destruction of the extracellular matrix, so it seems almost obvious in hindsight that they would be involved. A range of supporting evidence makes it seem plausible that inflammation causes disarray in the role of immune cells in regeneration and tissue maintenance, and comparisons between highly regenerative and less regenerative species suggest that immune cells strongly determine the quality of regeneration. Fibrosis in the lungs and other organs can be reversed through the use of senolytic treatments that destroy some fraction of senescent cells, a result so far demonstrated in animal studies only.
The research noted here is an example of bypassing all of these consideration in favor of outright sabotage of a crucial mechanism in tissue maintenance that is needed for fibrosis to occur. Unfortunately, this will also sabotage other important forms of normal regeneration, which may well limit its application to the treatment of critical cases after the fact, rather than as a form of prevention to keep the damage of fibrosis to a low level. Other forms of medicine with similar downsides have done well - think of the biologics for autoimmune disease that work through blanket suppression of parts of the immune system, for example - but I would hope that the research community can do better than this class of approach in the years ahead.
Blocking Matrix-Forming Protein Might Prevent Heart Failure
Researchers tested a manufactured peptide called pUR4 to block the fibronectin protein in human heart cells donated by heart failure patients. The treatment prevented the human heart cells from failing and restored their function. The treatment also reduced fibrosis and improved heart function after a simulated heart attack in mice.
Fibronectin is normally a good actor in the body. It helps form a cell-supporting matrix for the body's connective tissues, aiding tissue repair after injury. But after a heart attack, fibronectin overreacts, it polymerizes and helps produce too much connective matrix. It also causes hyperactive production of clogged and dysfunctional cardiac myofibroblast cells that damage the heart. The pUR4 compound is designed so it will attach to surface points on fibronectin, effectively inhibiting its effects in injured heart cells.
The pUR4 molecular treatment used in the current study is one of several compounds that show promise in preliminary preclinical research data. A key question in the current study was verifying the results of pUR4 targeted molecular therapy in both the mouse models and human heart failure cells. In mice with simulated heart attack that as a control experiment received a placebo therapy, the animals developed significant fibrosis and heart failure. When researchers treated mice with pUR4 for just the first seven days after heart attack, or genetically deleted fibronectin activity from the heart cells of mice, these reduced fibrosis and improved cardiac function. Treatment of human failing heart cells with pUR4 also reduced their fibrotic behavior.
The researchers emphasize it's too early to know whether the experimental therapy in this study can one day be used to treat human heart patients clinically. Extensive additional research is needed first, including proving pUR4's safety in larger animal models and then moving on to establish proof-of-principal effectiveness treating heart failure in those models.
Inhibiting Fibronectin Attenuates Fibrosis and Improves Cardiac Function in a Model of Heart Failure
Fibronectin (FN) polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblasts (MF) following cardiac injury. We hypothesized that interfering with FN polymerization or its genetic ablation in fibroblasts would attenuate MF, fibrosis, and improve cardiac function following ischemia/reperfusion (I/R)-injury.
Mouse and human MF were utilized to assess the impact of the FN polymerization inhibitor (pUR4) in attenuating pathologic cellular features such as proliferation, migration, extracellular matrix (ECM) deposition, and associated mechanisms. To evaluate the therapeutic potential of inhibiting FN polymerization in vivo, wild-type (WT) mice received daily intraperitoneal injections of either pUR4 or control peptide immediately after cardiac surgery, for seven consecutive days.
pUR4 administration on activated MF reduced FN and collagen deposition into the ECM and attenuated cell proliferation, likely mediated through decreased c-myc signaling. pUR4 also ameliorated fibroblast migration. In vivo, daily administration of pUR4 for seven days post-I/R significantly reduced MF markers and neutrophil infiltration. This treatment regimen also significantly attenuated myocardial dysfunction, pathologic cardiac remodeling, and fibrosis up to 4 weeks post-I/R. Finally, inducible ablation of FN in fibroblasts post-I/R resulted in significant functional cardioprotection with reduced hypertrophy and fibrosis.
Genetic Manipulation to Increase the Proportion of Brown Fat Tissue is Shown to Modestly Extend Mouse Life Span
The operation of metabolism determines species longevity, and in short-lived species this link tends to be highly variable in response to circumstances: exercise, diet, and consequences such as amounts and types of muscle and fat tissue. Longer lived species such as our own are, if anything, remarkable for the comparative lack of variation in life span across large differences in diet and the configuration of muscle and fat in our bodies. As researchers continue to map the interaction of metabolism and aging in laboratory mice, one interesting theme that has emerged is the importance of brown adipose tissue. In the open access paper noted here, the authors report that increasing the proportion of fat tissue that is brown rather than white can produce a 10-15% increase in mouse life span. They suggest this is mediated by SIRT3 activity and downstream effects on mitochondrial function.
The results here might be compared with a very intriguing study published last year in which researchers described what happens to metabolism and fat tissue in mice if their sense of smell is disabled. That resulted in healthier, metabolically superior mice characterized by a greater proportion of brown fat tissue. It built upon a range of past research suggesting that sense of smell plays a sizable role in the metabolic reaction to food. Unfortunately, for these and all other similar metabolic manipulations, we can't expect sizable results to transfer to humans and other long-lived mammals. For those interventions wherein researchers can directly compare mice and humans, the outcome on human life spans is much smaller, and supporting evidence strongly suggests that this holds up across the spectrum of everything involving diet, fat, and metabolism. The health benefits - distinct from effects on the pace of aging - may still be worth pursuing, if the costs are reasonable, however. Consider calorie restriction, for example.
There is also the point that a 10% life span effect in short-lived species is somewhere in the margin of error, and may well be hard to replicate. Looking back at the past few decades, 10% effects come and go in mice. One of the challenges is that an intervention may make mice choose to eat less for any number of reasons. The effects of calorie restriction are so large that they can swamp whatever else is going on in the study. The researchers here report carefully on the details of their many measures of metabolism, but one always has to read those details in order to understand whether they rule out a calorie restriction effect. That may not be the case here, for all that various aspects of the biochemistry under study match up well with what is presently known.
Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14
There are two distinctly different types of fat found in mammals: white adipose tissue (WAT), which is an essential site for triglyceride storage, and brown adipose tissue (BAT). The BAT is a protective mechanism of recent interest. BAT enhances energy metabolism and protects against cold exposure and obesity. A novel model to investigate the role of BAT in healthful aging and lifespan is the mouse model of the gene knockout (KO) of the regulator for G protein signaling 14 (RGS14), which has increased BAT.
Most prior work on RGS14 focused on its effects on embryonic development and on the visual cortex and central nervous system. The role of BAT in RGS14 KO and its ability to enhance lifespan and improve metabolism, the focus of the present investigation, have never been explored. To confirm the essential role of BAT in mediating the protection in the RGS14 KO, we transplanted BAT from RGS14 KO to wild type (WT) mice, a technique that is equivalent to a BAT KO, as it disrupts the salutary phenotype in the RGS14 KO and transplants these features to their WT, receiving the BAT.
Lifespan was monitored in the mice, and we observed significantly longer lifespan of RGS14 KO vs. WT mice. Median lifespan was increased by 4 months from 24 to 28 months. Median lifespan and maximum lifespan were increased to a similar extent in females and males. The older RGS14 KO mice were also protected from aging-induced atrophy of the thymus. It is also important that BAT protects against the aging phenotype, for example, graying and loss of hair, dermatitis, and hunched back, all of which were observed in old WT mice, but not observed in old RGS14 KO mice or in old WT mice, which received BAT transplants.
RGS14 KO mice had improved body composition compared to WT mice. RGS14 KO mice had lower body weight and WAT index (% of white fat to total body weight). The BAT index (% of brown fat to total body weight) was increased in RGS14 KO by 77% compared to their WT littermates. From RT-qPCR analysis to profile changes in BAT transcript levels, we found that BAT-specific markers were significantly upregulated. As healthful longevity and BAT are known to improve metabolic function, we assessed metabolism through indirect calorimetry and demonstrated greater oxygen consumption in RGS14 KO than WT mice.
In the RGS14 KO, SIRT1 was downregulated, while SIRT3 was upregulated. To confirm the role of the SIRT3 mechanism, a double KO (RGS14 KO X SIRT3 KO) was studied. The RGS14 X SIRT3 double KO mice lost their improved metabolism, pointing to SIRT3 as a mediator of the beneficial effects on metabolic regulation in the RGS14 KO animals. Therefore, RGS14 deficiency promotes increased SIRT3 activity, not only by increasing its expression levels, but also by increasing the availability of NAD+, an important cofactor required for sirtuin function. SIRT3 activation, in turn, leads to improved mitochondrial biogenesis, providing the molecular basis for healthful aging in the RGS14 KO animals.
Continuing the Debate Over the Heart of the Mitochondrial Theory of Aging
Every cell contains hundreds of mitochondria, the distant descendants of ancient symbiotic bacteria. They have evolved to become cellular components, tightly integrated into many vital functions, but still replicate like bacteria, and still contain a small remnant circular genome, known as mitochondrial DNA. Of the varied tasks undertaken by mitochondria, the most important is the generation of the chemical energy store molecule ATP, used to power cellular operations. This is a necessarily energetic operation and produces oxidative molecules as a byproduct, capable of reacting with and damaging the proteins that make up cellular machinery. This sort of reaction happens constantly and is repaired constantly, as a cell is a fluid bag of countless proteins and other molecules bumping into one another. Too much is harmful, however.
Mitochondrial DNA encodes a few vital proteins, necessary for the correct function of mitochondria, particularly when it comes to the mechanisms of ATP generation. Unfortunately mitochondrial DNA is right next door to the machinery that produces ATP and reactive molecules, it replicates far more frequently than the DNA of the cell nucleus, thus generating errors at a greater rate, and in addition has inferior protective and repair mechanisms in comparison to nuclear DNA. Mutations accumulate over time, in a random way.
The core of the mitochondrial theory of aging is that this mutational damage contributes to aging. The mechanism of production of ATP is disrupted, moves to much less efficient modes, and generates excessive reactive byproducts. Cells appear in which mutant mitochondrial have taken over, being more resistant to cellular quality control systems, or being able to replicate more efficiently. These cells cause harm to surrounding tissues, exporting large numbers of reactive oxidative molecules, resulting in oxidatively damaged lipids travelling far and wide in the body via the bloodstream, contributing to the progression of degenerative aging. As the open access paper here notes, however, there is an ongoing debate in the research community over which forms of mutation are more important, and how they occur. The evidence is contradictory, and each new attempt to produce mice in which certain forms of mitochondrial mutation are prevalent muddies the waters further. The paper is an example of the continued scholarly discussion on this topic.
The SENS rejuvenation research approach to mitochondrial DNA damage is to copy the thirteen vital mitochondrial genes into the cell nucleus, suitably altered so that the proteins will be shipped back to mitochondria. The advantage of this approach is that it doesn't matter how the mutations happen - the approach will fix the problem regardless of its source. No matter how ragged mitochondrial DNA might become, the proteins needed for correct function will still be available. It bypasses the need to fully understand the roots of the problem, a task that is proving to be challenging, slow, and expensive. To date, the SENS program - at the Methuselah Foundation and later the SENS Research Foundation - has funded the work that led to Gensight Biologics and their focus on copying the ND4 gene into the cell nucleus, and then demonstrated a similar proof of concept for ATP6 and ATP8.
Is There Still Any Role for Oxidative Stress in Mitochondrial DNA-Dependent Aging?
The central principles of the mitochondrial theory of aging are that (i) mitochondrially produced reactive oxygen species (ROS) can damage mitochondrial DNA (mtDNA), and (ii) ROS-induced lesions in mtDNA can lead to somatic mutations that accumulate, affect the integrity of respiratory chain, and cause mitochondria-dependent aging. More recent data seem to indicate that mtDNA might be more resistant to oxidative damage than previously thought. Instead, many have suggested that the origin of somatic mtDNA mutations is associated with the fidelity of the mtDNA polymerase γ (POLG). Additionally, there seems to be little experimental support for the vicious cycle theory, which attempts to explain the age-dependent accumulation of mutations by proposing a mutation-dependent increase of mitochondrial ROS production that, in turn, would result in elevated oxidative mtDNA damage.
Rather, the age-dependent increase in the somatic mutation load of mtDNA reported by many groups can be explained sufficiently by the replicative segregation of mitochondrial mutations. This theory has been supported by evidence that individual cells of aged persons accumulate high levels of only one specific mutation. Additionally, the effect of mtDNA mutations on mitochondrial ROS production has been reported to be strongly mutation dependent. Only certain mutations that affect the activity of Complex I and Complex V have been convincingly shown to increase mitochondrial ROS production, while random mtDNA point mutations do not seem to be associated with elevated oxidative stress.
One of the most important issues relating to the mitochondrial theory of aging is the very low frequency of somatic mutations detected in the mtDNA in tissue samples from older individuals. Obviously, the mitochondrial genome is present in multiple copies (approximately 10 copies per mitochondrium), and it is a well-established fact that intact mtDNA can complement for mutated genomes. Therefore, it is difficult to imagine how minor changes in the mitochondrial genome could lead to functional effects on the cellular level. Only a mosaic distribution of mutated genomes, resulting from preferential accumulation of mutants in certain cells, can explain the occurrence of such functional effects in these cells. To cause a functional effect within a cell, a pathogenic point mutation must typically exceed 85-90% heteroplasmy, while deletions appear to cause functional effects at heteroplasmy levels above only 60%.
This threshold concept has been validated in tissue samples from numerous patients with mitochondrial diseases harboring pathogenic point mutations or mtDNA deletions, which contain a mosaic of cells with defects in oxidative phosphorylation (OxPhos) that are usually detectable by testing for missing cytochrome c oxidase (COX). Similar mosaics of cells that do not have COX have been reported in postmitotic tissues, such as skeletal muscle, heart muscle, or the brain. However, the number of cells lacking COX in these cases is much lower than that reported in cases of mitochondrial diseases.
First attempts have been made to clarify the potential physiological impact of low amounts of cells lacking COX on intact tissues. In research studying such effects on mouse hearts, compelling evidence has been provided that if the frequency of deletions in a small number of individual heart cells exceeds the above-mentioned threshold, then arrhythmia - a typical symptom of age-related heart disease - may develop. Similarly, it is easy to imagine that individual neurons with impairment of OxPhos, which have been detected in many central nervous system disorders and in the aging brain, can affect the function of complex neuronal networks. However, this hypothesis remains to be investigated and further substantiated.
As Cicero Said, We Must Fight Against Aging as We Would Against a Disease
The firm distinction made between aging and age-related disease is a modern phenomenon, a product of the way in which the regulation of medical research and development has progressed. It wasn't so very long ago, considered in the grand scheme of things, that much of dementia and cardiovascular disease were thought parts of aging, prior to the ability to accurately map and categorize specific biological manifestations of aging. Present regulatory systems are set up to approve (a) the existence of clearly defined and bounded medical conditions based more on their biochemistry than their epidemiology, and (b) treatments narrowly applied to one approved condition. The result is a slow slicing of aging into a potentially endless series of named conditions, as each small piece of the enormously complex end state of decline is defined and given a name. This implicitly favors the poor strategy of trying to control narrow parts of the complicated end stage of disease, pretending they are isolated when in fact they are not, and makes it harder to pursue the much better strategies of either prevention or ways to repair and reverse the root causes of aging.
Aging and age-related disease are clearly not distinct from one another. Aging is just a collection of countless age-related diseases, the few defined and the many not yet defined. Age-related diseases are just arbitrary lines drawn around parts of aging. Looking at it a different way, an age-related disease is an aspect of aging that has progressed far enough to be unbearable. Aging and age-related disease are caused by the same underlying mechanisms - the cell and tissue damage outlined in the SENS research proposals.
Is aging as a whole a disease? Can we just draw a line around the whole thing? This question has been asked ever more frequently of late. It is trivial semantics - except that regulators will not let a treatment for aging progress to the clinic unless they agree that aging is a disease by their formal definitions. Which they currently do not. Absent a defined path to the clinic, research funding for efforts to treat aging as a medical condition is much harder to obtain than would otherwise be the case. The whole development pipeline suffers, all the way back to fundamental science in this part of the field. It has required philanthropy and advocacy and non-profit organizations dedicated to aging to make any meaningful progress since the turn of the century. Now that it is becoming plausible to effectively reverse some of the causes of aging, such as via senolytic therapies to destroy senescent cells, it becomes ever more important that this ridiculous situation is resolved in a way that allows funding to flow and therapies to reach the clinic.
The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates
The longstanding question if old age is itself a disease has been addressed since ancient times, starting from the Roman playwright Terentius, who claimed "senectus ipsa est morbus" (old age itself is a disease), and Cicero who some decades later argued in De Senectute: "pugnandum, tamquam contra morbum sic contra senectutem" (we have to fight against aging, as we do against a disease). These quotations elegantly summarize a long-held view of aging and old age addressed by several scholars. Notwithstanding, with the birth of modern medicine in the nineteenth century, this old tenet has been somehow put apart, as the main interest at that time was to define precise medical entities (diseases and syndromes) and their causes (infections, genetics, degenerative processes, inflammation, etc.). This process ended up in considering aging and diseases as separate phenomena that could eventually interact but that are essentially different in nature.
In this review, we will reappraise and challenge the old tenet that aging and age-related diseases (ARDs) and geriatric syndromes (GSs) are separate entities, and we will suggest instead that both should be considered as parts of a continuum. To support this hypothesis, we will highlight that aging and ARDs/GSs share the same basic molecular and cellular mechanisms. Aging is the predominant risk factor for most diseases and conditions that limit healthspan. Accordingly, interventions in animal models that end up in an extension of lifespan prevent or delay many chronic diseases. Why? For many years the explanation was that aging per se is a physiological condition, which favors the onset of many diseases. However, their relationship is likely much more complex, and a major reason is because they share the basic mechanisms. Assuming that aging and ARDs/GSs share the same mechanisms, which are commonalities and differences?
We will argue that an integrated hypothesis, fitting most epidemiological and experimental data, is to consider ARDs/GSs as an acceleration of the aging process. The conceptualization of accelerated aging started from the observation of rare genetic disorders such as Hutchinson-Gilford progeria. Here, we extend the concept of acceleration of aging to those members of the general population undergoing ARDs and GSs, in comparison with a small minority of people, such as centenarians, who reach extreme age largely avoiding or postponing most ARDs/GSs. This consideration is reinforced by the observation that among centenarians there are few subjects who never suffered of any overt ARDs. These exceptional individuals can be taken as a proof of principle that "healthy" aging and diseases can occur separately, as phenotypes at the extreme of a continuum, which is fueled by a common set of molecular and cellular mechanisms.
Which are the basic mechanisms shared by aging and ARDs/GSs? A group of international experts identified "seven pillars" which actually include adaptation to stress, loss of proteostasis, stem cell exhaustion, metabolism derangement, macromolecular damage, epigenetic modifications, and inflammation. Following this idea, the very difference between aging and diseases would relay on the speed and intensity of aging cellular and molecular processes, combined with the genetic and lifestyle predisposition of specific organs and systems. Thus, on the long run, all the functional domains undergo a physiological decline that eventually can lead to overt clinical diseases, favored by system-specific genetic and environmental factors. This progressive path generates a continuum between the healthy juvenile status and the impaired unhealthy elderly one. Accordingly, all major ARDs/GSs are characterized by a long subclinical incubation period, where the diagnostic signs of diseases are largely unobservable due to the high operational redundancy of biological systems.
In conclusion, a debate exists on whether aging is a disease in itself. Some authors suggest that physiological aging (or senescence) is not really distinguishable from pathology, while others argue that aging is different from age-related diseases and other pathologies. It is interesting to stress that the answer to this question has important theoretical and practical consequences, taking into account that various strategies capable of setting back the aging clock are emerging. The most relevant consequence is that, if we agree that aging is equal to disease, all human beings have to be considered as patients to be treated, being an open question when this treatment should start. Many mechanisms proposed to cause aging are the same as those known to underlie ARDs/GSs, lending support to the hypothesis that the aging phenotype and ARDs/GSs are not separate entities but rather the visible consequences of the same processes which likely proceed at different rates.
A second conclusion is that medicine should combat aging to combat many ARDs at a time and not one by one. In this perspective, one could envisage following two possible strategies to attain this result: (A) Try to slow the aging rate through changes in life style, and possibly drugs or medical treatments that counteract the impairment of mechanisms such as those proposed in the "seven pillars." This strategy should help people to stay healthy and active as long as possible and pospone ARDs for decades, ideally until the apparently inevitable limit of human lifespan. (B) More radically, try to rejuvenate human tissues, organs, and whole body. In this case, also the limits of human lifespan could be likely overtaken.
We are relatively ready to the first strategy that appears more feasible and acceptable from an ethical and social point of view, as it would be very similar to what is already happening nowadays, i.e., an increase in life expectancy and in the number of people who attain 90 or 100 years of age and more in good health. We are not yet ready, in particular from a social and ethical point of view, for the second strategy, which opens uncanny scenarios of rejuvenating bodies and very long life for the bulk of the population, a topic addressed in utopian, dystopian, and science fiction novels. Taking into account the fantastic, unprecedented rate of scientific discoveries in the field of aging and rejuvenation, it is timely and urgent to open a large debate.
Delivery of Exosomes Improves Recovery from Stroke in Pigs
The benefits of most first generation stem cell therapies, in which the overwhelming majority of transplanted cells die fairly rapidly, appear to be mediated by the signals briefly generated by those cells. A sizable portion of the signaling between cells is carried by extracellular vesicles such as exosomes, tiny membrane-wrapped packages of molecules. Given these two points, why not skip the cells in favor of delivering exosomes? This is an expanding area of activity in the regenerative medicine community. Some initiatives, such as the one noted here, have advanced to animal studies - human trials will not be so very many years away.
As regenerative research and development evolves away from the standard practice of the stem cell medicine of the past two decades, the future appears to involve a split of the community into two broad paths. The first path is as described above, to isolate the signals that are important in spurring regeneration, and thus gain control over the behavior of native cells. The second is to solve the problem of transplanted cells dying rather than thriving to undertake useful work. Progress is being made on this front in the form of tissue patches: rather than delivering cells haphazardly, researchers first build a structured pseudo-tissue patch of cells and scaffolding, closer in form to the native tissue. This makes the cells much more resilient and ready to integrate. The next decade in this field will see important advances in the ability to treat many degenerative conditions, I believe.
ArunA Biomedical today announced the publication of data demonstrating that neural stem cell-derived extracellular vesicles (NSC EVs) improved tissue and functional recovery in pigs following ischemic stroke. This is the first ever study to evaluate the therapeutic potential of human NSC EVs in a large animal model representative of the human brain. The neural-derived exosomes, a form of EVs, are a new class of cell-free biologics and cell-mediated drug delivery systems to treat central nervous system and neurodegenerative disorders.
"This study, coupled with our previously published studies focused on a mouse model, represents the first time that a company demonstrated proof-of-concept of the therapeutic potential of extracellular vesicles in two divergent animal species and two stroke types - embolic and ischemic." This is the third study recently completed by ArunA, the first two of which demonstrated improved outcomes in middle-aged and aged mice following embolic stroke.
Study results showed NSC EV treatment: was neuroprotective; eliminated intracranial hemorrhage in ischemic lesions; improved behavior and mobility; decreased cerebral infarct volume and brain swelling; and led to significant improvements at the tissue and functional levels.
Calorie Restriction as the "Most Reasonable Anti-Aging Intervention"
The practice of calorie restriction slows aging in near all species and lineages tested to date. It produces significant health benefits in humans. Unfortunately the gain in life span scales down as species life span scales up. While calorie restriction extends maximum life span in mice and median life span in short-lived, small primates by 40% or more, it is not likely to have an effect size of more than five years when it comes to human life spans. That said, calorie restriction is by far the most robust and well tested of the few means available to adjust life span. Is it, however, as the authors of this paper would have it, the "most reasonable anti-aging intervention?"
Reliability is good, but size of effect is also important. Calorie restricted individuals still age and die on much the same schedule as the rest of us, just a fraction less rapidly. Good health practices can't add decades to life: three quarters of the healthiest people are dead by age 90, even given access to the best of medical technology over the course of the past half century. Calorie restriction, like exercise, is something that everyone should consider because it is essentially free, and has some benefit. But future life spans will be determined by new medical technology such as senolytic therapies, built on the SENS model of repairing the damage that causes aging, not by calorie restriction or recreation of some of its effects via pharmaceuticals.
Research on the biology of ageing has been conducted for centuries. Survival curves showing the surviving proportion of a population versus time are an intuitive means of illustrating the whole lifespan of a group of organisms and remain a key component of ageing research. Various anti-ageing interventions have been demonstrated to extend the lifespan of model organisms ranging from nematodes to fruit flies to rodents, with contradictory reports in rhesus monkeys. These interventions have mainly included calorie restriction (CR), genetic manipulations, and pharmaceutical administration.
However, whether these interventions extend the lifespan via universal or distinct patterns remains unclear. Traditionally, in ageing research, survival data from lifespan experiments are mainly analysed in the original study, and data are not collected and stored together. Meta-analyses are mainly limited to either sufficiently large subsets of survival data acquired under identical conditions or the application of methods accounting for varying additional factors. The published meta-analyses of survival data have mostly assessed CR. For example, reportedly, CR significantly extends lifespan, and the proportion of protein intake is more important for lifespan extension than the degree of CR. No study has demonstrated whether CR, genetic manipulation, or pharmaceutical administration is superior at extending lifespan and delaying ageing.
Here, we attempted to resolve this question by conducting a comprehensive and comparative meta-analysis of the effect patterns of these different interventions and their corresponding mechanisms via survival curves. We have focused our analyses on Caenorhabditis elegans and Drosophila, powerful model systems that are widely used in ageing research. We developed an algorithm that enabled us to combine multiple strains of these species from a large number of studies and to extract general trends from relevant results.
Our study indicated that CR and genetic manipulations are effective ways in delaying senescence. The effect pattern of CR is superior to that of genetic manipulation in Caenorhabditis elegans but similar to that of genetic manipulation in Drosophila. Genetic manipulation in mammals faces many problems and risks, and CR, including changes in diet composition, time-restricted feeding, or CR mimetics, could be a more feasible approach for humans. These considerations and our results support CR as a feasible and effective anti-ageing intervention.
The Fight Against Aging and the Fight Against Ageism
If the old are thought to be inferior, used up, done, then would the rest of the population be less likely to support efforts to help older individuals? Ageism is certainly a real phenomenon, but it is an interesting question as to whether it is a major factor in the challenges we face in persuading the world to support work on rejuvenation therapies. Consider that those people with influence and wealth sufficient to steer the path of research and development in medicine are largely older, not younger. To the degree that ageism is a problem, I'd have to say that it seems likely to me to be a matter of the elderly accepting the mantle of this prejudice upon themselves. Or perhaps a matter of the old and declining leading implementations of discrimination against the elderly and declined. But this is just a viewpoint; the author here, a long-standing member of our community of patient advocates, argues that ageism is a core concern.
To me, efforts to counteract biological aging and fighting chronological ageism are two sides of the same coin. But for many this is probably not the case. For one, this is just not an issue at all people in general think about. And yet, all the people reaching adulthood and more are taking hits both from biological aging and from ageism during their lifetime. If you work on counteracting biological aging, you are working on fighting one form of ageism already. And am also hoping that if you think yourself as one who fights ageism you will recognize that understanding biological aging and support scientific efforts to extend healthy lifespan might be the most effective way to support the life of older people in the long term.
The World Health Organization defines ageism as the stereotyping, prejudice, and discrimination towards people on the basis of age. The claim I would like to make is there are two forms of discriminatory ageism, but only one of them has a connection to biological age. The first type is intergenerational ageism, and the main machinery involved here is chronological age. If you think that the deleterious effects of biological aging is the main or only cause for prejudice against older people then imagine a world where biological aging doesn't exist, yet kids are still born and new generations develop their own culture and references. It seems clear that in a world like that ageism and tensions between generations would still be an issue. Biological aging is not needed in order for ageism to happen.
For the second type: does the existence of biological aging and the visible signs of biological aging trigger ageism all by themselves? Yes, this is classical ageism, rooted in a positive bias for the young, and it has a long, long history in human culture. This type of biologically triggered ageism goes one way though, as it affects only older people by definition.
By now you might have guessed the argument I'm going to construct: people working on interventions to counteract processes of biological aging are at the same time working on removing the physiological, cognitive differences between the biologically old and biologically young. So they fight not just biological aging but biologically driven ageism too. Minimizing the differences between biological ages and maximizing the differences between chronological ages, they will make it hard for decision-makers to build ageism into the very fabric of companies and other institutions.
Regenerative Medicine as an Approach to Treat Alzheimer's Disease
The authors of this open access paper consider the potential for regenerative medicine to treat Alzheimer's disease, such as by increasing production of new neurons, or delivering neurons via transplantation. While there has been something of an exodus from the amyloid hypothesis of late, given the litany of failure in clinical trials aiming to reduce amyloid in the brain, it still seems clear that protein aggregates (amyloid and tau) occupy a central position in the progression of neurodegeneration. Spurring greater brain tissue maintenance via generation of neurons is a beneficial goal in and of itself, but as a compensatory treatment, it can't be enough on its own to turn back neurodegeneration primarily caused by factors such as metabolic waste and chronic inflammation.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline. Tremendous efforts have been made to develop novel therapeutics to potentially reverse disease progression. Substantial neuronal loss is observed even in mild AD patients. Intuitively, increasing the number of neurons or replacing lost neurons are potential therapeutic strategies for AD. Stem cells are capable of renewing themselves continuously and differentiating into specialized cells, including neurons.
The process of generating new fate-specified, functional neurons from neural progenitor cells, which are functionally incorporated into a neural circuit, is defined as neurogenesis. Across different species, neural regeneration mainly takes place at the dentate gyrus of the hippocampus and the subventricular zone along the lateral ventricle. Notably, the dentate gyrus, which plays a crucial role in memory formation processes, is related to early memory loss in AD. Neurogenesis decline accompanies normal aging. For AD, accumulating evidence suggests that impaired neurogenesis plays a role in its pathogenesis. Multiple molecules involved in AD pathogenesis, such as ApoE, PS1, and APP were recognized to take part in neurogenesis modulation. Therefore, understanding the mechanism of neurogenesis dysfunction and intervening with neurogenesis represents an alternative AD therapeutic strategy.
Generally, neurogenesis can be modulated by multiple factors that are related to lifestyle, including learning, exercise, social interaction, caloric restriction, blood oxygen level, and even microbial colonization. In this regard, advocating a healthy lifestyle exerts at least a mild effect on preventing or controlling AD in the long run. Apart from lifestyle modification, which exerts mild effects, several pioneering studies identified key molecules or drugs that rescue or reverse NSC dysfunction in elderly animal models, such as via plasma exchange.
Transplanting stem cells to substitute for lost neurons is another intuitively feasible strategy. However, studies have confirmed that the main benefit of stem cell transplantation is a neurosecretory effect. Various neurotrophic factors involved in modulating multiple cellular functions that promote the amelioration of pathological features and cognition in animal models have been recognized. There has been increasing commercial interest to transform current advances in transplantation into clinical practice on human patients.
Inflammatory Signaling Reduces Pancreatic Islet Cell Replication in Aging
Aging is marked by rising chronic inflammation and a decline in many aspects of tissue maintenance, such as stem cell activity, and willingness of somatic cells to replicate. Chronic inflammation appears to disrupt regenerative processes, but there are many distinct mechanisms involved, varying by tissue type, and present understanding is far from complete. Researchers here investigate one narrow slice of the problem in the pancreas in zebrafish, finding that beta cells, important to metabolic function due to their control of insulin, reproduce less readily in old individuals due to greater inflammation.
A hallmark of aging is the reduction in cellular renewal and proliferation across different tissues and organs. The insulin producing beta cells, which reside in the islets of Langerhans, provide a good model to study regulators of cellular aging. Whereas young beta-cell are highly proliferative and increase rapidly in number from the prenatal phase until early stages of development in mammals, beta-cell proliferation becomes dramatically reduced in adults.
Previous studies have indicated that both extrinsic factors, such as the vasculature, and intrinsic factors, such as chromatin modifications, may influence the age-related changes in beta-cells. For example, rejuvenating the beta-cell environment by implanting old islets in younger animals is sufficient to restore the proliferative potential of the aged beta-cells. In addition, transcriptome and methylome studies revealed age-dependent DNA methylation changes at cell-cycle regulators, which may contribute to the quiescence of aging beta-cell.
To identify signals that change in beta-cells during organismal aging, we used the zebrafish as a model. We first characterized the rate of beta-cell proliferation in juvenile, younger, and older adults, and found that proliferation declines with advancing age. We performed transcriptomics of beta-cells from younger and older animals, which identified an upregulation of genes involved in inflammation, including NF-kB signaling. The analysis of inflammatory signaling with single-cell resolution confirmed that NF-kB signaling was activated in a heterogeneous manner at the level of individual beta-cells. Notably, beta-cells with higher levels of NF-kB signaling exhibit a more pronounced proliferative decline compared to their neighbors with lower activity.
An Interview with a Programmed Aging Theorist
Josh Mittledorf holds an interesting somewhat group selection based view on the evolution of programmed aging, and here is interviewed by the Life Extension Advocacy Foundation volunteers. I have long said that the important divide in the research community is between (a) those who think that aging is programmed, in the sense that evolution selects for epigenetic changes in later life that are a primary cause of damage and dysfunction, and (b) those who see aging as a stochastic process of damage accumulation, that occurs in later life because there is little to no selection pressure for ways to prevent it, and this damage causes epigenetic changes and dysfunction.
This is an important divide because the two views lead to very different strategies for the development of therapies to treat aging. The programmed aging theorist wants to force reversion of epigenetic changes to a youthful pattern, and expects damage and dsyfunction to be reversed as a result. In the damage accumulation view, exemplified by the SENS research programs, repair of damage is the right path, with the expectation that dysfunction and epigenetic changes will revert themselves once the damage is gone. In either case, if the other side is right, the chosen strategy will produce poor results. Now that the research community is earnestly engaged with the idea of treating aging, whether researchers and institutions invest in good or bad strategies is of great importance to the near future of medicine and our own lives.
It seems like the field of aging science has grown remarkably. Are you optimistic that we're on the verge of real breakthroughs in longevity improvements?
I'm not as optimistic as I was a few years ago. The Next Big Thing in the field is likely to be senolytic drugs. These are able to selectively remove the body's worn-out cells that have become toxic, without poisoning our healthy cells. I think they'll add a decade or more to the human lifespan. Calorie restriction mimetic and exercise mimetic drugs will be another boost if they can be made safe. After that, I think the big challenge will require taking control of our epigenetics (heritable changes that don't require changes to the genome itself). Epigenetics, I believe, is in control of aging at a deep level. Epigenetics is so complicated that 20 years into the age of epigenetics, we're still just beginning to understand how it works.
Why are you less optimistic about the potential for major breakthroughs in aging science now in 2018 than you were previously?
Originally, my thinking went like this: The conventional view has been that aging exists despite evolution's best efforts over hundreds of millions of years to eradicate it. Evolution is already trying to make us live as long as possible, and for humans to extend our lifespan, we'll have to do some pretty fancy thinking to come up with something that evolution hasn't already tried. However, this conventional view is wrong. In fact, evolution has preferred defined lifespans to indefinite lifespans. So, we might hope that we can eliminate aging entirely by understanding the mechanisms of self-destruction that evolution has built into our life history and biochemically disabling them. I had thought that this could probably be done by blocking the signals, jamming the works. Pharmaceutical companies are generally quite good at turning off a hormone or a whole biochemical pathway once it's been identified.
The reason I'm less optimistic now is that I believe that the evolved mechanism of self-destruction involves gene expression, which is to say epigenetics. Different genes are turned on at different stages of life (this is a big part of what epigenetics is), and the genes turned on late in life turn the body against itself. Mechanisms like apoptosis (cell death), autoimmunity, and inflammation are all dialed up. The reason my expectations are scaled back now is that epigenetics has turned out to be enormously complicated. We once thought that a few transcription factors controlled a large number of genes, turning them on and off en masse. We now know that there are thousands of different transcription factors, almost as many as there are genes. And there is wide overlap between genes that have transcriptional functions and genes that have metabolic functions.
Could you flesh out a little your contributions to aging science, in terms of the evolutionary theory of programmed death in humans and most other species?
In the modern understanding of evolutionary fitness, evolution is highly motivated to make you live as long as possible, so long as you are still churning out babies. So, where does aging come from? The standard answer is that there are genes that tie fertility directly to deterioration late in life, and evolution has not found a way around this; it has not found a way to have lots of fertility early in life without incurring damage later on, despite hundreds of millions of years of trying to overcome this limitation.
I have described a great mass of evidence against this picture. Much of it is common sense, but there is a lot of technical, genomic evidence as well. The evidence strongly points to the inference that natural selection has preferred shorter lifespans to indefinite (or very long) lifespans. Why might this be? My theory is that it is about ecosystem stability. It's not possible to construct a stable ecosystem out of selfish individuals that are each trying to live as long as possible and produce as many offspring as possible. In order to have stable ecosystems, nature has had to accept limits to fertility and to lifespan.
The reason that the evolutionary community is so resistant to this idea is that it requires natural selection to occur within entire ecosystems. In other words, this ecosystem persisted because it was stable, while that one collapsed because it was way out of balance. For largely historical reasons, evolutionary theory grew up in a way that was committed to the selfish gene. Most evolutionary biologists today believe that the selfish gene is the only mode by which evolution operates, though they could not articulate a reason why, if challenged.
CXCR4 as an Indicator of Microglial Involvement in Neurodegenerative Diseases
The open access paper noted here reports on the use of a genetic analysis to shed further light on the relative importance of shared mechanisms across a range of neurodegenerative conditions in which tau aggregation is thought to be important. The researchers find associations in gene expression between these conditions that suggesting microglial dysfunction is an important common determinant of disease progression.
If one looks over all of the most common neurodegenerative diseases, patients exhibit a number of overlapping mechanisms that appear plausible as proximate causes of brain cell dysfunction and death. Some conditions share the aggregation of damaged proteins such as amyloid-β and tau. Most share harmful alterations in the behavior of immune cells such as microglia, either causing or responding to a state of raised chronic inflammation. The progression of vascular aging, leading to inadequate delivery of oxygen and nutrients, and mitochondrial dysfunction are also common in neurodegenerative conditions. All of these observations, sadly, tell us far less than we'd like about cause and effect in the aging brain. All of the signs progress over time, and absent technologies that can carefully block one of those signs, in order to see what happens next, it is very challenging to determine causality by observation alone.
Uncovering the shared genetic architecture across neurodegenerative diseases may elucidate underlying common disease mechanisms and promote early disease detection and intervention strategies. Progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer's disease (AD) are age-associated neurodegenerative disorders placing a large emotional and financial impact on patients and society. Despite variable clinical presentation, PSP, AD, and FTD are characterized by abnormal deposition of tau protein in neurons and/or glia. While PD is classically characterized by alpha-synuclein deposits, recent studies support the role of tau and neurofibrillary tangles in modifying PD clinical symptoms and disease risk.
Genome-wide association studies (GWAS) and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in MAPT (which encodes tau) that increase risk for PSP, FTD, AD, and PD. However, beyond MAPT, the extent of genetic overlap across these diseases and its relationship with common pathogenic processes observed in PSP, FTD, AD, and PD remain poorly understood. Here, using previously validated methods, we assessed shared genetic risk across PSP, PD, FTD, and AD. We then applied molecular and bioinformatic tools to elucidate the role of these shared risk genes in neurodegenerative diseases.
We identified CXCR4 as a novel locus associated with increased risk for both PSP and PD. We found that CXCR4 and functionally associated genes exhibit altered expression across a number of neurodegenerative diseases. In a mouse model of tauopathy, CXCR4 and functionally associated genes were altered in the presence of tau pathology. Together, our findings suggest that alterations in expression of CXCR4 and associated microglial genes may contribute to age-associated neurodegeneration. Despite the lack of strong genetic association across these three neurodegenerative diseases, we found that CXCR4 expression was altered in brains that are pathologically confirmed for PSP, PD, and FTD. Thus, these findings support our hypothesis that these three neurodegenerative disorders share common pathobiological pathways.
CXCR4 is a chemokine receptor protein with broad regulatory functions in the immune system and neurodevelopment. CXCR4 has been shown to regulate neuronal guidance and apoptosis through astroglial signaling and microglial activation. Furthermore, it has been shown that CXCR4 is involved in cell cycle regulation through p53 and Rb. Our results provide additional evidence that immune and microglial dysfunction contribute to the pathophysiology in PSP, PD, and FTD. These findings have important implications for future work focused on monitoring microglial activation as a marker of disease progression and on developing anti-inflammatory therapies to modify disease outcomes in patients with neurodegenerative diseases.
Cells in High Risk, Unstable Atherosclerotic Plaque Exhibit a Cancer-Like Metabolism
Atherosclerosis is the development of fatty plaques in blood vessel walls, formed of damaged lipids and the debris of dead cells. Once developed in earnest, these become localized areas of chronic inflammation. Inflammatory signaling continually calls in macrophages that attempt to clear up the damage, become overwhelmed, and add their remains to the growing mass. In the late stage of the condition, blood vessels are narrowed and weakened, and the plaques become unstable, prone to rupture. Here, researchers show that cells found in unstable fatty plaque are distinct from those in stable plaque. They look more like cancer cells or activated immune cells in the operation of their metabolism.
This is interesting in light of the recent discovery that growth and instability in atherosclerotic plaque is driven in part by the senescence of macrophages. The macrophages attempting to clean up the plaque become senescent as they are overwhelmed by damaged lipids that they cannot effectively break down. They become foam cells as they are loaded with lipids, and the foam cells become senescent in response to their own damaged state and the plaque environment. Senescent cells secrete signals that promote inflammation and disruptive remodeling of surrounding tissue structure, and are different from normal cells in other ways as well. Removing just senescent macrophages can stabilize plaque and slow or reverse the progression of atherosclerosis. This is something to think about while looking over the results here.
Atherosclerotic plaques form over a long time by a focal accumulation of lipids, immune cells, and smooth muscle cells in the arterial wall and plaques that rupture can cause acute cardiovascular events, such as myocardial infarction and stroke. Rupture-prone, high-risk plaques are associated with clinical symptoms and characterized by histological evidence of vulnerability and a high inflammatory burden. While this knowledge has advanced considerably over the past few years, our understanding of the metabolic processes within plaques in this inherently metabolic disorder has been lagging behind.
Emerging research has shown that cell metabolism and the inflammatory response are tightly intertwined. Macrophages, abundantly found in atherosclerotic plaques, and other leucocytes, change their metabolism according to their tasks in the immune response. Activated leucocytes change to a predominantly anabolic metabolism by upregulating pathways, such as glycolysis, the pentose-phosphate pathway (PPP), and glutaminolysis, to provide the necessary energy to enable their activation and proliferation. In contrast, catabolic pathways, such as fatty acid oxidation (FAO), are downregulated in these cells. Recently, it has been shown that overutilization of glucose is crucial for blood monocytes and in vitro differentiated macrophages from patients with coronary artery disease (CAD) to mount a destructive inflammatory response. Yet, it remains to be determined whether such an interconnection between cellular metabolism and the inflammatory response is present in human atherosclerotic plaques.
Recent studies have challenged the established concept of the vulnerable atherosclerotic plaque and call for improved methods for identification of the high-risk plaque. Plaque metabolomics might be able to provide a largely unexplored layer of functional characterization of high-risk lesions and thus add value to future risk stratification strategies and novel therapeutic approaches. Metabolic profiling of atherosclerotic tissues has so far focused on comparing lipid metabolite levels in different parts of the same plaque or to plaque adjacent intimal thickenings without being able to produce clear biological insights of clinical significance.
A more clinically relevant approach is to distinguish high- from low-risk plaques according to their metabolic profile. Therefore, we assessed metabolite profiles of 159 highly stenotic carotid atherosclerotic plaques isolated from patients with or without symptoms. We show that high-risk plaques, characterized as being symptomatic, vulnerable by histology, and inflamed with elevated inflammatory mediators, had a specific metabolite signature, distinct from the metabolite profile of low-risk plaques. These data highlight a previously unappreciated role of cellular metabolism in the high-risk plaque and as a discriminating feature from low-risk plaques, indicating that metabolic pathways could be targeted to treat and identify high-risk atherosclerotic plaques.
Results from a Human Trial of Mitochondrially Targeted Antioxidant MitoQ
A range of mitochondrially targeted antioxidant compounds have been developed over the past decade or more: SkQ1, SS-31, and MitoQ, the subject of the trial here. The present consensus in the research community is that ordinary antioxidants are probably, on balance, somewhat harmful if used over the long term. They sabotage the oxidative signaling need for the beneficial response to exercise, for example. Mitochondrially targeted antioxidants, on the other hand, appear to modestly slow aging in a range of species, and have proven an effective treatment for some conditions characterized by inflammation and oxidative stress, meaning the excessive production of oxidative molecules and resultant damage to molecular machinery. It can be debated on a case by case basis as to the degree to which this is a compensatory treatment versus addressing a specific causative issue in any given condition.
Mitochondria in cells generate oxidative molecules in the course of producing chemical energy stores to power cellular processes. Moderately raised production can result in overall benefits, because cells react with increased housekeeping activities. Greatly increased production is harmful, however, and appears as aging progresses due to the accumulation of mitochondrial damage. It raises the level of oxidized lipids in the bloodstream, a contributing factor in atherosclerosis. It can cause cells to become dysfunctional, though the details are varied and tissue specific. It can spur chronic inflammation. In this trial, it is interesting to see confirmation of these various themes, with a focus on the vascular system in aging, though I think the pulse wave velocity data is mixed at best. The reduction in oxidized LDL cholesterol is more interesting, and more compelling when one considers that this outcome is the goal of statin drugs.
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality in developed societies. Advancing age is the primary risk factor for CVD, which is largely mediated by adverse changes to arteries. Two features of vascular aging that are key antecedents to CVD are the development of endothelial dysfunction, as assessed by reduced endothelium-dependent dilation (EDD), and stiffening of the large elastic arteries. Vascular dysfunction with age is a consequence of excessive superoxide-related oxidative stress, much of which is of mitochondrial origin. Given the projected increase in CVD prevalence in the coming decades, driven mainly by increases in the number of middle-aged and older (MA/O) adults, identifying novel strategies that reduce excess mitochondrial reactive oxygen species (mtROS) to improve vascular function and reduce CVD risk in this population is a biomedical priority.
MitoQ is a mitochondria-targeted antioxidant consisting of the naturally occurring antioxidant ubiquinol attached to a lipophilic cation; the lipophilicity and positive charge of this compound enable it to cross cell membranes and accumulate in the matrix facing the surface of the mitochondrial inner membrane where it is optimally positioned to reduce mtROS. MitoQ is now available as a dietary supplement and recently was administered chronically (3 weeks) to healthy young adults without adverse effects. However, presently, the efficacy of chronic MitoQ supplementation for improving vascular function in healthy MA/O adults is unknown. Accordingly, we sought to translate our preclinical findings to humans by conducting the first randomized, double-blind, placebo-controlled clinical trial with MitoQ in healthy late MA/O humans.
MitoQ was well tolerated, and plasma MitoQ was higher after the treatment versus placebo period. Brachial artery flow-mediated dilation was 42% higher after MitoQ versus placebo; the improvement was associated with amelioration of mitochondrial reactive oxygen species-related suppression of endothelial function. Aortic stiffness (measured via carotid-femoral pulse wave velocity) was lower after MitoQ versus placebo in participants with elevated baseline levels. Plasma oxidized LDL (low-density lipoprotein), a marker of oxidative stress, also was lower after MitoQ versus placebo. These findings in humans extend earlier preclinical observations and suggest that MitoQ and other therapeutic strategies targeting mitochondrial reactive oxygen species may hold promise for treating age-related vascular dysfunction.
SPATA31 Gene Family Copy Numbers as a Human Example of Antagonistic Pleiotropy
Antagonistic pleiotropy is the name given to the phenomenon in which evolutionary processes select for a genetic variant that aids in evolutionary fitness when young, but then causes harm to the individual later in life. Many theorists consider aging as a whole to be antagonistic pleiotropy writ large, but one can pick out individual mechanisms in many species that are compelling candidates to be the result of such a process. In the open access paper noted here, the authors point out one plausibly pleiotropic set of genes in our species.
Expansion of gene families with the concomitant acquisition of new functions can be a driving force for the evolutionary differentiation of species. Compared to other mammals, primate and human genomes include many interspersed segmental duplications, which may have been of special relevance for the evolution of the primate lineage. About 430 blocks of the human genome have been identified as having been subject to multiple duplications during hominoid evolution. Clustering analysis of these segmentally duplicated regions in the human genome suggests that a part of the duplication blocks have formed around a "core" or "seed" duplicon.
The SPATA31 gene family belongs to the core duplicon gene families and it has been shown to be one of the fastest evolving gene families in the human lineage. It has expanded from a single copy in mouse to at least nine copies in humans, located at seven different sites on both arms of chromosome 9. Compared to the mouse gene, we found that the human SPATA31 genes are broadly expressed and have acquired new functional domains, among them a cryptochrome/photolyase domain, suggesting the acquisition of a function in UV damage repair.
Antibody staining showed that the protein is re-localized from the nucleolus to the whole nucleus upon UV irradiation, a pattern known for proteins involved in UV damage sensing and repair. Based on CRISPR/Cas mediated knockouts of members of the gene family in fibroblast cell cultures, we found that the reduction of copy number in cells leads to enhanced sensitivity towards UV-irradiation. Given that increased UV-light resistance of the skin may have played a major role in human evolution, we proposed that the acquisition of an involvement in UV damage sensing or repair has lead to the adaptive evolution of SPATA31.
An interesting side effect of the SPATA31 gene knockouts was that the respective cells survived somewhat longer than normal primary fibroblast cell lines, although this was difficult to quantify. We have therefore used here the alternative approach, namely to over-express a representative member of the SPATA31 gene family, SPATA31A1, and study its effect on cell survival. We find that this over-expression results indeed in premature senescence of the cells, through interference with known aging related pathways. Based on these results, we asked whether natural copy number variation in humans correlates with senescence, in the sense that fewer SPATA31 copies should correlate with longer life span. We can indeed show this effect in a cohort of long-lived individuals. Humans that have reached an age of 95 or higher have on average fewer SPATA31 gene copies than a younger control population.
It has generally been suggested that there is a complex interaction between cellular senescence, tumor incidence due to somatic mutations, and aging. Our data imply that SPATA31 genes are part of this process and that their variation in copy number contributes via this effect to longevity in humans. Having more copies may lead to more somatic mutations, including some that cause cancer, while having fewer copies reduces this effect, thus allowing longer life spans.
The SPATA31 copy number effect on aging can be seen as an example for antagonistic pleiotropy. Higher copy numbers provide a benefit early in life, due to better protection of the skin against sunlight, allowing to spend more time during the day for foraging, social life, mate seeking and child care, all factors that should increase reproductive fitness. Hence, there would be positive selection for higher copy numbers. But more copies would also lead to a higher expression of SPATA31 and our cell-culture results show that such a higher expression induces DNA repair pathways. This could lead to a higher incidence of repair-induced damage in the cells and thus to cancer. If this becomes a problem during reproductive age, one would have a potential negative selection against high copy number. Hence, a balance in copy number should be maintained in the population, but with a certain variance. This variance has the effect that total lifetime beyond reproductive age is affected, with individuals with fewer copies having a higher probability to live longer.