Excess Fat is Bad, Intentional Loss of that Fat is Good
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One of the things that turns up in large sets of data on weight and mortality - by which I really mean amount of fat tissue and mortality - is that both maintaining excess fat tissue and later the loss of that fat tissue are associated with increased mortality. This is because visceral fat tissue causes chronic inflammation and other forms of metabolic dysregulation. The more of it you have, the worse off you are over the long term: it is actively causing harm that accumulates to significantly raise the risk of all of the common age-related disease. Later in life, the progression and treatment of many of these age-related conditions, such as cancer, are accompanied by involuntary weight loss. There are many reasons for this ranging from simple loss of appetite to disease mechanisms that impact the normal operation of metabolism in pathological ways. If you pick out a group of people who are sharply losing weight, especially older people, the mortality rate for that group will tend to be higher than for those who maintain their weight. This is because the losing group contains a larger number of individuals who are suffering the later stages of age-related disease.

This does not mean, as some have said in the past, that it is good to be overweight. You can't lump this data together and make that claim. Involuntary weight loss is so very joined at the hip to high mortality risk that it distorts the picture, and most of the good data sources for large numbers of people make no distinction as to how or why weight changes occur. Any number of people in the world want to be told that is is fine to be overweight and nothing bad is going to happen as a result: there is always a market for comforting lies. Even a moderate level of excess fat tissue has a significant impact on the future risk of incurring all of the common age-related diseases, however. If you want the best odds of living a healthy life for as long as possible, then don't allow yourself to become fat. It is a choice, and one that you can avoid or reverse with sufficient exercise of willpower.

Unlike involuntary weight loss, deliberately setting out to lose your excess fat tissue is a good thing and produces benefits. You are cutting out a source of damage to your health, and that makes a difference over the long-term to your mortality risk. That shows up in epidemiological data, as demonstrated here.

Intentional Weight Loss and All-Cause Mortality: A Meta-Analysis of Randomized Clinical Trials

Advanced age and obesity are risk factors for disability, morbidity, and mortality. Weight loss interventions in overweight and obese older adults positively affect several strong risk factors for mortality. Yet, many observational studies in middle-aged and older adults report an association between weight loss and increased mortality. Difficulty reconciling these contradictory findings (the so-called "obesity paradox"), coupled with the strong negative prognostic implication of rapid involuntary weight loss with advanced age, has led to a reluctance to recommend weight loss in older adults. Attempts to refine observational analyses to avoid confounding (i.e. distinguishing between intentional and unintentional weight loss, and restricting populations to those without co-morbid conditions or non-smokers) typically reveal no increase, and perhaps some decrease, in mortality risk with intentional weight loss.

Although results from a randomized controlled trial (RCT) of weight loss would theoretically resolve these issues, such a trial would require a large sample size over a long duration to detect clinically meaningful differences in mortality. In light of the high prevalence of obesity, its negative impact on health and quality of life, and the discrepancy between the proven risk factor improvements of short-term intentional weight loss and the inverse association of weight loss with increased all-cause mortality frequently seen in observational studies, we conducted a meta-analysis to estimate the effect of interventions which included intentional weight loss on all-cause mortality in overweight and obese adults. We hypothesized that intentional weight loss would be associated with reduced all-cause mortality. Further, as weight loss in older persons is a cause of clinical concern that may lead health care providers to recommend against weight loss for obese, older adults, we sought to examine the effects in a subset of trials with a mean baseline age of at least 55 years.

Trials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30-46 kg/m2, follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk. There was no evidence for heterogeneity of effect.

More Signs that Calico Will Fund Broad Mainstream Drug Discovery and Genetic Research
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Google is pouring a large amount of money into aging research via the Calico Labs initiative. Their declared aim is to produce treatments that impact the whole of age-related degeneration, and their open support of that goal is certainly going to make it easier for other initiatives to raise funding in the future - it adds that much more legitimacy to the space in the eyes of investors and philanthropists who have so far stayed away. That is the good part. However it has become increasingly clear that the Calico Labs approach, telegraphed pretty early on, is to broadly fund the central mainstream of research and development relating to aging, which at this time is the standard process of drug discovery and investigations of the genetics of longevity. In this they might be considered a second iteration of the Ellison Medical Foundation, a funding addendum to the present efforts of the NIA and pharmaceutical companies, but really introducing no fundamentally new and better strategy. So expect past performance to predict the next decade or so here.

The Ellison Medical Foundation achieved essentially nothing of great note over the course of its existence, a period when the same could be said of most NIA projects, because the mainstream approach to aging does not consist of strategies likely to produce any significant gains in healthy human life span. I've talked about why this is the case at length over the years, but in essence it boils down to the same reasons as to why I support the SENS programs for rejuvenation biotechnology development. The preponderance of evidence strongly suggests that aging is caused by an accumulation of damage to cells and tissues. The best approach, which is the SENS approach, is to repair that damage periodically but otherwise not tinker with the operation of our metabolism: it is complicated and we understand very little of it in comparison to our understanding of the damage that is linked to aging. This is not the mainstream approach, however. In the mainstream of aging research, where researchers are interested in treating aging at all that is, the focus is on finding ways to alter the operation of our metabolism so as to slow down damage accumulation.

It doesn't require a vast and detailed understanding of biology to grasp that slowing damage is a worse strategy than repairing damage in any system, complex or not. It cannot restore youthful function and is of limited utility to old people. Further, safely altering metabolism to achieve specific goals is much harder than repairing known and clearly demarcated forms of cellular damage. This is illustrated by the fact that a clear set of plans for damage repair exist with many different options for implementation, but at this time - and after decades of work and billions of dollars invested - researchers still don't have a clear understanding of how calorie restriction works or can be reproduced, and that is the simplest and most reliable altered state of metabolism known to extend life and improve health. Even if the calorie restriction response could be recreated with a drug, the outcome would be far less health and life gained than for even a partial implementation of repair treatments.

Here are some recent news reports on the Calico initiative that reinforce the point on the broad fundamental research strategy they are choosing to take, acting in essence as a supplemental fund for existing programs and approaches to drug development, with a heavy emphasis on genetics:

Broad Institute and Calico announce an extensive collaboration focused on the biology of aging and therapeutic approaches to diseases of aging

The Broad Institute of MIT and Harvard has entered into a partnership with Calico around the biology and genetics of aging and early-stage drug discovery. The partnership will support several efforts at the Broad to advance the understanding of age-related diseases and to propel the translation of these findings into new therapeutics. "This alliance is a key part of Calico's strategy to bring the best cutting-edge science to bear on problems of aging. The Broad Institute is one of the nation's preeminent research organizations whose outstanding research has repeatedly revealed fundamental mechanisms of the biology and genetics of disease," said Art Levinson, Chief Executive Officer of Calico.

Calico, QB3 Launch Longevity R&D Partnership

Google-back Calico said Tuesday it will partner with the University of California institute QB3 to study longevity and age-related diseases, as well as create and foster an interdisciplinary community of scientists in those fields. The four-year partnership is designed to generate discoveries that will translate into greater understanding of the biology of aging and potential therapies for age-related diseases. The partnership plans to identify, fund and support QB3 research projects focused on aging, using committed funding from Calico - which focuses on aging research and therapeutics. "We are all aging, and we will all benefit from the discoveries made in this program and the therapies that will result," QB3 director Regis Kelly said in a statement. "We are grateful to Calico for recognizing the deep expertise at the University of California that attracts so many scientists of exceptional ability."

For those of us who do support the SENS repair approach, the lesson to take home and remember is that we will see mainstream funding of SENS-related research and development when that work becomes mainstream. Not before. It is already the case for cancer and stem cell science, where there are strands of SENS-like work taking place in many laboratories, but for the other forms of tissue repair there must be demonstrations of effectiveness. We can learn from the growing interest in senescent cell clearance: that only emerged in earnest after the 2011 demonstration of improved health in accelerated aging mice. This year we are seeing the fruits of that interest in the form of new demonstrations of effectiveness in normal mice and the first company founded to commercialize an approach to clear senescent cells. More researchers, more results, more programs underway.

However frustrating it might be, funding follows success. This is why it is so important that we continue to raise funds for early stage SENS research in order to create the technology demonstrations that can pull in that attention and funding. We are, after all, winning at this game step by step. Five years ago senescent cell clearance was something that no research groups looked at in earnest, and now we have mice that are healthier as a result of treatments that remove senescent cells. Ten years from now there will be clinical trials underway in humans. Meanwhile there are four or five other important forms of damage repair that must make the same leap, and that is only going to happen with the support of you, I, and other philanthropists.

DNA Methylation and Natural Variation in Human Longevity
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DNA methylation is an epigenetic alteration in which genes are decorated with methyl groups. It is one of a range of epigenetic processes that establish a feedback loop linking the pace at which specific proteins are built from genetic blueprints, the activities of those proteins once built, and environmental circumstances in tissues such as nutrient availability, temperature, damage, and disease. All of the switches and dials for molecular machinery inside cells are essentially built on top of the circulating levels of specific proteins, and these are altered via epigenetics: protein levels are in constant flux, as are countless epigenetic modifications to DNA.

In recent years researchers have demonstrated that specific patterns of DNA methylation within this broader tapestry correlate very well with age. Researchers can use these patterns in a tissue sample to identify an individual's age with an accuracy of five years or so. We all age due to the same underlying processes, some of us faster than others largely due to unfortunate lifestyle choices such as lack of exercise, excess weight, and smoking. Small differences in stochastic damage to cells and tissues snowball over the years into comparatively large differences in outcomes: the roots of variability in the mean time to failure in a very complex system. Given that the same forms of damage accumulate in all of us as a side effect of the same metabolic processes, it shouldn't be surprising to find that researchers can pull out patterns in the controlling mechanisms of metabolism - epigenetic alterations - that are tightly coupled to age. These are reactions to the environmental state of being damaged.

Studies that investigate DNA methylation from other perspectives should pick up the same signs of the same underlying processes, and same broad similarities between individuals. This is the case even when looking for signs of differences between old individuals, in search of a better explanation of the genetic contribution to extreme longevity in humans. So far genetic studies have turned up very few associations between genetic variants - meaning actual differences in the structure of specific genes - and longevity. Those that are found in one study rarely show up in others. This suggests that if variants are important in determining survival in extreme old age, then there must be a very large number of such variants with individually small effects, and the patterns of genetic differences must vary widely between regional populations. A very complex picture with little hope of complete understanding or any sort of resulting application in medicine in the near future, in other words. Is this in fact the case, however? These researchers suggest that epigenetic changes are instead where we should look, and that the picture isn't as complex as feared:

A Genome-Wide Scan Reveals Important Roles of DNA Methylation in Human Longevity by Regulating Age-Related Disease Genes

Human longevity is believed to be an integrating result of genetic and environmental factors. Although previous studies have shown that genetic variation may explain 20-30% contribution to human longevity, much remains to be known for its underlying genetic mechanism. In the past decade, a number of genes were discovered, in which some specifically genetic alterations may confer advantage in extending the organisms' lifespan, suggesting the existence of longevity genes. These findings however could not fully explain the significantly reduced incidence of age-related diseases in centenarians and their offspring, as it requires a broad effect of longevity genes, including conferring beneficial effects in extending life span as well as suppressing deleterious influence from the disease-associated genes. Alternatively, it is possible that the low prevalence of the age-related diseases in the long-lived people is attributed to a much lower frequency of risk alleles. Unfortunately, the latter notion fails to find support from a recent study in which the long-lived people were shown to carry similar frequencies of risk alleles as did in the young controls. This observation seems to echo with the suggestion that the longevity-related variants may compress the morbidity of long-lived people as these variants were significantly enriched in disease-related genes.

Hitherto, the obtained genetic evidence, based virtually on mutation screening, find no support for the hypothesis that lack of disease-related mutations contributes to healthy aging. However, taking into account the heterogeneity in longevity, in which multiple ways could be adopted to achieve longevity, and the crucial role of epigenetic modification in gene regulation, we hypothesize that suppressing the disease-related genes in the longevity individuals is likely achieved by epigenetic modification, e.g. DNA methylation. A reduction of genome-wide DNA methylation level and locus-specific hyper-methylation has been observed with aging, whereas changes in DNA methylation were reported to be associated with the occurrences of age-related diseases, such as cardiovascular disease, diabetes and cancer.

To test this hypothesis, we investigated the genome-wide methylation profile in 4 Chinese female centenarians and 4 middle-aged controls. 626 differentially methylated regions (DMRs) were observed between both groups. Interestingly, genes with these DMRs were enriched in age-related diseases, including type-2 diabetes, cardiovascular disease, stroke and Alzheimer's disease. This pattern remains rather stable after including methylomes of two white individuals. Further analyses suggest that the observed DMRs likely have functional roles in regulating disease-associated gene expressions. Therefore, our study suggests that suppressing the disease-related genes via epigenetic modification is an important contributor to human longevity.

I'd want to see a much larger study before taking this result at face value, but to find consistencies across populations in this sort of data shouldn't be too surprising given the points made above about the fact that we all age in the same way. Patterns of similarity should be there to be found in many different ways.

What Can Other Primates Teach Us About Aging and Neurodegeneration?
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It has been said that the only thing worse than using animals in medical research is to refrain from the use of animals in medical research. It is both terrible and necessary. Throughout the modern history of medical science animal studies have been needed in order to make progress, not just in human medicine, but also veterinary medicine. Many people are opposed to animal studies, and to the degree that this is motivated by compassion - and leads to sensible forms of advocacy - this is to their credit. Unfortunately all too few of these individuals follow the logic though to its end and thus devote near all of their efforts to oppose the animal farming, hunting, and fishing industries. These activities cause harms to animals that tower over those of research. All the animal studies carried out in a year are a rounding error against a few hours of the meat industry.

That aside, animal studies will one day soon be a thing of the past. Some will be replaced by the use of engineered tissue sections, but eventually all will give way to experiments that run on simulation platforms, coupled with a much more modest use of engineered tissues to validate those simulations. Even the early steps on this road will be more effective and far cheaper than maintaining animal colonies and lineages for use in research. The only reason that this transition hasn't yet occurred is that only now has tissue engineering arrived at the point of mass production of functional tissue sections that mimic the real thing closely enough to be useful. I would hope that the farming of animals one day goes the same way, and that we as a species continue on a somewhat upward slope of culture and enlightenment that leaves this and other presently acceptable forms of institutional violence behind us. That is no doubt a much longer and harder road than merely transforming life science research.

Primate studies are already in decline. They are far more expensive than studies in shorter-lived species and far more difficult to arrange in the present climate. Any new study similar to the decades-long calorie restriction studies in rhesus macaques now coming to their final years is unlikely to take place given today's culture and pace of technological progress. Thus I think that these researchers are arguing for the last days of a paradigm that is firmly in its sunset period:

Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases

Why do we need animal models? The simplest answer to this question is to increase our general knowledge, to experimentally test theories. Animal model usefulness is manifold, from the study of physiological processes to the identification of disease-causing mechanisms. They are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates (NHPs). Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher.

NHPs have significantly contributed to understanding of aging and neurodegenerative diseases. Aging NHPs show striking similarities with elderly humans. Most of our understanding on the biological changes observed during aging comes from studies in rodents because they present clear advantages (short life span, fully characterized genetic aspects, easy genetic manipulation...). However, rodents and humans diverged much earlier than humans and NHPs, and this is likely to have led to fundamental differences in their aging processes. In one pioneering work, for example, researchers compared the transcriptome of the cerebral cortex in aging mice, rhesus macaques and humans, providing a broad view of the evolution of aging mammalian brain. They found that only a small subset of age-related gene expression changes are conserved from mouse to human brain, whereas such changes are highly conserved in rhesus macaques and humans.

Due to their genetic proximity to humans and their highly developed social skills, NHPs are extremely valuable as experimental animal models. However, as the number of available animals is restricted for ethical reasons and also because of the high cost and large space required for breeding colonies, NHPs should only be used when no other suitable method is available to fill the gap of our knowledge. In any case, rodent (or other small animal models) and primate experimental models need to be used in parallel in order to obtain robust and complementary information. Alongside other models, nonhuman primates should have a unique place in the overall aging and neurodegenerative research strategy.

Tissue Engineering of Lung and Gut Sections
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The first practical outcome of tissue engineering research is not therapies, but rather improved tools for further scientific work in this and other fields. At present the structured tissue sections created in the laboratory are largely too small or too dissimilar from natural organs for use in treatments, but these engineered tissues can nonetheless be very useful in drug testing, investigation of disease mechanisms, and many other aspects of medical research. Real tissue is a vast improvement over cells in a dish and animal models, and real tissue grown from patient cells is a tremendous step forward for work on genetic disorders. In the economic development of the field, the ability for companies to form and make money by providing these tools is a vital stepping stone on the way to improving the underlying technologies. That will lead in time to building whole organs to order, one step at a time.

Scientists grow 'mini-lungs' to aid the study of cystic fibrosis

Scientists have successfully created 'mini-lungs' using stem cells derived from skin cells of patients with cystic fibrosis, and have shown that these can be used to test potential new drugs for this debilitating lung disease. The research is one of a number of studies that have used stem cells - the body's master cells - to grow 'organoids', 3D clusters of cells that mimic the behaviour and function of specific organs within the body. Researchers used skin cells from patients with the most common form of cystic fibrosis caused by a mutation in the CFTR gene referred to as the delta-F508 mutation. Approximately three in four cystic fibrosis patients in the UK have this particular mutation. They then reprogrammed the skin cells to an induced pluripotent state, the state at which the cells can develop into any type of cell within the body.

Using these induced pluripotent stem cells, or iPS cells, the researchers were able to recreate embryonic lung development in the lab by activating a process known as gastrulation, in which the cells form distinct layers including the endoderm and then the foregut, from which the lung 'grows', and then pushed these cells further to develop into distal airway tissue. The distal airway is the part of the lung responsible for gas exchange and is often implicated in disease, such as cystic fibrosis, some forms of lung cancer and emphysema. "In a sense, what we've created are 'mini-lungs'. While they only represent the distal part of lung tissue, they are grown from human cells and so can be more reliable than using traditional animal models, such as mice. We can use them to learn more about key aspects of serious diseases - in our case, cystic fibrosis. We're confident this process could be scaled up to enable us to screen tens of thousands of compounds and develop mini-lungs with other diseases such as lung cancer and idiopathic pulmonary fibrosis. This is far more practical, should provide more reliable data and is also more ethical than using large numbers of mice for such research."

Researchers seek to make mini-guts that mimic life

"We are already making human mini-guts in the laboratory. We make them, we can freeze them." However, they are not a perfect model, and she hopes this project will result in better ones. Not only will they have the stretch and pull of living guts, but will also include the immune cells found underneath the epithelium of the gut and the mesenchymal and nerve cells that enhance the environment and function of the gut.

There are two major projects. Project one uses human intestinal enteroids (cells taken from the gastrointestinal tract) to analyze how those cell react to human rotavirus and vaccine replication as well as enteroaggreative E. coli, defining how the epithelial cell responses lead to pathology or disease. Project two will combine tissue engineering, biomaterial design and mechanobiology to develop specially tailored platforms for the human intestinal enteroids that can be stimulated mechanically, promoting cell and tissue polarity and differentiation of intestinal tissue to facilitate infection with the rotaviruses and E. coli. "Infectious disease labs that study enteric disease need better models that faithfully simulate the physiology of the intestine. This organ contains multiple types of cells that are arranged in complex patterns, and these tissues are constantly on the move. They contract and expand all the time."