Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!
To subscribe or unsubscribe please visit: https://www.fightaging.org/newsletter/
- A Cross-Section of Recent Work in the Aging Research Community
- Towards PCSK9 Gene Therapy to Reduce Cardiovascular Disease Risk
- GPER Knockout Reduces Oxidative Stress to Slow Cardiovascular Aging
- The Transhumanist Advocacy of Zoltan Istvan
- SENS after de Grey
- Latest Headlines from Fight Aging!
- The Moderate Drinking Effect on Health may be Explained by Wealth and Status
- PORCN Inhibition Spurs Greater Heart Tissue Regeneration
- SENS Research Foundation and Buck Institute to Collaborate on a New Approach to Clearing Neurofibrillary Tangles
- An Apparent Limit on the Quality of Longevity Therapies is Only a Statistical Artifact
- Reviewing Methionine Restriction as a Basis for Calorie Restriction Benefits
- Too Many People Think of Aging and Age-Related Diseases as Somehow Distinct
- An Indirect Test to Assess Risk of Cardiac Transthyretin Amyloidosis
- Early Coronary Artery Calcification Predicts Later Risk of Heart Disease
- A Call for More Study of Exceptionally Regenerative Species
- Searching the Lizard Genome for Regenerative Factors
A Cross-Section of Recent Work in the Aging Research Community
A recently published report from last year's Biomedical Innovation for Healthy Longevity conference, held in Russia, serves as a sampling of ongoing work in the field of aging research; a wide range of views on theories of aging are represented. One thing that strikes me from a review of the topics is that few of the people involved are working on anything related to rejuvenation, or, setting aside the much-needed consideration of biomarkers of biological age, any other projects with near term practical applications likely to significantly extend life. For the most part this is a field concerned with investigation, development of drugs that produce small effects on aging, and little else. The primary thrust is to map the cellular biochemistry of aging in as great a detail as possible, one small step at a time, with a sideline in finding drug candidates that might somewhat alter that biochemistry. Insofar as fundamental research goes, this is indeed the goal of science as a whole, to achieve greater understanding of the complex systems of the natural world. It has been argued that this is not the right focus for those groups that aim for the more rapid production of effective therapies capable of greatly extending healthy life spans, however, given the present state of knowledge.
Regular readers will know the argument already. The research community knows enough about the root causes of aging to strike out and build effective therapies even if the full details of the biochemistry involved have yet to be mapped out. Take senescent cells, for example. Their involvement as a cause of aging has become increasingly clear over the past thirty years of investigation. It is now demonstrated that removing senescent cells reliably reverses aspects of aging and extends life in mice. Yet at the level of cell mechanisms and signals, there lies ahead at least another decade or two of further work to catalog all of the relationships and interactions responsible for the harms caused by these cells. Scientists will undertake that work, of course. But it should not be the focus for clinical research, given that the basis for an effective therapy exists today in the form of destroying these cells, an approach that cuts through the unknown mechanisms, fixing them just as effectively as it fixes the problems that are known and understood.
Cellular senescence is but one example of many. Researchers in general do a very poor job of identifying and addressing root causes in aging, however. Because they are primarily engaged in mapping and discovery, they tend to focus on late stages of aging, working backwards from a state of dysfunction step by step and protein by protein in long and complex chains of cause and consequence. When they propose therapies as a result of their findings, these therapies necessarily take the form of tinkering with the already malfunctioning operation of metabolism - altering the downstream consequences of fundamental damage, rather than repairing that damage. The outcomes are inevitably marginal. Trying to keep a damaged engine effective by changing the oil or running it hot, while failing to replace the worn and damaged parts that are the cause of the issue, is a futile endeavor. This is just as true of our biology. So while there are many interesting items in the full report, just a few of which are quoted below, remember that interesting doesn't necessarily mean useful enough to justify the expenditure of a great deal of effort and funding.
A review of the biomedical innovations for healthy longevity
Blanka Rogina (University of Connecticut Health) "Indy reduction maintains fly health and homeostasis". Indy (I'm not dead yet) encodes the fly homologue of a mammalian transporter of the Krebs cycle intermediates. Reduced Indy gene activity has beneficial effects on energy balance in mice, worms and flies, and worm and fly longevity. In flies, longevity extension is not associated with negative effects on fertility, mobility or metabolic rate. Others and we show that Indy reduction extends longevity by mechanism similar to calorie restriction (CR).
Vladimir Skulachev (Moscow State University) in his lecture "Naked Mole Rats and Humans: Highly Social Creatures Prolonging Youth by Delay of Ontogenesis (Neoteny)" considered some physiological mechanisms responsible for longevity of eusocial mammals, i.e. a rodent (naked mole rat) and a primate (human). It is concluded that both naked mole rat and human are no more affected by dynamic natural selection due to specific organization of the socium (naked mole rat) and substitution of fast technical progress for slow biological evolution (human). Since aging is supposed to be a program stimulating evaluability by increasing pressure of natural selection upon an individual, such a program became a harmful atavism for naked mole rat and human. This is apparently why aging as a reason for death is very rare in naked mole rats younger than 30 years and humans younger than 55 years. Such an effect is achieved, at least partially, by prolongation of youth (neoteny). The numerous facts are described indicating that The Master Biological Clock responsible for timing of ontogenesis is retarded both in naked mole rat and in human. In these species, numerous traits of youth do not disappear (or disappear enormously slowly) with age.
David Gems (University College London) spoke on "The origins of senescent pathology in C. elegans". The biological mechanisms at the heart of the aging process are a long-standing mystery. An influential theory has it that aging is the result of an accumulation of molecular damage, caused in particular by reactive oxygen species (ROS) produced by mitochondria. This theory also predicts that processes that protect against oxidative damage (involving detoxification, repair and turnover) protect against aging and increase lifespan. However, recent tests of the oxidative damage theory, some using the short-lived nematode worm C. elegans, have often failed to support the theory. This motivates consideration of alternative models. One new theory proposes that aging is caused by the non-adaptive running on in later life of developmental and reproductive programmes. Such quasi-programmes (i.e. that are genetically programmed but non-adaptive) give rise to hyperfunction, i.e. functional excess due to late-life gene action, leading via dysplasia to the age-related pathologies that cause the late-life increase in mortality. Here we assess whether the hyperfunction theory is at all consistent with what is known about C. elegans aging, and conclude that it is.
S. Michal Jazwinski (Tulane University Health Sciences Center) presented "Metabolic and Genetic Markers of Biological Age". Biological and chronological age are not the same, as individuals depart in health from the average. Taking a systems approach, we developed an objective measure of healthy aging, a frailty index (FI34) composed of 34 health and function variables. FI34 is a much better predictor of mortality than is chronological age; therefore, it directly reflects biological age. It increases exponentially with chronological age, but it does so more slowly for offspring of long-lived parents. FI34 is also heritable. Thus, it can be used in genetic analyses. The patterns of aging described by the variables in FI34 are very different for offspring of long-lived and short-lived parents. We have examined the association of the components of energy metabolism with FI34 in the oldest-old. Surprisingly, there is a positive association of FI34 with resting metabolic rate (RMR). This points to the rising cost of maintenance of integrated body function with declining health during aging.
Daniel Belsky (Duke University) presented "Quantification of biological aging in young adults". Population aging threatens to bring a tidal wave of disease and disability. Strategies to prevent or treat individual diseases will be inadequate to contain costs and preserve economic productivity; interventions that address the root cause of multiple diseases simultaneously are needed. We studied aging in 954 young humans, the Dunedin Study birth cohort. To quantify biological aging in these individuals, we tracked multiple biomarkers across three time points spanning their 20s and 30s. We devised a longitudinal measure that quantifies the pace of coordinated physiological deterioration across multiple organ systems. This measure, the "Pace of Aging," showed substantial variation in young, healthy adults who had not yet developed age-related disease. Young adults with faster Pace of Aging were, by midlife, less physically able, showed cognitive decline and brain aging, self- reported worse health, and looked older.
Tamas Fülöp (University of Sherbrooke) presented "Are there any reliable biomarkers for immunosenescence?". Aging is accompanied by many physiological changes including those related to the changes in the immune system. These changes are called immunosenescence which is accompanied by the inflammaging phenomenon. Many biomarkers have been proposed to describe these age-associated changes in the immune system. One of the most consistent is the chronic Cytomegalovirus infection. Most of the elderly are affected in developed countries which about 70% and in developing countries about 100% at the age of 80. Despite the numerous studies there is no consensus which role the recurrent CMV infections play in the alterations of the immune system namely in the inflammaging process and in the more consistent phenotypic alterations of T cells.
Alexander Kulminski (Duke University) reported "Can age-specific genetic effects be relevant to biological age?". Living organisms are getting older and eventually die at a certain age. The actual time an organism has been alive refers to chronological age (CA). However, not all organisms die at the same chronological age even if they are of the same species. The idea of biological age (BA) is that the differences in lifespan of these organisms can be due to an internal clock. For humans, BA refers to how old that human seems. A problem, however, is how to quantify BA. A promising approach could be to express BA in terms of measurable phenotypes such as biomarkers. As phenotypes, biomarkers represent endpoints of a cooperative work of genes in an organism. Accordingly, BA could readily have a genetic origin. Does it necessarily imply that there should be specific genes regulating BA? The answer is not straightforward.
Ksenia Lezhnina and colleagues presented "Signaling pathways signature of sarcopenia identified by iPANDA algorithm." Sarcopenia is a losing muscle mass and function with aging. Decreased strength and power of muscle function may contribute to higher risks of accidents among older people and affects quality of life. Until recently sarcopenia was not even considered as a pathological condition and as a consequence clinical definition and diagnostic criteria is poorly developed. Mechanisms underlying sarcopenia are extensively investigated but still not fully understood. In order to study this we compare transcriptomic profiles of muscle tissues from young and old people, both women and men. We assume that aging process starts from the fourth decade of life. We apply a new algorithm in silico Pathway Activation Network Decomposition Analysis (iPANDA) to transcriptomic data to find signaling pathway signatures of aging in muscle tissues. Common pathway signatures can be considered as a target for development of new approaches for sarcopenia treatment.
Matt Kaeberlein (University of Washington) presented "Effects of transient mid-life rapamycin treatment on lifespan and healthspan". The FDA approved drug rapamycin increases lifespan and improves measures of healthspan in rodents. Nevertheless, important questions exist regarding the translational potential of rapamycin and other mTOR inhibitors for human aging, and the optimal dose, duration, and mechanisms of action remain to be determined. Here I will report on studies examining the effects of short-term treatment with rapamycin in middle-aged mice and dogs. We find that transient treatment with rapamycin is sufficient to increase life expectancy by more than 50% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodelling of the gut microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine, along with a dramatic shift in the cancer spectrum in female mice. In dogs, we have defined a dose of rapamycin that is well tolerated, and initial results are consistent with improvements in age-associated cardiac function similar to those observed in rapamycin-treated mice. These data suggest that a transient treatment with rapamycin may yield robust health benefits in mice, dogs, and perhaps humans.
Maxim Skulachev (Mosсow State University) presented "Development of mitochondrially-targeted geroprotectors: from the molecular design to clinical trials and marketing strategy". Research and development of geroprotectors is always challenging when the project passes from theoretical and laboratory work to routine drug development (preclinical and clinical trials and medical authority approvals). In this talk, we present an example of an anti-ageing RnD project aimed on creation of geroprotector drugs on the basis of rechargeable mitochonrially-targeted antioxidants. Our strategy is to get the potential geroprotector approved as a drug against a certain age-related disease, and then to expand the list of indications for this pharmaceutical to other traits of ageing. We synthesized a series of novel organic compounds, derivatives of plastoquinone. Our first pharmaceutical was designed for local administration (in the form of eye-drops) to speed up the process of clinical development and to get the clinical data faster. At the current stage of the project our first drug Visomitin (Rx eye drops with antioxidant SkQ1 helping in such age-related diseases as dry eye syndrome and cataract) has been approved and marketed in Russia and successfully passed phase II clinical trials in US. Systemic oral form of SkQ1 has entered clinical trials in Russia and completed preclinical program in US and Canada. We consider our project to be a valuable attempt to slow down human aging by a mitochondrial approach.
Towards PCSK9 Gene Therapy to Reduce Cardiovascular Disease Risk
The popular science article I'll point out today is indicative of the movement towards enhancement gene therapies that is taking place across the research community. More slowly in some parts than in others, but there is movement nonetheless. The enabling technologies for mammalian gene therapy have fallen greatly in cost and increased greatly in reliability over the past decade, culminating with the comparatively recent advent of CRISPR gene editing approaches. It is is thus perfectly feasible to discuss development of human gene therapies at this time, as the only remaining aspect to be brought up to the desired level of quality is the degree of cell and tissue coverage achieved by the therapy - how many cells are altered, and whether or not stem cells are altered in order to make the change more permanent. At the moment this coverage is quite variable and uncertain, so better methodologies are needed. Nonetheless, human gene therapy is possible, a few people have undergone enhancement treatments, and at the present time I'd say it is the heavy hand of regulation and a related timidity among researchers and clinicians that are the chief obstacles to be overcome.
Elective gene therapy for enhancements to the present human genome is a potentially enormous market. Unlike medicine for sick people, who comprise a small percentage of the population, this is medicine for every adult - a far greater number of individuals. So I don't believe that current regulatory stances will hold up in the face of medical tourism, not when the actual technologies are now so easily implemented by small groups. At present there are perhaps half a dozen genes for which there is enough evidence enough to feel comfortable of the safety profile of gene therapies: either existing human mutants, or animal lineages, or a great deal of research to support the alteration in question, achieved through ways other than gene therapy, such as antibody blockade of the protein produced from the genetic blueprint. That number will grow in the years ahead. The best candidates are follistatin overexpression and myostatin knockout for muscle growth and associated improvements in metabolism; there is an enormous amount of evidence in mammals for the benefits here.
Beyond this, interventions for some of the other promising genes have been observed in human and mouse mutants to significantly reduce the level of cholesterol in the bloodstream, and thus also significantly reduce cardiovascular disease incidence, with no negative side-effects. One of these is PCSK9, under discussion below, and another is ASGR1. Lowered cholesterol level is one way to reduce the impact of oxidatively damaged cholesterol on the walls of blood vessels, and thus slow the progression of atherosclerosis. This condition is essentially a positive feedback loop of tissue disruption and growth of fatty deposits in blood vessel walls, involving cholesterol, inflammation, inappropriate cell signaling, and malfunctioning immune cells. The more that any of these line items are present, the worse the situation. Interventions in any of these loop components can help to damp down the risk and pathology of atherosclerosis.
Injection could permanently lower cholesterol by changing DNA
People born with natural mutations that disable a specific gene have a lower risk of heart disease, with no apparent side effects. Now a single injection has successfully disabled this same gene in animal tests for the first time. This potential treatment would involve permanently altering the DNA inside some of the cells of a person's body, so doctors will have to be sure it is safe before trying it in people. But the benefits could be enormous. In theory, it could help millions live longer and healthier lives. The results of the animal study were described by Lorenz Mayr, of pharmaceutical firm AstraZeneca, at a genomics meeting in London. Mayr, who leads the company's research into a DNA editing technique called CRISPR, wouldn't say whether AstraZeneca plans to pursue this approach, but he was clearly excited as he presented the findings. "The idea would be to do it as a one-off. It should be permanent."
The PCSK9 protein normally circulates in the blood, where it degrades a protein found on the surface of blood vessels. This second protein removes LDL cholesterol from the blood: the faster it is degraded by PCSK9, the higher a person's cholesterol levels. But people who lack PCSK9 due to genetic mutations have more of this LDL-removal protein, and therefore less cholesterol in their blood. "They have a lower incidence of cardiovascular disease and no apparent side effects whatsoever." To mimic this effect, two companies have developed approved antibodies that remove the PCSK9 protein from the blood. These are very effective at lowering cholesterol and no serious side effects have been reported so far. It is yet to be shown if they reduce the risk of cardiovascular disease, but the first trial results are due to be announced in March.
However, the antibody drugs are extremely expensive and need to be injected every two to four weeks, so even if the antibodies work as well as hoped, they cannot be dished out to millions like statins. All attempts to develop conventional drugs to block PCSK9 have failed, but gene editing provides a radical alternative. Using the CRISPR technique, the team at AstraZeneca have disabled human versions of the PCSK9 gene in mice. They did this by injecting the CRISPR Cas 9 protein and a guiding RNA sequence into the animals. The RNA guide helps the Cas9 protein bind to a specific site in the gene. It then cuts the gene at that point, and when the break is repaired, errors that disable the gene are likely to be introduced. The big worry about using gene editing to alter DNA inside the body is that it could also cause unintended "off-target" mutations. In the worst case, these could turn cells cancerous. Mayr says the team has tested for off-target effects in 26 different tissues in the mice, and that the results will be published soon. "It's very promising in terms of safety."
GPER Knockout Reduces Oxidative Stress to Slow Cardiovascular Aging
In the research noted below, scientists report on the discovery that loss of the GPER gene can slow the pace at which cardiovascular disease progresses, albeit only modestly. Since the molecular biochemistry of a cell is so intertwined, and any given mechanism can be influenced by the presence or absence of numerous different proteins, the existence of any one demonstration of this nature means that should expect there to be a fair number of genes and proteins that might have similar effects if manipulated. Equally, we should also expect most to have only small effects, or to also have unwanted side-effects that make them unsuitable targets for comparatively blunt and sweeping operations such as gene knockout. Most proteins have numerous different roles in cellular processes, which makes it rare to find one that can be removed entirely. Thus the real interest occurs when it is demonstrated that a gene can indeed be done away with without ill effects, an entirely beneficial change - as is the case for PCSK9, mentioned yesterday, among others.
Considering the existence of beneficial mutations, one has to concede that evolution has gifted mammals with a genome that is suboptimal in many ways. Researchers have discovered single gene alterations that increase muscle mass, improve cellular housekeeping, make metabolism work better over the long term, reduce cardiovascular disease, and so forth. That these single gene alterations are there to be developed into a near future of enhancement gene therapies is one of many indications that evolutionary fitness doesn't correspond all that well to individual advantage. Natural selection favors an inferior model, or at least inferior when considered from the vantage point of being someone who is stuck with a body and biochemistry laboriously produced in this manner. Aging itself is the largest of our problems, and may well result from an evolutionary arms race to the bottom; one view of the evolutionary theory has it that aging helps species adapt to changing environments, and since the world does indeed change, the result is that near every present and historical species is made up of individuals who age to death. The immortals were out-competed, save for a few remnants here and there, such as hydra.
Researcher Discovers New Class of Drugs to Combat Aging Diseases
G protein-coupled estrogen receptor, or GPER, determines in part how our cells respond to the hormone estrogen and to estrogen-like substances. GPER plays a role in diseases like breast cancer and diabetes, but also mediates many beneficial functions in physiology. Researchers found that making GPER more active in mice placed on a high fat diet reduced the development of atherosclerosis, a condition in which the blood vessels harden and narrow. But another study's results with old mice were a surprise. The researchers observed mice that lacked GPER in all their cells as they aged. They tracked the mice over the normal mouse life span of about two years. They expected these mice to show increased levels of aging-related disease in their hearts and blood vessels. Instead, compared with normal aged mice, the GPER-lacking mice had healthier hearts and blood vessels. The team then conducted a series of experiments to learn why. They discovered an altered balance between certain signaling molecules in the smooth muscle cells of blood vessels and the heart.
One of those signaling molecules, superoxide, is a type of reactive oxygen species. Reactive oxygen species react quickly and strongly with nearby cellular proteins and impede those proteins' ability to perform their tasks. Over time, the cell's proteins and other components degrade enough to prevent normal cell functions. Almost every disease of aging is influenced by reactive oxygen species. The researchers next tested whether a GPER-blocking drug would improve smooth muscle cell function, as they observed in cells lacking GPER. They discovered that blocking GPER changed how the blood vessels' smooth muscle cells expressed their genes. One of the genes that the drug affected produces a protein called NOX1. NOX1 produces superoxide, one of the most reactive molecules the body produces. By blocking GPER, the team's drug also blocked NOX1 expression, reducing the amount of superoxide the cell produced and reducing cellular aging. The blood vessels of people, and mice, with chronic diseases like diabetes, heart disease and cancer show signs of accelerated aging. By preventing NOX1 expression to block a cell from producing excess superoxide, researchers hope to find a treatment for these conditions one day.
Obligatory role for GPER in cardiovascular aging and disease
Ligand-dependent activation of the G protein-coupled estrogen receptor (GPER) has been reported to confer cardiovascular benefits. However, we found that genetic absence of Gper conferred protection from cardiovascular pathologies associated with aging and hypertension. GPER activity was required to increase the abundance of the enzyme Nox1 in vascular smooth muscle cells, blood vessels, and myocardium, and was associated with enhanced production of tissue-damaging superoxide. Aged mice that were deficient in Gper developed much less cardiac fibrosis and hypertrophy and also retained greater cardiovascular function. In addition, a pharmacological inhibitor of GPER reduced blood pressure, superoxide production, and Nox1 abundance in hypertensive mice. Thus, inhibitors of GPER are potential therapies for cardiovascular diseases and conditions characterized by excessive superoxide generation. Our results indicated that GRBs represent a new class of drugs that can reduce Nox abundance and activity and could be used for the treatment of chronic disease processes involving excessive superoxide formation, including arterial hypertension and heart failure.
The Transhumanist Advocacy of Zoltan Istvan
During the recent presidential election, Zoltan Istvan chose to use one of the few potentially vaguely effective opportunities for grassroots advocacy via the US political process, and put himself forward as a candidate. The goal in doing this was much the same as for the early stages of any single issue political party in a European country, which is to say to leverage the media attendant to the political process in order to put out a message, rather than to actually win anything. Istvan and I are both transhumanists, as is much of the audience here, though I'd say that he is more ready to make that a brand rather than a common sense description of philosophical leanings.
We would both agree that progress in technology will enable our species to overcome the most important limits on the human condition, particularly aging to death, and that this is both plausible and desirable. The sooner it happens the better, but there is all too little public support for such goals at present, despite a considerable growth in the awareness of transhumanist ideals. The longevity science advocacy community of today is very much the cultural descendant of the transhumanist communities twenty years past, for example. Their ideas, once niche and radical, became a portion of the mainstream, some more rapidly than others, such as those involving artificial general intelligence and molecular manufacturing. Support for the use of biotechnology to bring an end to aging is only now arriving at the same place reached by those other fields, a decade later.
It is true, as recent commenters have noted, that I do not often write about politics. Firstly, who needs yet another person doing that? Secondly, insofar as I have a position on politics, I am against it. It is a poisoned chalice that drags down people who might otherwise have been productive, ensnaring them in corruption, waste, and endless, pointless distraction from what actually matters in life. Politicking is an undertaking of no consequence in comparison to the work of building new technology. The state of technology is what determines society, determines the shape of life, offers us new possibilities. In this picture the squabbles of politicians and their devotees are little more than background noise, as demonstrated by how soon today's crises and marches are lost to memory. If we want a better future, history teaches us that the most reliable way to achieve that goal is to choose to build better medicine, better computational devices, better means of transport, and all of the other implementations of scientific knowledge that make being alive a greater thing than it was before, more rich and full of possibility. Not talk about it, not debate funding bills, not distribute stolen largess from the public purse, but to actually set out and do it, as entrepreneurs and investors.
I have the greatest of admiration for someone such as Istvan, who has certainly devoted more time and energy than I of late to set out to persuade people to support the goal of an end to aging through medical research. I just wish he'd chosen a different approach to the problem of efficient advocacy, or perhaps that he was more focused on rejuvenation biotechnology after the SENS model. We don't get to direct the preferences of our fellow travelers, of course, but still. Politics is not the place to go if you want to change the world. It is the place to go if you want to boldly declare that you no longer have any good idea as to how to change the world for the better, and that the sum of your ambitions have become a matter of forcefully rearranging what is, rather than creating new wonders and improvements for the future.
600 Miles in a Coffin-Shaped Bus, Campaigning Against Death Itself
In the autumn of 2015, a man of my acquaintance purchased a 38-foot recreational vehicle - a 1978 Blue Bird Wanderlodge - and, having made to this vehicle such modifications as would lend it the appearance of a gigantic coffin, set out to drive it eastward across the great potbellied girth of the continental United States. His reasons for doing so were, in certain respects, complex and conflicting, but for now it will suffice to inform you that this voyage was undertaken in order to raise awareness of two distinct but related matters. The first of these was the regrettable fact of human mortality and the need to do something about it; the second was that of his candidacy in the following year's presidential election.
This man's name was Zoltan Istvan, and I had known him for about a year and a half by the time he began his progress across the country, from the Bay Area, where he lived, to Florida, and thence northward to Washington, where he planned to ascend Capitol Hill and, in coy allusion to Martin Luther's delivery of his 95 Theses, affix a Transhumanist Bill of Rights to the great ornate bronze door of the Rotunda. "It will be my way of challenging the public's apathetic stance on whether dying is good or not. By engaging people with a provocative, drivable giant coffin, debate is sure to occur across the United States and hopefully around the world. I'm a firm believer that the next great civil rights debate will be on transhumanism: should we use science and technology to overcome death and become a far stronger species?" For transhumanists, this could only be conceived of as a rhetorical question, the obvious answer to which was a resounding yes. I had spent the previous 18 months immersed in this diffuse and heterogeneous movement, through which I encountered many forms of radical optimism about the potential for technology to transform the human condition, to improve our bodies and minds to the point that we become something better.
I met Istvan on a Friday morning outside an empty secondhand bookstore in Las Cruces, N.M, accompanied by Roen Horn. I asked him how he wound up volunteering for Istvan's campaign. "I just really don't want to die," he said. "I can't think of anything that would suck more than being dead. So I'm just doing what I can to ensure that life-extension science gets the funding it needs." Horn, with his Calvinist background, seemed to me now a walking illustration of the way in which scientific progress had displaced divine providence as our culture's locus of faith. Istvan, by contrast, had come to transhumanism from a more secular background. While reporting on the large number of buried land mines still remaining in Vietnam's former DMZ, Istvan himself came very close to stepping on one. In the narrative he had constructed about his life, this was the moment he became a transhumanist - the moment he became consumed by an obsession with mortality, with the unacceptable fragility of human existence. "I have to admit," I said, "I find this whole immortality thing difficult to get behind. Doesn't your obsession with living eternally actually amount to your being totally imprisoned by death?" Horn said "Maybe, but aren't we all? Isn't that kind of the whole idea?" I told him that I took his point.
At the end of the day, progress towards the future of working rejuvenation therapies is built one step at a time. There must be persuasion, philanthropy, and investment alongside the necessary work undertaken by researchers. But ultimately, this progress is a mosaic built from individual choice, a great many people each choosing of their own volition to take a step in that direction. It is all too easy for those on the outside to look at any one particular step and and feel it is insignificant in the face of the work required to reach future goals, but all efforts contribute to the whole.
SENS after de Grey
A recent article on Aubrey de Grey, in which he is presented more in the mode of amiable fellow next door than the mode of instigator of the SENS rejuvenation research movement, reminded me that planned obsolescence is very much an anticipated goal for de Grey. He has for a while now seen a "retreat into glorious obscurity" ahead, perhaps wisely given the way movements tend to grow into unruly children, disrespectful of their founders. We'll see whether it actually comes to pass or not, given that a diet of interesting success is always a challenge to set to one side, but it is also true that going on two decades is a long time to be working what is essentially the same demanding, even consuming job. Still, look at folk like George Church and Craig Venter; there is no shortage of opportunity for third acts in this life. Note that the short article linked here is published by the Financial Times, and so you'll probably have to employ the usual stratagems to bypass their paywall; Google is your friend in this, at least.
Aubrey de Grey: scientist who says humans can live for 1,000 years
Fifteen years ago, de Grey was lead author of a paper in the Annals of the New York Academy of Sciences which claimed the "indefinite postponement of aging . . . may be within sight". Since then, he says, his position among gerontologists - the scientists of ageing and its related ills - has changed from sidelined dilettante to one of the discipline's most influential and public voices. While his science may now be more widely accepted, his pronouncements of impending immortality remain unpopular among his peers. Their squeamishness is unsupported by the evidence, he says. It belies an intellectual dishonesty that has at its heart a deeply emotional - and increasingly erroneous - attachment to the inevitability of death, according to de Grey.
In some ways de Grey's tumbledown mountain retreat seems a fitting castle for this self-appointed "spiritual leader of what I regard as the world's most important mission". To most eyes, the sprawling four-bedroom property falls on the wrong side of the line dividing shabby kitsch-and-chic from basic decrepitude. "The most expensive thing I had owned before this was a laptop. I don't like too much modernity and artifice, I like to be surrounded by mellow things." De Grey's asceticism amounts to more than a disregard for modern interiors and a voluminous beard. While many visionaries come to Silicon Valley to make a fortune, de Grey gave one away. In 2011, his mother - "the formative influence" of his life; his father left before he was born - died. De Grey, her only child, inherited her £10.5m fortune from two Chelsea houses she bought in 1953 and 1963 for a total, he estimates, of £30,000. De Grey took roughly £2.1m for himself, most of which, after inheritance tax, he spent on his home. The remainder, £8.4m, he donated to SENS. When his fiancée arrives he hopes, in time, to "retreat into glorious obscurity" with her, pulling back from a busy speaking schedule that takes him around the world to publicise his work.
It is in the nature of revolutions to bury those who led the first charge. The wages of wild success are indeed obscurity, and fighting that truth seems futile; a matter of standing against the tide. If you start a movement to change the world, and people can still easily pick you out from the crowd of change-makers and supporters fifty years later, then I'd say you didn't do so well. The point of the exercise is to create a sweeping wave of leaders, viewpoints, and endeavors that up-ends the present inadequate system to produce radical improvements. The point of the exercise is to make yourself irrelevant as rapidly as possible, in other words. Human nature being what it is, no matter how hard it was to convince the first few people, and no matter how much work was needed in the early days, the talking heads of the world will later agree that it was obvious in hindsight, anyone could have done it, and weren't those people in the second wave of activities, ten years in, far more important anyway? Validation in this scenario is something that you have to accomplish for yourself, which is worth thinking about while considering one's own efforts and future. Do the work because it is important to your eyes, and because you want to, not for any other reason.
It is true that there is a great deal left to accomplish in order to achieve the technical goal of robust mouse rejuvenation, through prototype implementations of therapies that repair the seven classes of cell and tissue damage that cause aging. The first such therapy, senescent cell clearance, seems a sure thing now, given the state of funding and the field. But the others? Still in the labs, some quite a way from realization. Still, SENS has won, the movement came into being. It is bigger than any one group of people, even now, while a sizable fraction of the necessary laboratory work remains coordinated by the SENS Research Foundation. The goals of SENS will survive the retirement or exodus of any given handful of people, and there are a number of alternative SENS-like formulations out there now, backed by their own advocates and researchers, such as the Hallmarks of Aging. The high-level concept of treating aging by reverting its distinct causes is now spread far enough not to fail. The next twenty years will be a matter of various viewpoints and implementations competing on the only metric that matters, which is the ability to produce rejuvenation in patients.
The battles of tomorrow will be fought over advancing the most plausible approaches more rapidly to the front of the queue, and obtaining the broadest possible funding and adoption by research groups. Later, the battles will be fought over ways to drive existing therapies into low-cost mass production, bypassing the existing regulatory system in favor of something simpler that will save vastly more lives, enabling widespread deployment of rejuvenation therapies both within and beyond the wealthier parts of the world as rapidly as possible. The very first seeds of that future are in progress today, but first things first. The construction of a new industry of rejuvenation biotechnology, from start to finish, is something that will span more than one career - though of course the hope is that it will not span more than a single lifetime, no matter how long it takes. Those who finish will be vastly more numerous, and an entirely different set of people, from those who start. That is the way of things.
Latest Headlines from Fight Aging!
The Moderate Drinking Effect on Health may be Explained by Wealth and Status
The scientific mapping of health and longevity variations in humans is largely a matter of mining demographic data for correlations, with little opportunity to directly determine causation over the decades needed for such studies. One particularly tightly-bound web of correlations involves intelligence, education, social status, wealth, and life expectancy. All influence one another, and a definitive determination of the root causes of these correlations remains a work in progress, and will probably continue to be so for some time yet.
Evidence for unexpected relationships exists, such as physical robustness being genetically linked to intelligence, as well as for the expected capacity of greater wealth to improve health and life expectancy. Analysis is certainly a complex business, and spirals out into many other possible correlations in behavior and circumstances. One of the better known lifestyle choices that touches on this area is moderate alcohol consumption, associated as it is with reduced mortality. It was always to some degree suspected that this association only exists because moderate drinking is in and of itself correlated with wealth and status, rather than being driven by any physical mechanism. One study to provide evidence in that direction is not enough on its own, of course, but it is something to take into account alongside others.
To assess whether a relationship between alcohol use and health exists for older adults before and after controlling for proxy and full indicators of socioeconomic status, we undertook a secondary analysis of data from 2,908 participants in the New Zealand Longitudinal Study of Ageing who completed measures of alcohol use, health, socioeconomic status proxies (income, education) and socioeconomic status itself. Sample mean age was 65, 52% were female, more than 80% were drinkers, and more than 75% had educational qualifications.
Moderate drinkers had better health and socioeconomic status than heavier or nondrinkers. The positive influence of moderate alcohol consumption on health was observed for men and women when controlling for socioeconomic status proxies, but was substantially reduced in women and completely disappeared for men when controlling for full socioeconomic status. socioeconomic status plays a key role in presumed "heath benefits" of moderate alcohol consumption for older adults. It accounts for any alcohol-health relationship in a sample of men of whom 45% consume at least one drink daily, and substantially attenuates the association between alcohol and health in a sample of women who are not frequent drinkers. Prior research may have missed the influence of socioeconomic status on this alcohol-health relationship due to the use of incomplete socioeconomic status measures.
PORCN Inhibition Spurs Greater Heart Tissue Regeneration
Researchers here report on a fortuitous discovery made while searching for potential cancer therapeutics based on the suppression of mechanisms essential to growth and cellular replication, such as the Wnt signaling pathway. To the surprise of the research team, inhibition of the protein encoded by the porcupine (PORCN) gene, required for Wnt signaling, was found to spur greater heart tissue regeneration.
An anticancer agent in development promotes regeneration of damaged heart muscle - an unexpected research finding that may help prevent congestive heart failure in the future. Many parts of the body, such as blood cells and the lining of the gut, continuously renew throughout life. Others, such as the heart, do not. Because of the heart's inability to repair itself, damage caused by a heart attack causes permanent scarring that frequently results in serious weakening of the heart, known as heart failure. Researchers have worked to develop a cancer drug targeting Wnt signaling molecules. These molecules are crucial for tissue regeneration, but also frequently contribute to cancer. Essential to the production of Wnt proteins in humans is the porcupine (Porcn) enzyme, so-named because fruit fly embryos lacking this gene resemble a porcupine. In testing the porcupine inhibitor researchers developed, they noted a curiosity.
"We saw many predictable adverse effects - in bone and hair, for example - but one surprise was that the number of dividing cardiomyocytes (heart muscle cells) was slightly increased. In addition to the intense interest in porcupine inhibitors as anticancer agents, this research shows that such agents could be useful in regenerative medicine." Based on their initial results, the researchers induced heart attacks in mice and then treated them with a porcupine inhibitor. Their hearts' ability to pump blood improved by nearly twofold compared to untreated animals. Importantly, in addition to the improved pumping ability of hearts in the mice, the researchers noticed a reduction in fibrosis, or scarring in the hearts. Collagen-laden scarring that occurs following a heart attack can cause the heart to inappropriately increase in size, and lead to heart failure. Preliminary experiments indicate that the porcupine inhibitor would only need to be used for a short time following a heart attack, suggesting that the unpleasant side effects typically caused by cancer drugs might be avoided. "We hope to advance a Porcn inhibitor into clinical testing as a regenerative agent for heart disease within the next year."
SENS Research Foundation and Buck Institute to Collaborate on a New Approach to Clearing Neurofibrillary Tangles
The SENS Research Foundation staff have over the past decade pioneered the field of medical bioremediation, mining the bacterial world for enzymes capable of breaking down the various forms of metabolic waste associated with aging and age-related disease. Suitable enzymes can form the basis for rejuvenation therapies that work via clearance of these waste products, and thus far the SENS teams have spun off the results of their work into development programs at Human Rejuvenation Technologies, to treat atherosclerosis, and Ichor Therapeutics, to treat macular degeneration. Today the SENS Research Foundation announced a new collaboration with the Buck Institute for Research on Aging in order to apply this same approach to the clearance of altered forms of tau protein that cause harm in Alzheimer's disease and other tauopathies. Much of present day Alzheimer's research focuses on clearance of amyloid, but it is becoming clear that both amyloid and tau aggregates are involved in the pathology of the condition. Unfortunately, while there are some signs of progress, work on tau clearance lags years behind the efforts put into amyloid clearance. Here is a chance for that side of the field to catch up:
The SENS Research Foundation (SRF) has launched a new research program in collaboration with the Buck Institute for Research on Aging. A leading expert on age-related neurodegenerative diseases will be leading the project in the Andersen lab at the Buck. The program is focused on the formation of tau tangles in the progression of neurodegenerative diseases. It will explore the elimination of these age-related waste products in brain cells, using the same approach that SRF has applied in its atherosclerosis and macular degeneration research projects in recent years. The Andersen lab will bring its own world-leading expertise in age-related neurodegeneration to the project. "Our ultimate goal is to find treatments for Alzheimer's and Parkinson's disease. Working with SRF will enable us to look at whether it is possible to use a new method to reverse and prevent the formation of tau tangles, which will help us make significant progress in addressing these complex disorders."
This research has been made possible through the generous support of the Forever Healthy Foundation and its founder Michael Greve, as well as the support of our other donors. The Forever Healthy Foundation is a private nonprofit initiative whose mission is to enable people to vastly extend their healthy lifespans and be part of the first generation to cure aging. In order to accelerate the development of therapies to get aging under full medical control, the Forever Healthy Foundation directly supports cutting edge research aimed at the molecular and cellular repair of damage caused by the aging process. "We are extremely proud to be supporting this project and partnering with the Buck. With this and other collaborations we are planning, SRF looks forward to expanding our contribution to the advancement of medical research on pathologies associated with human aging."
An Apparent Limit on the Quality of Longevity Therapies is Only a Statistical Artifact
Some time ago, statistical correlations in mortality data were used to suggest that interventions that reduce early mortality would lead to later accelerated aging. This view has become fairly widespread in aging theory, and we can see its echoes in studies that provide evidence for early physical prowess to correlate with faster aging, to pick one example. Not everyone agrees, however. Researchers here provide evidence to show that this relationship is an artifact of statistical methods, and there is thus no underlying physical basis for such an outcome. This in turn means that researchers should not be concerned in forging ahead to build therapies to reduce mortality at all ages.
The Strehler-Mildvan correlation was reported in 1960 in a now-famous and very well cited paper. It relates to the Mortality Rate Doubling Time (MRDT) and Initial Mortality Rate (IMR), two parameters of Gompertz mortality law. The original paper does not only introduce the empirical correlation, but also provides a sophisticated theory of aging behind it that is widely accepted among researchers. It says that if the mortality rate is reduced by any interventions at an earlier age, the MRDT goes down, i.e aging accelerates. This hypothesis leads to obstructions to the development of anti-aging therapies and makes optimal aging treatments impossible. Over years, quite a few researchers expressed doubts whether there was any biological meaning behind this correlation or not.
The Gero team prefers to use evidence based science approach over machine learning techniques for anti-aging therapies design, focused on physical reasoning behind mortality dependence on biologically available signals, ranging from gene expression to locomotor activity. Trying to determine physical processes behind Strehler-Mildvan correlation, the team noticed the fundamental disagreement between analytical considerations and possibility of SM correlation for Gompertz mortality law. They showed that SM correlation arises naturally as a degenerate manifold of Gompertz fit.
"We worked through the entire life histories of thousands of C.elegans that were genetically identical, and the results showed that this correlation was indeed a pure fitting artifact. The problem is not as complicated for worm experiments, though it gets pretty tough if humans are involved (the ratio of Gompertz slope to IMR is too large). Thus it seems like SM correlation is an artifactual property of the fit, applied in a limit where the fit does not work, rather than a biological fact. Elimination of Strehler-Mildvan correlation from theories of aging is good news, because if it was not just a negative correlation between Gompertz parameters, but a real dependence, it would have removed the potential for optimal anti-aging interventions and limited human possibilities for life extension."
Reviewing Methionine Restriction as a Basis for Calorie Restriction Benefits
The practice of calorie restriction has been shown to extend life in most mammalian species tested, including primates, and to at least greatly improve measures of health in humans. There is some consensus for the primary mechanism of calorie restriction to involve sensing of methionine levels in the diet, as feeding animals a normal level of calories using foods that contain very little methionine produces fairly similar outcomes to those observed in calorie restricted animals. Methionine is one of the essential amino acids, those not manufactured by our biochemistry and which must be obtained via the diet. It is required for synthesis of proteins, and so less of it requires cells to recycle more aggressively, among other changes.
Methionine restriction (MR) extends lifespan across different species. The main responses of rodent models to MR are well-documented in adipose tissue and liver, which have reduced mass and improved insulin sensitivity, respectively. Recently, molecular mechanisms that improve healthspan have been identified in both organs during MR. In fat, MR induced a futile lipid cycle concomitant with beige adipose tissue accumulation, producing elevated energy expenditure. In liver, MR upregulated fibroblast growth factor 21 and improved glucose metabolism in aged mice and in response to a high-fat diet. Furthermore, MR also reduces mitochondrial oxidative stress in various organs such as liver, heart, kidneys, and brain. Other effects of MR have also been reported in such areas as cardiac function in response to hyperhomocysteinemia, identification of molecular mechanisms in bone development, and enhanced epithelial tight junction. In addition, rodent models of cancer responded positively to MR, as has been reported in colon, prostate, and breast cancer studies.
The beneficial effects of MR have also been documented in a number of invertebrate model organisms, including yeast, nematodes, and fruit flies. MR not only promotes extended longevity in these organisms, but in the case of yeast has also been shown to improve stress tolerance. In addition, expression analyses of yeast and Drosophila undergoing MR have identified multiple candidate mediators of the beneficial effects of MR in these models. In this review, we emphasize other in vivo effects of MR such as in cardiovascular function, bone development, epithelial tight junction, and cancer. We also discuss the effects of MR in invertebrates.
Too Many People Think of Aging and Age-Related Diseases as Somehow Distinct
There is a lot of confused thinking out there in the world when it comes to aging and age-related disease. You don't have to look much further than the fact that most people are entirely supportive of research to treat and cure age-related diseases, such as cancer, heart disease, and Alzheimer's, but those very same people are not in favor of treating aging as a medical condition in order to extend healthy life spans. Yet the progression of aging and the development of age-related disease are one and the same process, meaning the accumulation of biological damage and its consequences to the operation of cells and tissues. The only way to prevent age-related disease is to control that damage, keep it down to a low level by periodically repairing it. Given sufficiently comprehensive repair therapies, undergoing treatment will also put a halt to aging, even produce rejuvenation. The goal of curing age-related diseases across the board necessarily means extension of healthy life; absent damage, people will continue in vigor and good health indefinitely. Unfortunately, most people are disinclined to support the only feasible approach that can achieve this goal.
If you've ever tried to advocate for rejuvenation, you know it is hard. Usually, people deem the idea as crazy, impossible, or dangerous well before you get to finish your first sentence. Living too long would be boring, it would cause overpopulation, 'immortal' dictators, and what have you. However, you've probably never heard anyone use the same arguments to say that we should not cure individual age-related diseases. This is largely because people have little to no idea about what ageing really is, that it cannot be untangled from the so-called age-related pathologies. These are nothing more, nothing less, than the result of the life-long accumulation of several types of damage caused by the body's normal operations. Unlike infectious diseases, the diseases of old age are not the result of a pathogen attack, but essentially the result of your own body falling apart. As I was saying, people are largely unaware of this fact, and therefore expect that the diseases of ageing could be cured one by one without having to interfere with the ageing process itself, as if the two weren't related at all. The result of this false expectation would be that you could cure Alzheimer's, Parkinson's, and so on, but somehow old people would still drop dead around the age of 80 just because they're old.
That is like saying that people will die of being healthy. Back to reality, this can't be done. To cure the diseases of old age, you need to cure ageing itself. If, for whatever reason, you think that curing ageing as a whole would be a bad idea and it should not be done, the only option is to not cure at least some of the root causes of ageing. Consequently, some age-related pathologies would remain as untreatable as they are today. The typical objections raised against rejuvenation tend to sound reasonable at first. To some, the statement 'We should not cure ageing because it would lead to overpopulation' sounds self-evident. However, if we consider the implications of this statement, things start getting crazy. As said, not curing ageing implies not curing some of its root causes, which in turn implies not curing some age-related diseases. Therefore, the sentence 'We should not cure ageing, because otherwise fewer people would die and this might lead to overpopulation' implies 'We should not cure Alzheimer's disease, because otherwise fewer people would die and this might lead to overpopulation.' I don't think I need to point out why that statement is utterly ridiculous. I'm all for discussing potential problems brought about by the defeat of ageing, so that we can prevent them from ever happening; however, I'm not going to buy a pig in a poke and accept blatant nonsense as valid objections to rejuvenation.
An Indirect Test to Assess Risk of Cardiac Transthyretin Amyloidosis
Researchers have only recently started to understand the degree to which transthyretin amyloidosis contributes to heart failure. This condition is thought to be a majority cause of death in the very oldest people, but there is now evidence to show that heart disease in earlier old age is also caused by a build up of this form of amyloid in tissues. The growing presence of various amyloids is one of the fundamental differences between old tissue and young tissue, and any future rejuvenation toolkit must include the means to remove them. Since there is at least one viable clearance treatment under development for transthyetin amyloid, that worked on at Pentraxin Therapeutics, an important next step in the process of raising the funds needed to complete passage through the heavy-handed regulatory systems of the US and Europe is to gather more evidence of the need for such a therapy. That in turn requires better clinical tests, or indeed any viable clinical tests, as at present the evidence for transthyretin amyloid to cause heart disease is largely obtained from post-mortem studies. Here, researchers report on progress towards an indirect approach to testing for the risk of this form of amyloidosis in heart tissue:
Researchers have developed a new diagnostic test that may help doctors identify patients with a condition called cardiac amyloidosis. Cardiac amyloidosis is caused by abnormal folding of proteins that deposit in the heart. These protein deposits can also occur in other organ systems in the body and can cause life-threatening organ failure. Cardiac amyloidosis that results from the mis-folded protein transthyretin is called ATTR amyloidosis, and this form of the disease occurs in older patients. Amyloid deposition can cause electrical abnormalities and decrease the heart's ability to relax and contract, leading to congestive heart failure.
The diagnosis of ATTR amyloidosis can be challenging for doctors, and amyloidosis in many patients remains un-recognized, sometimes until the time of death. However, recent studies suggest that as many as 10 percent of older patients with certain types of congestive heart failure may have cardiac amyloidosis. In this study, researchers identified that a specific blood protein named retinol-binding protein 4 (RBP4) can be used to determine the likelihood of ATTR amyloidosis in a patient with congestive heart failure.
In addition the research team developed a mathematical calculator that incorporates RBP4 and other commonly ordered clinical tests that can be used to estimate the probability of ATTR amyloidosis in a given patient. An important advantage of this algorithm is that it can be used in the context of a doctor's office visit at the point-of-care. According to the researchers, this discovery could guide clinical decision making and increase recognition of this disease. Since many new drug therapies are in various stages of development now for ATTR amyloidosis, recognition and accurate diagnosis is essential to get a patient on the correct treatment.
Early Coronary Artery Calcification Predicts Later Risk of Heart Disease
Researchers here find that even quite low levels of calcification of arteries at younger ages associates with a raised risk of heart disease going forward. Calcification is a process that has is yet to be firmly placed in the chain of cause and consequence for age-related damage in blood vessel tissues. The evidence leans towards it being a consequence of primary damage such as waste accumulating in cell lysosomes, forms of persistent cross-linking that stiffen blood vessels and senescent cell accumulation that produces inflammation, insofar as growing calcification appears to be a cellular process, the result of changed and inappropriate cellular behavior. So in this sense, calcification is a marker of the progression of damage in aging, and more of it should absolutely be expected to correlate with the risk of age-related disease.
Researchers have found that the mere presence of even a small amount of calcified coronary plaque, more commonly referred to as coronary artery calcium (CAC), in people under age 50 was strongly associated with increased risk of developing clinical coronary heart disease over the ensuing decade. The study also revealed that those with the highest coronary artery calcium scores, as measured by computed tomography (CT) scan, had a greater than 20 percent chance of dying of a heart event over that same time period. CAC has long been associated with coronary heart disease and cardiovascular disease. However, prognostic data on CAC in younger adults - people in their 30s and 40s - have been very limited.
"We always thought you had to have a certain amount of this plaque before you were at risk of having events. What our findings demonstrate is that, for women and women less than 50 years of age, any amount of coronary artery calcium significantly increased risk of clinical heart disease. Any measurable CAC in early middle age - scores of less than 100, and even less than 20 - has a 10 percent risk of acute myocardial infarction, both fatal and non-fatal, over the next decade beyond standard risk factors." The study points to CAC as a very specific imaging biomarker for identifying those people who are at risk earlier in life for heart disease, and who may benefit from proven interventions such as cholesterol and blood pressure management, working toward a healthy BMI and smoking cessation, although more work is needed.
Data for this study comes from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a longitudinal, community-based study that recruited 5,115 black and white adults ages 18-30 in four cities - Oakland, California; Minneapolis; Chicago; and Birmingham, Alabama - beginning in 1985 and followed them for 30 years. CT scans were performed on 3,330 subjects for the CAC study, and the mean follow-up period was 12.5 years. CAC of any amount was seen in 30 percent of that group. Investigators sought to answer two primary questions: can the simple presence of CAC on a chest CT inform clinical practice? And is a CAC score greater than 100 associated with premature death? The answer to both was yes. "The presence of any coronary artery calcification, even the lowest score, was associated with between a 2.6 and tenfold increase in clinical events over the next 12.5 years. And when it comes to those with high CAC scores (100 or above), the incidence of death was 22 percent, or approximately 1 in 5. Very few times do you get a biomarker, be it genetic or imaging, that predicts death at a level of 22 percent over 12.5 years."
A Call for More Study of Exceptionally Regenerative Species
A range of higher animal species are capable of regrowing organs and limbs, such as the zebrafish and axolotl. Research groups have for some years investigated the differences between the biochemistry of these species and mammals, and given the promising progress to date, the authors of this commentary call for an increased investment in this field:
Increasingly more studies of nontraditional vertebrate model organisms with extraordinary regenerative capacities are providing valuable insight into the mechanisms of complex tissue regeneration. For example, the zebrafish (Danio rerio) can regenerate many tissues after injury including cardiac, fin appendages and spinal cord. Another ray-finned fish, the bichir (Polypterus senegalus) can also regenerate cardiac and fin appendages. Urodeles (salamanders and newts), such as the axolotl (Ambystoma mexicanum), can regenerate whole limbs. Studies of models with robust regenerative capacities have advanced our understanding of regenerative mechanisms by identifying genes that are necessary and sufficient for regeneration in vivo. Regenerative biology has historically focused on defining the cellular and molecular mechanisms within individual species. Within the last 15 years, rapid advances in genome sequencing technology and gene editing strategies have advanced the understanding of the molecular and cellular processes that define tissue regeneration. Unfortunately, they have also unintentionally created silos that encase individual animal models and discourage examination of regenerative capacity in nontraditional model systems.
Comparative studies of regeneration can be framed in a phylogenetic context where model organisms are selected to identify conserved gene regulatory mechanisms for regeneration. These limb regeneration traits are in stark contrast to mammals where it is limited to the very ends of digits in mice, rats, monkeys, and humans. Given that urodele taxa can regenerate limbs, it suggests that limb regeneration is an ancestral trait of urodeles. Furthermore, it is plausible that appendage regeneration is an ancestral trait of all jawed vertebrates as both ray-finned fish and urodele taxa can regenerate appendages. Alternatively, limb regeneration may be a derived trait. No reports of appendage regeneration have been published among cartilaginous fishes (chondrichthyes). The last common ancestor of jawed vertebrates appeared approximately 420 million years ago providing for an opportunity to find common mechanisms for appendage regeneration.
With increasing knowledge of proregenerative mechanisms, the next challenge is to identify small molecules to enhance regeneration following injury in humans. A target-based strategy where compounds are identified to target particular genes, proteins or pathways is a complementary strategy. Proregenerative lead compounds could then be tested in nonregenerative models, such as the mouse, to determine whether they promote regeneration. The demonstrated benefits of studying the genetic pathways for regeneration in highly regenerative species should motivate us to re-examine the allocation of research funds. Additional investment to create genetic and molecular resources to study nontraditional models, such as the zebrafish and axolotl, are needed to accelerate these comparative studies. The zebrafish represents a good start, its genome was characterized in 2003 and many genetic tools have been developed to work with it, which are already yielding fruit. The progress on therapies for heart regeneration, for instance, has been 'spectacular', according to researchers who discovered in 2002 that zebrafish can regenerate heart tissue after 20% of the ventricle has been removed.
Other model organisms are still unexploited, however. High levels of research funding using mouse models over several decades have built a vast repertoire of tools and resources for the mouse. Currently, over 70% of traditional research grants involve mouse studies. Increasing funding for studies that involve a broader set of model organisms, like the zebrafish and axolotl, across all biomedical fields would result in more tools and resources for these diverse models. In turn, these investments would provide the critical genetic and molecular tools and resources for nontraditional model organisms needed to accelerate comparative studies of regeneration.
Searching the Lizard Genome for Regenerative Factors
Some of the research aimed at understanding - and potentially replicating - the greater regenerative capacity of lizards is fairly reductionist in nature. The genome is sequenced for a lizard species, the proteome cataloged, and then compared with mammalian biochemistry in search of possibly interesting differences for further examination. This open access paper summarizes one such finding, and the background behind it:
It is likely that all animals have the capacity to regenerate damaged body parts, although the degree of regeneration seems to be different in different species. Regeneration is more vigourous in invertebrates than it is in vertebrates. Indeed, many invertebrates, such as hydra, planarians, and starfish, have bidirectional regeneration capcity, so they can generate two sets of the same animal by regrowing missing parts, while regeneration processes in vertebrates occur unidirectionally, in which the animal reproduces only damaged parts at the site of injury. Amongst vertebrates, fishes and amphibians have the greatest regenerative capacities, and amniotes such as reptiles, birds, and humans, seem to have lost the capability to regenerate, although many lizards can reproduce their tails.
In lower vertebrates, natural regeneration occurs mainly by virtue of the intrinsic plasticity of mature tissues, which involves cellular proliferation, migration of remaining parts, and regrowth of damaged or missing parts. The most prominent event in tissue regeneration in lower vertebrate may be formation of a blastema. The blastema shares many characteristics with stem cells, and can eventually redevelop into various tissues, including muscle, skin, bone, and blood vessels, that were originally present at the damaged site. The blastema is formed through the dedifferentiation process, and this step is omitted in the higher vertebrates such as birds and mammals. Thus, it could be that the lack of regenerative capacity in birds and mammals may be evolutionarily related to loss of the capacity to dedifferentiate.
In fact, mammals share many key factors for regeneration with lower animals, such as fibroblast growth factor (FGF), Wnt/beta-catenin, and bone morphogenic protein (BMP)/Msx signaling, which are known to be involved in wound healing and cellular proliferation. Through such processes, mammals can repair damaged tissues to some extent. Nevertheless, mammals have little regenerative capacity compared to lower animals, probably because they lack the capability to dedifferentiate. Damage to human organs, such as the heart, brain, and liver, often leads to serious pathological conditions. Although stem cell-based transplantation could be clinically performed, additional strategies may be required for proper treatment of organ injuries in humans. Thus, study of the mechanisms of blastema formation and the development of protocols for mammalian dedifferentiation will be a breakthrough for regenerative medicine and stem cell biology.
Mammalian cells have been known to undergo dedifferentiation in vitro by enforced expression of Oct4, Sox2, Klf4, and c-Myc. Although this induced pluripotent stem cell (iPSC) strategy is an innovative tool in human tissue regeneration and stem cell therapeutics, it has drawbacks including low efficiency and uncertain safety. For example, use of oncogenes such as Klf4 and c-Myc in iPSC generation raised concerns about the safety of iPSCs for practical applications. Although other substitutes such as Nanog and Lin28 have been suggested, these oncogenes may be regarded as indispensable to the efficiency of dedifferentiation. The first gene identified as a dedifferentiation factor from proteomic studies in lizards was a lactoferrin. Recent discoveries showed that lactoferrin can substitute for Klf4, and even provide greater efficiency for dedifferentiation of human fibroblasts. Although lactoferrin by itself is not enough to replace all the oncogenes necessary for dedifferentiation of human cells, and further identification of other factors should be performed, this finding indicates that comparative studies of lizards would be a promising strategy to reveal the mechanisms of regeneration.