Fight Aging! Newsletter, February 13th 2017

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 gene action later in life, leading via dysplasia to the age-related pathologies that cause the age-correlated 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 half again 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.

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."

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.

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.

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 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.

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 10.5m 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.

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.

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."

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 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."

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."

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.

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.

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 a tenth 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.

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."

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.

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.