It has been a decade since researchers first discovered the recipe for reprogramming ordinary somatic cells into induced pluripotent stem cells, capable of generating all other cell types in the same way as embryonic stem cells. This was a transformative advance, as the ease of the method allowed near any research group to work with pluripotent cells. Making use of induced pluripotency in research and medicine is still very much a work in progress, however: great strides are being made in the production of cells and tissues for drug testing and other tissue engineering for research use, but the goals of generating patient-matched cells and tissues for cell therapies and transplantation are not proceeding as smoothly as was perhaps hoped by some. This popular science article surveys the field:

Human cortex grown in a petri dish. Eye diseases treated with retinal cells derived from a patient's own skin cells. New drugs tested on human cells instead of animal models. Research and emerging treatments with stem cells today can be traced to a startling discovery 10 years ago when researchers reported a way to reprogram adult mouse cells and coax them back to their embryonic state - pluripotent stem cells. A year later, they accomplished the feat with human cells. The breakthrough provides a limitless supply of induced pluripotent stem cells (iPSCs) that can then be directed down any developmental path to generate specific types of adult cells, from skin to heart to neuron, for use in basic research, drug discovery and treating disease. The dazzling iPSC breakthrough has spurred rapid progress in some areas and posed major challenges in others. It has already proved a boon to basic research, but applying the new technology to treat diseases remains daunting. Some types of cells have proved difficult to reprogram, and even the protocols for doing so are still in flux as this is still a very young field.

Six years after the iPSCs discovery, researchers in a very different field developed a new gene-editing technology of unprecedented speed and precision, known as CRISPR-Cas9. The potent new tool has revolutionized efforts to "cut and paste" genes and has been very quickly adopted by thousands of researchers in basic biology and drug development. CRISPR's speed and precision may some day allow stem cell researchers to reach their most ambitious goal: Genetically abnormal cells from patients with inherited diseases such as sickle cell anemia or Huntington's could be reprogrammed to the pluripotent stem cell state; their genetic defects could be "edited" in a petri dish before being differentiated into healthy adult cells. These cells could then be transplanted into patients to restore normal function. While that goal is still beyond reach, many early-stage clinical trials are underway using induced iPSCs to treat diseases, from diabetes and heart disease to Parkinson's. One trial has already treated its first patient. In 2014, scientists made iPSCs from skin cells of a woman with macular degeneration and then differentiated them into adult retinal cells. Surgeons transplanted the retinal cells into her eyes in order to treat the disease - the first patient treated using iPSCs. Preparations to treat a second patient using patient-derived cells were stopped because the researchers detected a mutation in one of the genes in the iPS cells. No reports had linked the gene to cancer, but they decided not to use the stem cells to eliminate any risk.

The success of treatments relies in part on stem cells' rapid rate of proliferation. Hundreds of billions of cells may sometimes be needed for a transplantation. But if just a few of the stem cells fail to differentiate into the target adult cells, they may reproduce rampantly when transplanted and form a tumor. "It's a two-edged sword. In the pre-transplant stage, you want stem cells that proliferate very rapidly. But after the transplant, if there are only five or 10 cells that didn't differentiate into adult cells, they can reproduce infinitely. They create a kind of residue of tumor." Research to ensure that all stem cells differentiate before transplantation is now one of the main issues in this field. To eliminate cancer risk, the researchers are now "deep sequencing" the genetic makeup of each of the stem cell lines they might use. They have also decided to use donor cell lines rather than the patient's own cells. This avoids the very expensive prospect of having to carry out quality checks like deep sequencing of each patient's own pluripotent cell lines.

The originators of the iPSC methodology are concerned about public perception that the rate of progress may be slower than expected. "I am fascinated by how rapidly science is advancing. It's amazing. But for the most part, developing new treatments - doing the science, testing the safety and effectiveness of new therapies­ - takes a great deal of money and many years. Developing new treatments may take 10 years, 20 years, 30 years. That is what we have been trying to say to our patients: 'We are making great progress, so do keep up your hope. But it takes time.'"

Link: https://www.ucsf.edu/news/2016/09/404271/induced-pluripotent-stem-cells-10-years-after-breakthrough

There are presently a few different biomarkers of aging under development based on changes in patterns of DNA methylation, an epigenetic decoration to DNA that determines the rate at which specific proteins are manufactured. The molecular damage that causes aging is the same in all of us, and thus some portion of the cellular reaction to environment and circumstances will also be the same in all of us: as damage accumulates, cells change their behavior in response. A good biomarker that accurately reflects biological age can, once validated, be used to greatly speed up development of therapies that slow or repair the causes of aging. At present the only reliable way to assess outcomes is to run life span studies, something that is for many organizations prohibitively expensive when carried out in mice, and out of the question when it comes to gathering human data. If lengthy life span studies can be replaced with a biomarker measurement before and after a short period of treatment, then the cost and time taken to evaluate potential rejuvenation therapies will be greatly reduced, and many more research groups will participate in the research and development process.

A team of 65 scientists in seven countries recorded age-related changes to human DNA, calculated the biological age of blood and estimated a person's lifespan. A higher biological age - regardless of chronological age - consistently predicted an earlier death. Drawing on 13 sets of data, including the landmark Framingham Heart Study and Women's Health Initiative, a consortium of 25 institutions analyzed the DNA in blood samples collected from more than 13,000 people in the United States and Europe. Applying a variety of molecular methods, including an epigenetic clock developed in 2013, the scientists measured the aging rates of each individual. The clock calculates the aging of blood and other tissues by tracking methylation, a natural process that chemically alters DNA over time. By comparing chronological age to the blood's biological age, the scientists used the clock to predict each person's life expectancy.

"Our findings show that the epigenetic clock was able to predict the lifespans of Caucasians, Hispanics and African-Americans in these cohorts, even after adjusting for traditional risk factors like age, gender, smoking, body-mass index and disease history. We discovered that 5 percent of the population ages at a faster biological rate, resulting in a shorter life expectancy. Accelerated aging increases these adults' risk of death by 50 percent at any age." For example, two 60-year-old men both smoke to deal with high stress. The first man's epigenetic aging rate ranks in the top 5 percent, while the second's aging rate is average. The likelihood of the first man dying within the next 10 years is 75 percent compared to 60 percent for the second. The preliminary finding may explain why some individuals die young - even when they follow a nutritious diet, exercise regularly, drink in moderation and don't smoke. "While a healthful lifestyle may help extend life expectancy, our innate aging process prevents us from cheating death forever. Yet risk factors like smoking, diabetes and high blood pressure still predict mortality more strongly than one's epigenetic aging rate."

The precise role of epigenetic changes in aging and death, however, remains unknown. "Do the epigenetic changes associated with chronological aging directly cause death in older people? Perhaps they merely enhance the development of certain diseases - or cripple one's ability to resist the progression of disease after it has taken root. Future research is needed to address these questions." Larger studies focused only on cases with well-documented causes of death will help scientists tease out the relationship between epigenetic age and specific diseases. "We must find interventions that prolong healthy living by five to 20 years. We don't have time, however, to follow a person for decades to test whether a new drug works. The epigenetic clock would allow scientists to quickly evaluate the effect of anti-aging therapies in only three years."

Link: http://newsroom.ucla.edu/releases/epigenetic-clock-predicts-life-expectancy-ucla-led-study-shows

The reprogramming of ordinary somatic cells into induced pluripotent stem cells, capable in principle of then generating any other type of cell, was a major advance for cell biology and its application to medicine. It is still sufficiently recent for the implications and uses still to be a work in progress. One of the more interesting observations to emerge from the recent years of experimentation is that this reprogramming appears to erase some aspects of mitochondrial aging. Take fibroblasts with damaged mitochondria from a skin sample from an aged individual, reprogram them to generate a population of induced pluripotent stem cells, differentiate those stem cells into a new set of fibroblasts, and the resulting cell population has dramatically improved mitochondrial function. One possibility is that reprogramming triggers some aspects of the comprehensive repair programs that take place very early in embryonic development, wiping away as much of the parental molecular damage as possible. Parents are old and babies are born young, so something of this ilk must be hidden away somewhere in the repertoire of cellular behavior. That isn't to say it can be usefully applied in adults, of course: there are any number of vital, intricate structures in our organs, the brain particularly, that would probably be fatally disrupted by the operation of such a program. Time will tell.

Is this apparent mitochondrial rejuvenation actually mitochondrial rejuvenation, however? Is it fixing the all-important damage to mitochondrial DNA, for example? Every cell has hundreds of mitochondria, the descendants of ancient symbiotic bacteria, complete with a leftover fragment of the original DNA that still encodes a range of necessary proteins used in mitochondrial functions. Mitochondria still divide like bacteria to make up their numbers, even though they are treated just like any other cellular component and broken down for recycling when damaged. Their most important function is the generation of energy store molecules to power cellular operations, but this process produces oxidizing molecules as a side-effect. They damage the cellular machinery they react with, and the most vulnerable target is the mitochondrial DNA right next door. Most oxidative damage to proteins and DNA in cells is rapidly repaired, but mitochondrial DNA isn't as well protected as the DNA in the cell nucleus. Further, some forms of mitochondrial DNA damage, such as large deletions, can produce mutant mitochondria that are both dysfunction and resistant to being culled by cellular quality control mechanisms. They quickly outcompete the normal mitochondria, and a cell taken over in this way becomes dsyfunctional itself, carrying out a range of bad behavior that contributes to the progression of aging. Thus mitochondrial DNA damage is an important topic; if researchers observe what looks like mitochondrial rejuvenation, then the quality of the mitochondrial DNA is a key question.

The authors of this commentary discuss a paper published earlier this year that argues against repair of mitochondrial DNA in the course of cellular reprogramming. If confirmed that means that a potential shortcut to allow cell therapies to better treat the diseases of aging may not in fact exist: dealing with mitochondrial DNA damage when using a patient's own cells is still required, one way or another. The favored method is that outlined in the SENS proposals, using gene therapy to move critical mitochondrial genes into the cell nucleus. There are other possible approaches, though none of those seem to be as far along towards clinical application. While one door closes, another opens, however. As pointed out below, the preservation of mitochondrial damage might indicate that reprogramming as it presently stands, in which only a tiny number of cells are successfully converted, may be a good way amplify rare mutations in cell samples. That in turn might help with the still challenging task of putting reliable numbers to the degree to which mitochondrial DNA is damaged in old cells.

Aging vs. rejuvenation: reprogramming to iPSCs does not turn back the clock for somatic mitochondrial DNA mutations

The process of cellular reprogramming is believed to be able to "turn back the developmental clock" by allowing somatic cells to acquire a state that is normally associated only with embryonic stem cells (ESCs). Indeed, human induced pluripotent stem cells (iPSCs) can be obtained from aged individuals and still show the key properties of ESCs, including self-renewal, elongated telomeres, and round-shaped mitochondria with underdeveloped cristae. However, it remained to be determined whether reprogramming to pluripotency could actually erase aging-associated signatures and thus represent a rejuvenation route. A new paper now clearly demonstrates that iPSCs not only do not erase the signs of aging but, due to their clonal origin, may even reveal aging-related defects in the mitochondrial DNA (mtDNA) that were not detectable in the whole parental tissues.

Using iPSCs derived from both skin fibroblasts and peripheral blood mononuclear cells (PBMCs) researchers have shown that all iPSCs exhibited mtDNA mutations that could not be observed in the whole-tissue DNA extracts of the parental cells. These mutations were originally considered as negative by-products of reprogramming as a consequence of oxidative stress-mediated genomic damage. However, it was demonstrated that also skin fibroblasts grown as individual clones exhibit mtDNA mutations that are not seen in the pooled fibroblast population. Hence, individual cloned fibroblasts and iPSCs may both represent the progeny of a single parental fibroblast cell, thereby enabling the detection of mtDNA mutations that were already present in the original fibroblast population but remained undetectable due to their relatively low presence. Several studies indicate that mtDNA mutations, including large-scale deletions, increase with aging. In accordance, researchers detected increased presence of mtDNA mutations in fibroblasts and iPSCs derived from aged individuals compared to young individuals. Moreover, the identified mutations in somatic cells and derived iPSCs were mostly located in coding genes, while ESCs displayed mtDNA variants primarily within the non-coding D-loop. This gives further support to the notions that the majority of mtDNA alterations seen in adults is of somatic rather than embryonic origin.

An important point to be addressed was the functional consequence of the detected mtDNA mutations. The presence of mtDNA alterations that were not seen in the pooled parental fibroblasts were previously found to not cause major bioenergetic defects, as all generated iPSCs could efficiently undergo the extensive metabolic shift that is associated with cellular reprogramming. However, detailed analyses unveil diminished metabolic function in iPSCs carrying high heteroplasmic mtDNA mutations. Hence, in order to correctly employ patient-derived iPSCs for disease modeling and therapeutic studies, it will be imperative to include the detection of mtDNA integrity as part of the basic characterization toolkit. This will be especially relevant when dealing with patients of advanced age who may harbor increased amount of mtDNA mutations. Overall, this work strongly confirms that, in addition to nuclear genome integrity, mitochondrial genome integrity will become a key parameter to investigate for all medical applications of iPSCs. Furthermore, it highlights the strength of single-cell studies, which may reveal the real biological variability that pooled population studies have so far prevented to be identified. In conclusion, in order to allow faithful and meaningful discoveries, future analysis of iPSCs and their derivatives should not shy away from mitochondrial genome monitoring and single-cell technology.

Supercentenarians, people who have passed 110 years of age, are very rare. Accordingly, the sort of information on their physiology that can only be obtained through autopsy or donation of the body to science is similarly thin on the ground. It has been some years now, for example, since the evidence was first gathered to show that most supercentenarians are probably killed by transthyretin amyloidosis, something that has a smaller but significant contribution to heart disease in earlier old age. Here, researchers assess the postmortem state of the brains of four supercentenarians, an exercise that well demonstrates that the oldest of humans don't escape unscathed:

Supercentenarians (aged 110 years old or more) are extremely rare in the world population (the number of living supercentenarians is estimated as 47 in the world), and details about their neuropathological information are limited. Based on previous studies, centenarians (aged 100-109 years old) exhibit several types of neuropathological changes, such as Alzheimer's disease and Lewy body disease pathology, primary age-related tauopathy, TDP-43 pathology, and hippocampal sclerosis. In the present study, we provide results from neuropathological analyses of four supercentenarian autopsy cases using conventional and immunohistochemical analysis for neurodegenerative disorders. In particular, we focused on the pathology of Alzheimer's disease and Lewy body disease, as well as the status of hippocampal sclerosis, TDP-43 pathology, aging-related tau astrogliopathy, and cerebrovascular diseases.

Three cases were characterized as an "intermediate" level of Alzheimer's disease changes (NIA-AA guideline) and one was characterized as primary age-related tauopathy. TDP-43 deposits were present in the hippocampus in two cases. Neither Lewy body pathology nor hippocampal sclerosis was observed. Aging-related tau astrogliopathy was consistently observed, particularly in the basal forebrain. Small vessel diseases were also present, but they were relatively mild for cerebral amyloid-beta angiopathy and arteriolosclerosis. Although our study involved a small number of cases, the results provide a better understanding about human longevity. Neuropathological alterations associated with aging were mild to moderate in the supercentenarian brain, suggesting that these individuals might have some neuroprotective factors against aging. Future prospective studies and extensive molecular analyses are needed to determine the mechanisms of human longevity.

Link: http://dx.doi.org/10.1186/s40478-016-0368-6

I'm far from convinced it is the best path forward in the matter of treating aging, but much of the research community is focused on finding drugs that can alter patterns of gene expression and the operation of signaling pathways that tend to change with aging in order to run in a more youthful manner. There are hundreds of potential candidates at this point, described in the geroprotectors database; things like metformin and rapamycin are in that list. This seems to me to be putting the cart before the horse, in that these changes are not the cause of aging but rather downstream consequences of cell and tissue damage. It is possible that some benefit can be obtained by forcing a more youthful function of cells despite the underlying damage that they are reacting to, but trying to coax a damaged machine into better function without actually repairing that damage tends to be an expensive exercise in obtaining only marginal results. Most of the medicine for age-related disease created over the past century establishes the bounds of the possible here, as next to none of it touches on the root causes of aging. You can slow things down, or make things somewhat better, but you can't produce the large improvements that would be possible by reverting the damage that causes aging. Is that worth the effort now, at a time when addressing the root causes of aging is actually plausible? I'd say no. Pursue the better strategy instead, that outlined by the SENS rejuvenation research program, a focus on repair of fundamental damage rather than trying to compensate for it.

A significant rise in the proportion of seniors worldwide is underway, resulting in increasing rates of chronic, debilitating disease and long term residential care, shrinking the supporting workforce, and threatening to sink current health care systems. Prevention will be crucial moving forward. If aging can be delayed and diseases prevented, productive years can be extended and retirement age redefined. Anti-aging therapies have been sought since the dawn of human civilization, but with the rise of modern biology, big data, and information sciences, intelligent approaches to geroprotector discovery may finally be within reach. The outward features of aging, including decline in function and rise in susceptibility to stress and disease, are associated with a set of structural and functional changes at the cellular level. While these changes vary by tissue, many are genetically regulated, and many genes mediating longevity, termed gerontogenes, have been identified. The identification of these genes and experimental manipulation of their products to extend lifespan in model organisms has bolstered the notion that aging is not just a natural process but a treatable disease and added credence to the movement to identify drugs or other factors that may also extend lifespan, or, more favorably, healthspan, in humans. These are termed geroprotectors.

There are now over 200 substances that have shown geroprotective effects in model organisms. Human-based studies, however, may turn out to be more productive. Several of the most promising attempts at developing geroprotectors have involved identifying FDA-approved drugs with life-extending qualities and repurposing them as geroprotectors for human use. These include rapamycin and metformin. However, a number of problems still hamper the widespread approval and use of these or other drugs for this purpose. Most notably, longevity is a difficult parameter to study in humans without large, longitudinal designs, and since these drugs would presumably be administered to aging but otherwise healthy individuals, the effect size would have to be substantial and side effects almost non-existent. In addition, the FDA does not consider aging an approved disease indication. At this time, no drug has sufficiently met these conditions, and new approaches to drug discovery - and drug repurposing - are needed.

The drug discovery process is slow and expensive, burdened by many projects that dead-end before clinical trial or fail thereafter. Improved prediction of drug performance prior to lengthy experimentation would cut waste. Vast datasets now exist that enable such prediction with the help of sophisticated computational methods. Two particularly valuable datasets in this respect are the literally millions of gene expression profiles stored in repositories and a number of increasingly diverse compound screening libraries. While gene expression data can be used to pinpoint target pathways for a particular disease, compound libraries can be screened for drugs that target these pathways. All of this can be done in silico, at relatively little cost. Recently, a method was developed that would do just this - capitalize on existing gene expression data and compound libraries to improve prediction of targeted drugs. The method involves the use of an algorithm termed Oncofinder. Oncofinder quantifies Pathway Activation Strength (PAS) in a given sample based on gene expression patterns relative to another sample. Thus PAS values can be computed for a disease state in comparison to a normal state, old versus young, or any other set of physiological conditions. Here, we used an aging-based extension of Oncofinder, known as GeroScope, in a search for novel geroprotective substances.

We first quantified activation of age-related pathways in hematopoietic and mesenchymal stem cells from "old" (vs "young") human donors. We then shortlisted substances predicted to best target those pathways, restore a "young" cellular profile, and extend viability. From that list, we proceeded to experimentally test the effects of each substance in human fibroblasts. The top geroprotector, in terms of performance in both enhancing viability and rejuvenation was PD-98059, a highly selective inhibitor of MEK1 and the MAP kinase cascade. MEK inhibition along with PI-3K inhibition has been shown to decelerate cellular senescence via the mTOR/S6 pathway, a known target for anti-aging interventions. Aside from PD-98059, most of the studied geroprotectors had effects on either cellular viability or senescence features.

Link: http://dx.doi.org/10.18632/aging.101047

As I'm sure many people are aware these days, with the greater availability of historical materials and their analysis, Isaac Newton was as much alchemist as scientist. His worldview encompassed mysticism, mathematics, and cosmology in equal parts, a function of his time. You can't really pick apart Newton the scientist from Newton the mystic, Newton of the equations and proofs from Newton of the search for the philosopher's stone. A person is a fusion, not a collection of parts. You also can't paint Newton as somehow distinct from his peers in this - he was an outlier in his intelligence, his vision, and his work ethic, not in his views on alchemy. Keep this in mind as a framing device; I point it out because the mix of futile, magical endeavors and the sound application of science, both pursued with equal vigor, is far from left behind in Newton's era. It continues today, and it is of great relevance to progress (or lack thereof) the field we all care about, advancing the state of the art in living longer, healthier lives.

I, and others in our community, believe that the "anti-aging" marketplace as it stands is both terrible and an opportunity. Ultimately if the good can chase out the bad, then these are people with clinics, funds, and the desire to do something about aging, exactly those who could do a great deal of good in pushing forward research, development, and clinical availability if they so chose. As real rejuvenation therapies emerge, the entrepreneurs of that marketplace will stop trying to sell products based on cherry-picked scientific studies, outright lies, and magical thinking. You can't make money selling tables that fall apart when the people next door sell tables that work. The same applies to medicine. Consider what a medical market with even partially effective treatments looks like: no-one today makes much of a business selling charms against heart disease. For sure, it exists, but will-workers and traveling tinkers certainly aren't the first port of call for the average individual - patients seek out doctors and clinicians in the knowledge that there are treatments that can product useful results. The end result is never an end to fraud and superstition, but the crushing of it into a tiny corner of economic activity. I suspect that this is going to be a drawn out and messy process for longevity science, however, just as it has been elsewhere in the past. Will we see clinics selling working rejuvenation therapies such as senescent cell clearance infusions in a package with nonsense like apple stem cell skin cremes? No doubt. Caveat emptor, just as true ten years from now as it is today.

Many folk feel that the "anti-aging" market is too much of a threat to have anything to do with. That it will not reform and will poison whatever it touches. Certainly there are people in there with that mix of adherence to mysticism and science that has characterized many figures in the history of science and technology, whether giants like Newton or the rank and file who get far lesser mention in the pages of history. The Life Extension Foundation principals are comfortable pushing useless nonsense on the one hand (overhyped supplements based on dubious research results taken out of context, anything that Suzanne Somers has to say about health, and so forth) while on the other hand helping to fund stem cell research trials and SENS-like programs of development such as thymic regeneration. They've given a good deal more money to those worthy causes than I have. Nonetheless, the alchemy, the alchemy. It is painful. There is a certain anxiety that people we might persuade to the cause of human rejuvenation take in things like the recent RAAD Festival, and as a consequence throw out everything they see, baby and bathwater, as the author did here. When the first few samples raised up to the light for examination are evident nonsense, why check the others carefully?

A weekend watching the promise of immortality get sold and bought at the Revolution Against Aging and Death Festival

I was invited to attend RAAD after I wrote about people who want their pets to live forever. I was initially confused by the phrase "age reversal." As it turns out, RAAD sells something more audacious than pricey cosmetics or Li'l Brad Pitt. RAAD stands for Revolution Against Aging and Death. It sells the promise of eternal youth. Also, Suzanne Somers was going to be there. The people who organized RAAD are members of the Coalition for Radical Life Extension, which is the nonprofit offshoot of People Unlimited, a Scottsdale, Arizona-based group that describes itself as "a community of people living physical immortality." People Unlimited charges a monthly membership fee, and holds regular meetings where members swap antiaging tips and listen to guest speakers. The coalition's online mission statement shoehorns immortality into a historical narrative of moral and social progress. Radical life extensionists believe that eternal life will eventually be viewed as a sort of buried human right, as soon as they convince people that they're not delusional.

Though immortalists aren't mainstream, radical life extension has a burgeoning fan base in the tech industry. Along with Alphabet's Calico, which is a secretive Google spinoff focused solely on the study of aging, other prominent antiaging research labs and biotech firms have budded up among the techno-utopians. While the search for ways to stop aging and "cure" death is booming from a business perspective, the reality of biotech solutions for age-related problems is far more nuanced than the vision presented at RAAD, where researchers spoke in highly optimistic terms about progress just around the corner. Assuming that this research will lead to insight on how we age is one thing. Assuming it will free us from the bonds of mortality is an enormous leap. And so even within the community of researchers who study old age and life extension, immortalists are considered radical, and sometimes accused of peddling pseudoscience.

To cast the widest possible net for converts, RAAD touted many different twists on the concept of living forever. No one path to immortality was placed above another. There were many different denominations of immortalists present, with a patchwork of philosophies and goals: stem-cell facials, telomerase research, transhumanism, cryonics, brain uploading, cyborgism, vitamins, blood transfusions, marathon running, sex. After she ran through her spiel, Suzanne Somers sat down with Bill Faloon, another superstar within the life extension movement. Faloon founded the Life Extension Foundation in 1980, and he was ready to back up every last irresponsible word Somers uttered. "There is a tremendous amount of peer-reviewed literature to substantiate what Suzanne has said, including diet and health," Faloon said. Faloon applauded Peter Thiel for donating money to antiaging causes. Thiel has donated to gerontologist Aubrey de Grey, who founded the SENS (Strategies for Engineered Negligible Senescence) Research Foundation. De Grey is a British man with objectively too much beard who is famous among futurists and infamous among scientists for claiming that the first person who will live to a thousand years old is alive today. He's good at raising money for antiaging research and courting celebrities to join his cause. SENS has an ad campaign that features Steve Aoki, Herbie Hancock, Edward James Olmos, and the guy who played Little Carmine on The Sopranos.

This is the messiness of the business of persuasion in action. Though I have to say that the author here is evidently smart enough to realize there's something down there at the science end of the pool, but chose to write the article this way anyway rather than working harder at the more interesting picture that is presented. Work on telomerase is arguably pretty important in aging research. Cryonics is a logical response to death in an age of technological progress. Aubrey de Grey's SENS Research Foundation is serious business, a part of the very real, very promising road to working rejuvenation therapies. Suzanne Somers on the other hand is a great illustration of the fact that business fundamentals trump everything else, including having products that actually work, or making claims that are actually sound, true, and supported by evidence. The Life Extension Foundation's Faloon has a foot in both camps. There you have the span from science to mysticism in just three people.

This is what human endeavor looks like when existing products have very marginal effects, and thus fraud is both easier to carry out and harder to suppress. But as I noted above, that will start to change soon enough. Senescent cell clearance will be in clinics five to ten years from now, alongside before and after DNA methylation biomarkers of biological age, and that will be indisputably effective in comparison to everything else out there claimed to have an impact on aging. From there matters might start to clean up somewhat, as the first of the frauds and the mystics begin to exit, stage left. Where am I going with this? Well, it would be great if everyone thought more or less the way I do about longevity science, but you have to live in the world that is, not the world that you'd like to exist. You work with the hand you've been dealt. Newton was an alchemist, and fundamentals of human nature haven't changed since then. The people getting things done today will inevitably tend to spend only a fraction of their time on projects and publicity that you or I might consider to be the most important items on the list, and many will embrace mysticism and counterproductive activities along the way. This is the way things go. It is certainly far from ideal, but still we move ahead. The end goal of a "anti-aging" community even halfway converted and backing the right approaches to human rejuvenation is, I think, too much of a potential boost to throw away because of the present situation. That means building the bridges now, in exactly the same way that bridges must be built to Big Pharma, governments, and other relevant institutions that are themselves less than ideal.

Visceral fat is the fat tissue packed around the abdominal organs, as opposed to the more visible subcutaneous fat under the skin. It is much more harmful and metabolically active. The more visceral fat tissue you have, and the longer you carry it, the shorter your life expectancy, the higher your lifetime medical costs, and the greater your risk of suffering all of the common age-related diseases. At present the research community consensus is that chronic inflammation is the major mechanism connecting these items; visceral fat tissue acts to increase inflammation through a number of processes, and inflammation is a major contributing factor to the pace at which age-related disease and dysfunction emerges.

Studies have shown that people who carry excess abdominal fat around their midsection tend to face higher risks of heart disease compared to people who have fat elsewhere. A new study adds to the growing body of evidence that regional fat deposits are harmful and further suggests that the density of the stomach fat (measured by CT scan) is just as important as how much fat you have. In general, the higher the fat content, the lower the attenuation, or fat density, that is shown on the CT image. "What's really interesting is that we show that an increase in the amount of stomach fat and a lower density fat is associated with worse heart disease risk factors - even after accounting for how much weight was gained. This hasn't been shown before. Measuring fat density is a new measure that we are still working to understand and warrants further investigation. We used it as an indirect measure of fat quality and found that lower numbers were linked to greater heart disease risk."

Researchers sought to determine whether there was a link between anatomical changes in belly fat - both its volume (quantity) and density - and changes in a broad array of cardiovascular disease risk factors during the average six-year study period. They reviewed CT scans to assess how much abdominal fat had accumulated, its location and it's density in 1,106 participants from the Framingham Heart Study who received this imaging as part of a larger study to measure coronary and abdominal aortic calcification. Participants' average age was 45 years and 44 percent were women. Both subcutaneous adipose fat, the fat just under the skin, and visceral adipose fat, the fat inside the abdominal cavity, were measured. Over the six-year follow-up period, participants had a 22 percent increase in fat just under the skin and a 45 percent increase in fat inside the abdominal cavity on average. In general, increases in the amount of fat and decreases in fat density were correlated with adverse changes in heart disease risk. Each additional pound of fat from baseline to follow up was associated with new onset high blood pressure, high triglycerides and metabolic syndrome. Even though increases in both types of fat were linked to new and worsening cardiovascular disease risk factors, the relationship was even more pronounced for fat inside the abdominal cavity compared to fat just under the skin.

Overall, associations remained significant even after adjusting for changes in BMI or waist circumference. Researchers also grouped participants into three groups according to abdominal adipose tissue volume and density change; they found that those with greater increases in fat volume and more decreases in fat density had relatively higher incidence of heart disease risk factors. In terms of next steps, more work needs to be done to understand fat density, and why and how it is associated with metabolic consequences of obesity (e.g., hypertension, abnormal cholesterol, diabetes, inflammation and insulin resistance). As well, it will be important to tease apart how less dense fat, along with simultaneous increases in the amount of fat may spur the development of harmful cardiometabolic changes.

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=168201&CultureCode=en

Many researchers are investigating potential means to spur greater muscle growth and regeneration in older people, ways to at least partially compensate for the characteristic loss of muscle mass and strength that occurs with age, a condition known as sarcopenia. Physical weakness is a sizable component of the frailty of aging, and restoring the ability of the elderly to move and act with confidence would be a tremendous gain. The current range of candidate therapies tend not to address root causes, the underlying molecular damage that causes aging, and vary from the debatable amino acid supplementation to the very promising myostatin blockade. Here researchers propose another possible target and present initial results in mice:

Sarcopenia, age-related loss of muscle quantity and quality, is a crucial determinant of geriatric fragility. Sarcopenia increases susceptibility to muscle damage, serious falls, obesity and diabetes. Age-related changes in muscle are thought to depend on a decrease in muscle stem cells and their niche, which results in global changes in associated gene and protein expression as well as posttranslational modifications. Skeletal muscle regeneration is a multistep process. In response to stimuli generated by exercise or injury, satellite cells re-enter the cell cycle to produce myoblasts, subsequently withdraw from the cell cycle, and differentiate into myocytes, which fuse into new myotubes or with host myofibers. This fusion process is crucial for postnatal growth, maintenance and repair of skeletal muscle in the adult stage. Myotube formation is completely Ca2+ dependent, and requires net Ca2+ influx into myoblasts.

With aging, skeletal muscle shows impaired myogenic potential, which, in turn, induces atrophy. Ca2+ signaling molecules are reported to be associated with age-dependent muscle degeneration. Among the various Ca2+ sensors and channels, inositol 1,4,5-triphosphate receptor type 1 (ITPR1) expression was dramatically decreased in aged muscles and myoblasts. Here, we have provided new evidence that decreased expression of ITPR1 triggers dysregulation of Ca2+ oscillation, which in turn modulate gene expression, resulting in defective myogenesis. Ca2+ oscillation is known to modulate gene expression in many tissues, including muscle.

Multiple studies suggest an important role for the Ras-ERK1/2 pathway in the development, maintenance, and pathology of mammalian skeletal muscle. ERK activity promotes the proliferation of myoblasts and the terminal differentiation of myotubes. We further investigated whether EGFR-Ras-ERK signaling is activated in aged skeletal muscle with decreased ITPR1 expression. Notably, the age-related ITPR1 decline in mice and human skeletal muscles was correlated with increased activation of EGFR-Ras-ERK signaling. To establish whether ERK activation is responsible for inhibition of myogenesis, the ERK pathway was blocked with a specific inhibitor, U0126, in old primary myoblasts. To further evaluate the therapeutic potential of ERK signaling inhibitors for sarcopenia, we examined the effects of U0126 on impaired muscle regeneration in aged mice. U0126 was injected on a daily basis into 6 and 24 month-old C57BL/6 male mice for 13 days after injury. Quantitative real-time PCR data revealed that U0126 induced higher expression of not only myogenic regulatory genes but also those involved in hypertrophy in aged muscle. Consistently, measurements revealed that the newly formed myofibers of U0126-treated muscle had significantly larger diameters than those of controls, supporting the potential of ERK inhibitors as new candidate therapeutic agents for sarcopenia.

Link: https://dx.doi.org/10.18632/aging.101039

Since calorie restriction is the topic for the day so far, I thought I'd finish up by pointing out a recent paper that examines just one of the many concrete benefits that are produced through the practice of calorie restriction. In this case the focus is on blood vessel integrity, and the researchers demonstrate that a low calorie diet in mice reduces the risk of suffering an aneurysm, a localized weakening and consequent distortion of blood vessel walls. Aneurysms in major blood vessels ultimately lead to rupture and bleeding that is far more often fatal than survivable. Larger aneurysms in the brain can cause significant issues even without rupturing because they displace neural tissue, possibly disrupting vital functions as a result.

It isn't too difficult to walk through what is known of the various contributions that increase the risk of aneurysm, and the reasons why that risk rises with age. The first place to start is hypertension, increased blood pressure. Greater pressures means that ever lesser degrees of structural weakness will fail and bulge out into an aneurysm. Hypertension appears to be largely driven by stiffening of blood vessels, as the cardiovascular system reacts incorrectly to the feedback it is given by stiffened vessels. This loss of elasticity is in turn a consequence of cross-linking in the extracellular matrix of blood vessel walls, one of the fundamental forms of damage described in the SENS rejuvenation research portfolio. The normal processes of metabolism generate hardy sugar compounds that can link the complex collagen macromolecules of the extracellular matrix. The structure and movement of those macromolecules determines tissue characteristics such as elasticity, and cross-linking degrades that flexibility to produce stiffening. Other contributions to vascular stiffening include calcification in blood vessel walls and various secondary consequences of the chronic inflammation that accompanies aging, disrupting the signaling involved in blood vessel constriction.

Another group of mechanisms worth emphasizing are those that lead to atherosclerosis: damaged lipids in the bloodstream, such as those produced as a result of the harmful actions of cells with age-related mitochondrial damage, can cause an overreaction when they lodge in blood vessel walls. This produces lesions in which inflammation and immune cell death runs amok, growing into fatty plaques in the blood vessel wall. One of the ways in which such an atherosclerotic plaque can prove fatal is through weakening the blood vessel wall sufficiently for an aneurysm to develop and then rupture. Another is for the plaque to break apart and block a blood vessel elsewhere. Either way, the consequences are unpleasant. To the degree that atherosclerosis is a type of immune overreaction, it is accelerated by the rising levels of chronic inflammation that accompany aging.

Almost all of these processes are modestly reduced in magnitude while an individual is practicing calorie restriction. Inflammation is reduced, mitochondrial function improved, the immune system works more effectively to remove problem cells, and cells do a better job of internal quality control. Other environmental influences on the constriction of blood vessels are improved. Since calorie restriction is known to slow near all measures of aging, it perhaps isn't surprising to see it also reducing aneurysm risk. This is all relative, of course: despite the fact that calorie restriction produces perhaps the largest available long-term benefits for basically healthy individuals, you nonetheless can't reliably diet your way to a life span of a century. Rejuvenation therapies are on the horizon, however, and thus it is perhaps wise to pay attention to the few choices you can make now that are reliable and proven in their effects, likely to add a few years of health to your life span. Missing out by a few years when you could have benefited would be a terrible thing. Unfortunately, beyond calorie restriction and exercise there is little worth the candle at the moment, given the balance of evidence: efforts beyond the health basics are better directed to speeding progress towards human rejuvenation, helping the development of therapies that can repair the molecular damage that causes aging.

Consuming Fewer Calories Reduces the Risk of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a localized enlargement of the main artery in the abdomen caused by a weakening of the blood vessel wall. With over three million cases per year in the US, preventing the development of AAA is crucial because, if the aneurysm bursts, the mortality rate can be as high as 80%. The risk of developing AAA increases with age and can be exacerbated by other factors such as smoking. Calorie restriction has been shown to have a variety of health benefits in mice and humans due to its far-reaching effects on the body's metabolism. Researchers wondered whether the risk of AAA might be reduced by a calorie-restricted diet. The researchers placed mice prone to developing AAA on a calorie-restricted diet for 12 weeks and found that the animals were less likely to develop aneurysms than control mice fed a normal diet. The calorie-restricted mice also showed lower rates of AAA rupture and death.

The researchers determined that calorie restriction reduced the levels of an enzyme called MMP2 that degrades the protein matrix surrounding blood vessels. This was because, after 12 weeks of reduced calorie intake, vascular smooth muscle cells in the wall of the aorta up-regulated a metabolic sensor protein called SIRT1, which can epigenetically suppress multiple genes, including MMP2. The researchers found that calorie restriction was unable to reduce MMP2 expression and the incidence of AAA in mice whose vascular smooth muscle cells lack SIRT1. The study suggests that reducing calorie intake can protect mice from AAA by up-regulating SIRT1.

Calorie restriction protects against experimental abdominal aortic aneurysms in mice

Abdominal aortic aneurysm (AAA), characterized by a localized dilation of the abdominal aorta, is a life-threatening vascular pathology. Because of the current lack of effective treatment for AAA rupture, prevention is of prime importance for AAA management. Calorie restriction (CR) is a nonpharmacological intervention that delays the aging process and provides various health benefits. However, whether CR prevents AAA formation remains untested. In this study, we subjected Apoe-/- mice to 12 weeks of CR and then examined the incidence of angiotensin II (AngII)-induced AAA formation. We found that CR markedly reduced the incidence of AAA formation and attenuated aortic elastin degradation in Apoe-/- mice. The expression and activity of Sirtuin 1 (SIRT1), a key metabolism/energy sensor, were up-regulated in vascular smooth muscle cells (VSMCs) upon CR. Importantly, the specific ablation of SIRT1 in smooth muscle cells abolished the preventive effect of CR on AAA formation in Apoe-/- mice. Mechanistically, VSMC-SIRT1-dependent deacetylation of histone H3 lysine 9 on the matrix metallopeptidase 2 (Mmp2) promoter was required for CR-mediated suppression of AngII-induced MMP2 expression. Together, our findings suggest that CR may be an effective intervention that protects against AAA formation.

The practice of calorie restriction is demonstrated to slow near every aspect of aging in laboratory species, and in humans it greatly improves measures of health related to risk of age-related disease. Here researchers look specifically at effects on the molecular biochemistry of cells in the brain, protective mechanisms that slow the progression and impact of age-related neurological disorders:

Mechanisms that increase longevity and, perhaps most importantly, promote longer health spans (lower or delayed incidence of age-related diseases) have always attracted attention. The most effective intervention known to date to prevent age-related decline and promote better health spans in a wide variety of organisms, ranging from yeast to primates, is caloric restriction (CR). This dietary intervention typically consists of a 20-40% reduction in caloric intake without micronutrient limitation relative to an ad libitum diet. Perhaps the most striking group of age-related diseases prevented by CR is in the brain. A large number of neurological disorders are age-related, and CR has been demonstrated to effectively prevent these disorders. CR also improves age-related declines in memory and learning abilities observed in elderly animals. Although the mechanisms by which CR exerts its effects are poorly understood, mitochondria, as master regulators of cellular metabolism, are believed to play an important role in the cellular adaptations that take place with the diet.

In the brain, increases in mitochondrial activity may change the susceptibility to excitotoxicity, a pathological process associated with many age-related neurological conditions such as stroke, Alzheimer's disease and Parkinson's disease, in which excessive activation of postsynaptic receptors results in cell death. This neurodegenerative process involves the binding of glutamate or glutamate analogues to NMDA and AMPA receptors, resulting in pathological increases in cytosolic calcium levels and a rapid decrease in ATP levels due to the activation of ionic balance restoration pathways. Mitochondria are the main site for ATP production in neurons and contribute toward cellular calcium buffering by accumulating this ion in a membrane potential-dependent manner. Indeed, interventions that increase mitochondrial calcium buffering capacity protect against excitotoxicity and related conditions. Interestingly, while intermittent fasting (a dietary intervention that consists in offering food ad libitum on alternate days) has been found to be neuroprotective under excitotoxic conditions, the effects of CR on excitotoxicity have not been well explored to date. Furthermore, mechanistic insights toward possible neuroprotective effects of this diet are still scarce. The aim of this study was to determine the effects of CR on excitotoxicity and dissect the molecular mechanisms involved.

We show that CR is also effective in preventing direct excitotoxic damage. Our data show that mitochondria in the brains of CR animals have enhanced electron transport capacity, accompanied by higher levels of some electron transport proteins and proteins involved in mitochondrial morphology and dynamics. Interestingly, the increase in electron transport chain (ETC) enzyme activities does not seem to affect the respiratory rates of isolated mitochondria. Cells seem to be able to regulate independently many different mitochondrial features. In our case, CR increases the levels of cardiolipin in the brain, while the activity of citrate synthase remains constant. Moreover, some, but not all, mitochondrial proteins are enriched in a per mitochondrion basis after CR. Some of the metabolic adaptations that CR induces in the brain seem to be mediated by molecule(s) present in the bloodstream. Indeed, CR serum promotes mitochondrial adaptations in primary neurons analogous those observed in vivo, namely protection against glutamate excitotoxicity. Previous reports in other tissues indicate that metabolic effects observed with CR can be partly reproduced in vitro using serum from animals subjected to the diet. These results support the notion that the metabolic remodeling that takes place with CR can be triggered by circulating molecules. A possible candidate is adiponectin, which is elevated in CR animals. Adiponectin protects against excitotoxicity both in vivo and in vitro.

Our results in brain mitochondria show that CR promotes sizable increases in both the rate and the accumulation capacity for calcium. As a result, under excitotoxic conditions, CR neurons possess a largely enhanced ability to buffer cytosolic calcium levels, which explains the strong resistance toward excitotoxic damage conferred by this dietary intervention both in vitro and in vivo. Overall, we demonstrate that CR is a highly effective intervention to prevent excitotoxic neuronal cell death by enhancing antioxidant capacity, mitochondrial respiratory rates, preventing mitochondrial permeability transition and thus enhancing calcium accumulation capacity, resulting in lower cell death. These properties may be central to the mechanism through which this dietary intervention promotes its many beneficial neurological effects.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12527/full

Calorie restriction, reducing calorie intake while maintaining optimal levels of micronutrients, produces beneficial alterations in near all aspects of metabolism. It extends healthy life spans in near all species investigated to date, through this effect is much larger in short-lived species that have evolved a greater plasticity of life span in response to circumstances. In humans the consensus is that it might make a difference of a few years to overall life span, but it certainly greatly improves measures of health and lowers risk of age-related disease, suggesting the effect on healthspan is probably larger. Here, researchers discuss the effects of calorie restriction and some of the candidate calorie restriction mimetic drugs. It is a lengthy paper, but worth reading if you'd like a comprehensive overview of past investigations:

The aging process is undoubtedly the single most significant contributor to disease and death. Although this has been the inevitable outcome of all life on this planet, is aging an unavoidable consequence or can it be treated and potentially cured? As of yet this question remains unanswered, but many believe that the aging process is essentially a disease. Environmental conditions, including lifestyle, can greatly affect the rate of aging. For example, obesity or excessive ingestion of calories has been linked to increased incidents of age-related pathologies. Several lines of research indicate that certain behaviors can increase our health and potentially lifespan, such as exercise and regimes to improve cardiovascular function. One such intervention is the use of dietary/caloric restriction (CR); the reduced intake of calories/nutrients without causing malnutrition. In recent years, this observation has been verified across a large number of model organisms. These observations not only demonstrated an increase in the lifespan, but also in healthspan (time spent being healthy) of these organisms coincident with a significant decrease in age-related pathologies such as cardiovascular disease, diabetes and a number of cancers. For example, when fed a diet consisting of 35% of the ad libitum intake but enriched with vitamins and minerals, mice lived an average of 53 months, compared to 35 months in the control ad libitum-fed group.

Several drugs or naturally occurring compounds in food have been found to "mimic" the phenotypes of CR and could be potential alternatives to this somewhat difficult to follow dietary regime. An obvious first question: Do these compounds mirror the effects of CR? A large body of outstanding research focuses on the impact of CR and mimetics on autophagy in the regulation of longevity and in promoting apoptosis in cancer cells; however, the mechanism and impact on genome function (gene expression) and organization (epigenetic changes and physical genome folding) are less well understood. The oxidative damage attenuation hypothesis states that increased metabolism from high levels of nutrients/calories leads to higher rates of reactive oxygen species (ROS) and that lowering these levels will prevent lipid, protein and DNA damage. Damage such as this would lead to decreased function of cellular components as well as to increased rates of mutation. However, the other side of this hypothesis states that lower metabolic rates results in decreased rates of DNA damage and increased genome stability, and thus in fewer incidents of cancer. Although this is logical, some data does indicate that there is not a significant enough change in free radical production upon CR to significantly decrease ROS levels indicating that the benefits of CR might not be elicited through this mechanism. Although CR increases lifespan, it may not be due to a reduction of the ROS levels produced by mitochondria, but may result from an increase in the expression of enzymes that protect against these highly reactive molecules, reducing net oxidative stress. However, in D. melanogaster exposed to CR, no link between lifespan extension and increased resistance to oxidative stress has been found.

The altered glucose-insulin hypothesis indicates that CR causes a decrease in the circulating levels of both insulin and glucose, leading to decreased insulin signaling. This is based on observations that decreased insulin signaling promotes increased lifespan in a variety of model organisms. Increased glucose and insulin in the circulatory system will cause peripheral cells to absorb this glucose and convert it to ATP. In addition, insulin will also send positive growth and proliferative signals, pushing cellular balance toward growth and cell division. Therefore, CR may promote increased lifespan by decreasing rates of cell division and favoring repair and maintenance. The growth hormone-IGF-1 axis hypothesis states that increased signaling through these pathways advances the aging process by promoting cell growth and proliferation. Similarly to the glucose-insulin level hypothesis, CR causes the reduction of growth hormone/IGF-1 signaling, favoring a switch from cell growth and proliferation to maintenance and repair in mice. However, in human studies over a 2 year period of CR, no change in circulating IGF-1 levels were observed. These findings hint at two potential conclusions; (1) CR does not work in humans, only in mice, or (2) CR does not impact IGF-1 levels; however, it does impact other pathways, leading to at least increased healthspan, if not lifespan.

The hormesis hypothesis states that low levels or intensity of stress leads to "priming" in which cells/tissues/organs can then withstand other stresses that would normally prove terminal. It is thought that with hormesis, cells move from active growth and proliferation to a state that favors repair and maintenance. CR may prime cells by activating stress pathways to deal with later assault such as DNA damage. Other specific observations appear to favor this model, activating transcription factors and mechanisms controlling gene expression leading to increased levels of proteins mediating cellular stress responses. A large number of gene expression studies have been performed in order to determine the impact of CR on genome function. CR is well known to elicit a change in cell behavior marked by a decrease in cell proliferation and shift to cellular maintenance and repair. Changes in phenotype are accompanied by changes in gene expression; therefore, what impact does CR have on gene expression from across the genome?

It is clear that CR results in decreased energy and changes in cellular AMP:ATP and NAD:NADH ratios. Compounds that mimic CR do so by impacting cellular function resulting energy readouts or interfering with signaling down-stream cellular energy levels. The main proteins that appear central to mediating this response are AMPK and SIRT1 which regulate cycles of deacetylation and phosphorylation of a large number of proteins to control gene expression and cellular functions. Many of the CR mimetics of naturally occurring compounds identified either modulate SIRT1/AMPK function or, for example with rapamycin, target downstream signaling hubs to mediate potential health and lifespan effects. Of these targets NF-κB and the FOXO family of transcription factors, are pivotal in promoting decreased cell proliferation and increased maintenance in normal cells, while facilitating apoptosis and cell death in cancer cells. Furthermore, although all compounds appear to confer life and healthspan extending impacts across numerous cell types and model organisms via this SIRT1/AMPK interaction, the downstream impact on genome function (gene expression) is varied, across cell-type, organism-type, and compound-type in addition to variations in experimental details (such as exposure times, drug concentrations). This suggests that although mechanisms mediating health and lifespan in response to CR and these compounds are similar, the effects on gene expression mean that these compounds may not be direct mimetics of CR or of one another.

Link: http://dx.doi.org/10.3389/fgene.2016.00142

Here I'll point out a good article on cryonics and its nuances in the online press; it includes thoughts from people working at cryonics providers, people signed up for cryopreservation, and advocates with various viewpoints. Like any community there are a range of opinions on what constitutes progress and the best strategy for moving ahead, and just as many motivations as there are individuals involved. What is cryonics? It is the low-temperature preservation of at least the brain as closely following death as possible. Early preservations in the 1960s and 1970s were a matter of straight freezing, and thus the preserved individuals are most likely characterized by extensive tissue damage due to ice crystal formation. Later preservations have used increasingly better forms of vitrification, in which cryoprotectants are perfused into tissues during the cooling process, resulting in the near absence of ice crystals and high quality preservation of fine structures. This is a technology that scientists are nowadays seeking to bring to the organ transplant industry, a way to revolutionize the logistics of that field by allowing indefinite reversible storage of donated organs for later use. It has been a few years since the reversible vitrification of a rabbit kidney followed by transplant and a few hours of function was demonstrated: work proceeds on pushing forward the state of art to the quality needed for everyday medical use, but this demonstrates the basic viability of the approach, provided the initial vitrification is of good quality. Similarly, maintenance of long term memory through vitrification and thawing has been shown in lower animals.

The point of this is life: the data of the mind is stored in fine structures in the brain, and at some point, future technology will include the necessary capabilities to restore a vitrified individual to life. That will require, at the least, a very mature and sophisticated regenerative medicine industry, incorporating rejuvenation biotechnologies after the SENS model, and equally capable applications of molecular nanotechnology to deal with the cryoprotectant and forms of damage that cells cannot handle on their own. For so long as the data is intact, the option remains for rescue at some future date. It is an open question as to the degree to which earlier cryopreservations have managed to save the individual. Ultimately reconstruction of a frozen, ice-crystal-damaged brain and its data will probably be possible, but will that be the same person if considerable extrapolation is required? Continuity of identity through the same structure associated with the data of the mind seems important, or else you become one of those folk who believe a copy of the self is the self - a dangerous idea, to my eyes. The technological side of the future of cryonics seems a safe bet. The risks all lie in whether or not you manage to obtain a good cryopreservation, and whether or not the storage company survives the intervening years. A lot of thought and effort has gone into these matters over the four decades that cryonics has been a professional concern; you can peruse the materials at Alcor's website for a sampling of it.

Thus cryonics is a wager as well as a so far small industry, a bet on technology continuing its upward trend. The odds are unknown, but infinitely better that those provided by any other end of life choice. We are heading into an era of rejuvenation therapies, but all too many people will run out of time before those therapies arrive. Are we barbarians, writing off these countless individuals? I would hope not. A fallback plan that offers some chance is better than a certainty of oblivion, and the more people who choose to sign up for cryonics, the better the chances become. A larger industry means more research and development, faster progress towards improved preservation techniques, more effective lobbying to change laws on euthanasia so as to make preservation a reliable, scheduled, low-cost event, and so forth. There is much that can be done to improve present matters, just as there is much that has been accomplished to make present day cryonics far more advanced over its beginnings.

Generation Cryo: Fighting Death in the Frozen Unknown

Alcor Life Extension Foundation is the first and largest cryonics firm in the world. Its only true competitors are the Cryonics Institute located near Detroit - a 7,000-square-foot facility that currently hosts 100 preserved individuals - and KrioRus near Moscow - the world's first cryonics firm based outside the United States. Futurist Robert Ettinger came up with the idea of cryonics in the 1960s, but it was Frederick and Linda Chamberlain who formed a nonprofit organization in 1972 dedicated to cooling recently deceased people down to liquid nitrogen temperatures, and maintaining their bodies until it was possible to "reanimate" them. They called their new California-based organization the Alcor Society for Solid State Hypothermia - "Alcor" being a faint star in the Big Dipper. After dealing with some uncomfortable political squabbles and bureaucratic hurdles in California, the organization moved its operations to Arizona in 1990. Arizona offered a stable environment, free from earthquakes, floods, and other natural disasters, and state laws that were more amenable to Alcor's unconventional activities.

Alcor may be a not-for-profit 501(c)(3), but it needs to be profitable to survive, and to ensure the long-term prospects of those preserved at the facility. The core staff of Alcor - all of whom are signed up - have a vested interest in the success of the company. Alcor CEO Max More says, "We want this for ourselves." Registering with Alcor comes at a price. To help pay for it, most clients take out a second life insurance policy and name Alcor as the beneficiary. To ensure that Alcor can take possession of the deceased, clients donate their bodies to the organization for scientific study. And yet, very few people are actually ready to go the distance. Around 2.6 million people die each year in the United States. Alcor, the world's leading cryonics institute, has only 1,569 full members after four decades - and that includes the 148 patients currently in cryostasis. Undaunted, More says that there will be a tipping point, that cryonics will "eventually be the norm" and even "a regular fixture of medical care." He sees hospitals of the future having the expertise and facilities to perform their own cryopreservations. He compared the slow buy-in to the length of time it took germ theory and open heart surgery to be accepted. "The current problem is that it's hard to sell something without a guarantee. We make absolutely no promises about our offering-and in fact, we even provide our clients with a lengthy list of all the things that could go wrong."

A surprising number of things can and do go wrong, from the moment death is declared to the lowering of a body into the shiny dewar. With advance warning of death, a standby team is dispatched to wait until clinical death has been declared. Within seconds, the patient is placed in an ice bath to start cooling, and a mechanical respirator is used to restart circulation. The goal is to maintain normal bodily processes, even after "clinical death" has been declared. Decomposition starts almost immediately. The team then administers 16 different kinds of medication, including propofol to suppress consciousness in the event that cardiopulmonary support unintentionally revives the patient. Even at this early stage in the process, the line that divides life and death is blurred. The other medications work to reduce metabolism and stave off other problems that occur when the body stops functioning. The idea isn't to freeze the body, but to take it down to slightly above the freezing point of water to prepare it for transportation to Alcor. This is the ideal scenario, but there can be catastrophically long delays. Each passing hour or day following clinical death means preservation will be that much lower in quality. As Alcor likes to say, "Time is trauma."

Sometimes, disapproving family members deliberately refrain from alerting Alcor that one of their clients has passed away, in direct violation of the recently deceased's wishes. If a person was crushed by a streetcar, there may not be much left to preserve. Likewise, an autopsy will almost certainly result in a seriously compromised cryopreservation. And if the person died of an aggressive brain tumor or neurodegenerative disorder, any memories or aspects of personality that were damaged by the disease will almost certainly not be restored at a future date. Once the body arrives at Alcor, it's quickly taken to the operating room. For whole-body preservations, surgeons connect all the major blood vessels of the heart to a heat exchanger (a device that lowers the patient's body temperature to a few degrees above the freezing point of water), and a perfusion machine, which delivers chemicals to the body. The idea is to wash out the body's blood and other fluids as quickly as possible, and replace them with a cryoprotectant. This high-tech gel is gradually added to the body to prevent ice crystal formation - the mortal enemy of biological sustainability. The quality of this process varies according to the state of the patient. Things tend to go smoothly for people with a fully-functioning circulatory system, but for others, who have had prior surgery or other conditions, this can lead to less than ideal conditions. Aneurysms and bleeding in the brain are not good.

Alcor prides itself on transparency and commitment to "evidence based cryonics," and it publishes detailed case reports for each preservation. These reports include notes about deficiencies and problems that happened during the process. Despite Alcor's strict protocols, there's no proof that its method of cryopreservation is actually working. For all we know, every single person at the facility is a goner. Alcor has published micrographs of cryogenically preserved brain cells on its website, and claim the images "demonstrate good structural preservation with dehydration artifacts, but no ice damage." But as More himself admits, they haven't been able to prove that the neural connections have remained intact, though he remains hopeful. Kenneth Hayworth, president and co-founder of the Brain Preservation Foundation and an expert in the burgeoning science of connectomics, is critical of Alcor's micrographs. Hayworth says that chemical fixation, in conjunction with cryonics, is the future of brain preservation, and that Alcor has it all wrong. Alcor, on the other hand, steadfastly believes that chemical fixation is a catastrophe. The process uses aldehyde to fix the brain in place, preventing any shrinking on account of dehydration (a serious problem during the cooling process). More says this is a big no-no because it's irreversible, and that this "destructive" form of preservation is not a true form of survival. He and others believe this process will essentially kill the individual - and all their biological bits - for all time. More admits that the resulting brain scans could help future scientists reconstruct an individual, but many Alcor members argue that it would be a mere copy of that individual. "Not a lot of people will accept that."

Aschwin de Wolf, the editor of Cryonics Magazine and CEO for Advanced Neural Biosciences, says it's good that Hayworth and others are holding Alcor to a high standard, because it pushes the science of cryonics forward. Having said this, he worries that Hayworth is rehashing old misconceptions about Alcor's techniques. "For a long time cryonicists were criticized for causing ice formation in the brain and now that we have eliminated this phenomenon through vitrification we are told that electron micrographs do not look like controls yet. We know this! Hayworth's position seems to be that a cryonics organization should only offer cryopreservation services if its electron micrographs are indistinguishable from controls. That seems an extreme and ethically troublesome position to me. As long as we have good reason to believe that the original state of the brain can be inferred from the altered state, offering cryonics services is not only reasonable but an ethical mandate."

Robin Hanson, an economist at George Mason, has been an Alcor member since the 1990s, and he says it rarely crosses his mind. "It hasn't occupied very much of my attention or thought over the years. It's not some kind of part-time job that requires your constant attention." Simon Smith, a Toronto-based digital health marketer, husband, and father of two, has been an Alcor member for nearly a decade, and he concurs. "I think it's like a life insurance policy. A lot of people have life insurance policies, but they don't walk around thinking about them everyday." Smith is disheartened at the slow pace of technological development. An avid futurist and life extension advocate, he'd like to see more emphasis placed on technologies that will prolong human life, whether it be advances in pharmacology, biotechnology, molecular nanotechnology, or improvements to cryogenic techniques. But he remains optimistic. "The odds of reanimation being successful are better today than they've ever been and are continuously getting better, while the odds of coming back from burial, cremation or every other alternative remain the same."

This review paper takes a look at some of what is known of the contribution of mitochondrial dysfunction to age-related loss of muscle mass and strength, progressing towards the condition known as sarcopenia. The hundreds of mitochondria packed into every cell act as power plants; these evolved descendants of symbiotic bacteria are responsible for, among many other things, generating chemical energy stores to power cellular operations. This process also produces potentially disruptive reactive oxygen species as a byproduct, but the structures most likely to take the brunt of that disruption are the mitochondria themselves. Mitochondrial damage is important in the aging process, producing a growing population of dysfunctional cells that export harmful reactive molecules into surrounding tissues, giving rise to damaged proteins that contribute to a range of age-related conditions. Declining energy store production is also a significant problem in tissues that need greater amounts of energy to function and maintain themselves, such as muscles:

Loss of muscle mass and muscle wasting are clinical symptoms associated with many chronic diseases as well as with the aging process. The loss of muscle mass accompanied by a decrease in muscle strength and resistance which occurs in the elderly is termed sarcopenia. In the population over 65 years of age, this decay in muscle function is particularly associated with increased dependence, frailty, and mortality. In fact, sarcopenia is the main cause of disability among the elderly. Among the mechanisms that contribute to sarcopenia have been described the decrease in physical activity, the decrease in anabolic hormones, and an increase in proinflammatory cytokines as well as the increase in catabolic factors. Further, recent studies have also identified that not only mitochondrial metabolic dysfunction but mitochondrial dynamics and mitochondrial calcium uptake too could be involved in the degeneration of skeletal muscle mass. A growing body of evidence suggests that muscle quality plays a systemic role in the aging process. Thus, it has become apparent that mitochondrial status in muscle cells could be a driver of whole body physiology and organism aging.

Reactive oxygen species (ROS) are produced in the mitochondria as a byproduct of an inefficient transfer of electrons through the electron transport chain (ETC). During the aging process, ROS production increases as well as mitochondrial damage and dysfunction. These phenomena have also been observed in age-associated diseases. In fact, it is supposed that the observed increase in ROS is derived from a decline in mitochondrial function. Interestingly, in flies, the development of genetic sensors which can be targeted specifically to a tissue or to an organelle within the cell is helping to reveal which tissues are subject to redox dysregulation during aging. Increased production of ROS in aged and age-related phenotypes has also been observed to be accompanied by alterations in mitochondrial DNA (mtDNA) quality and quantity. It has been proposed that increases in ROS could easily target the mtDNA which lacks histone protection. Furthermore, it is argued that with aging, DNA repair mechanisms efficiency decline and could lead to mutations in mtDNA.

Consistent with the paradigm, in mice, it has been found that ROS production is increased in aged muscles and directly affects the complex V (ATP synthase) of the ETC, oxidizing, thereby preventing the synthesis of ATP by the oxidized protein. One possible consequence of this process is that the damaged mtDNA promotes the biogenesis of damaged mitochondria, in turn producing more ROS, enabling a vicious cycle to continue. Contrasting these results, recent deep sequencing of mitochondrial genomes in mice suggests, otherwise, that mutations in the mtDNA arise from replication errors during early life. Increased ROS species in the cell have also been associated with diminished ROS scavengers activities during aging. Interestingly, recent evidence has demonstrated that genetic manipulation of mitochondrial antioxidants, given by the overexpression of human mitochondrial catalase in old mice, protects from oxidative damage and age-associated mitochondrial dysfunction, together with protecting from energy metabolism diminution in age. Several questions remain open regarding the behavior of ROS during organism and muscle aging. For example, when in lifespan do ROS first appear in the muscle? Or which concentrations of ROS are required to alter the gene and protein networks that ensure mitochondria and muscle quality functions? These are still matters to be addressed.

Link: http://dx.doi.org/10.1155/2016/9057593

In this op-ed, Aubrey de Grey of the SENS Research Foundation argues that finding effective ways to treat the causes of the aging process should be the highest priority for our societies. No other single thing causes anywhere near as much suffering, loss, and death, and yet few resources are devoted to bringing an end to aging. Few people seem to realize just how plausible it is to build rejuvenation therapies in the near future given the present advanced state of biotechnology and medical research. Some of those therapies are under development in startup companies even today, but much more work remains ahead, at present supported only by a low level of funding. So much more could be achieved, and far more rapidly, given sufficient material support.

What is medicine for? Surely an easy question, right? Apparently not. I have always believed that the purpose of medicine is to alleviate the suffering caused by ill-health and death. One must include both, because death itself is very effective in ending the suffering caused by ill-health, and even though there is vibrant debate concerning the appropriate access to assisted suicide, society overwhelmingly adopts the policy that life is sacred and must be extended at virtually all cost. Or does it? There is a bizarre contradiction in our collective approach to the ill-health of old age. On the one hand we are happy to allocate billions upon billions to the quixotic pursuit of extended but functionally impaired life, under the banner of geriatric medicine, but on the other hand we overwhelmingly express deep ambivalence, if not outright opposition, to the idea of future medicine that would actually work - that would entirely abolish those ailments and maintain youthful mental and physical function to much greater chronological ages. When asked to consider such a world, most people are far more inclined to raise concerns about how society would manage the likely side-effect of increased average longevity, than to pay any attention whatever to the prospective alleviation of so much suffering.

The ill-health of old age currently accounts not only for over 70% of deaths worldwide but also for a similar proportion of medical expenditure. In the industrialised world, these numbers are in the region of 90%. What if we had medicine that would prevent the conditions on which all that money is spent? The money would be saved! Sure, the medicines that achieved this prevention would themselves cost money, but there is no reason (not even any hypothetical reason) why prevention should not be better (i.e. cheaper) than cure in this case as it usually is. And that's just the start. Do you, or does anyone you know, have a parent with advanced Alzheimer's or any other age-related chronic disease? How much productivity is lost from the burden of caregiving as a result? It's astronomical. And beyond that, consider the wealth that the elderly could contribute to society if only they remained able-bodied. The economic benefit would be unimaginable.

How is this not completely obvious to everyone? My only explanation is that the powers that be are just as irrational about aging as the rest of society. There can be no doubt that policy-makers are acutely aware of the economic realities that I summarise above, but their decisions are based on their perceptions of the impact on their priorities. And it seems that policy-makers remain convinced that it is not in their interests to inject relatively minuscule sums into research that could pay for itself literally millions of times over. Why? Only two explanations seem available. One is that the reward is further in the future than the current electoral cycle, such that whatever the logic of such a course, it would be against the nearer-term vested interests of the political elite. The other is that these decision-makers truly feel, in spite of all the scientific evidence trumpeted by biogerontologists every day, that the probability of actual success (i.e., of a substantial hastening of the defeat of ageing) from such expenditure really is less than one in a million, thus outweighing the benefit that success would bring. Neither such attitude is remotely excusable.

Link: https://www.opendemocracy.net/neweconomics/anti-aging-medical-research-must-be-our-top-priority/

In the open access paper I'll point out today, the authors dig into some of the details of DNA methylation changes that occur with aging, seeking to build a better biomarker of aging. This methylation is one of the epigenetic decorations to DNA that act to alter the expression of particular genes, determining whether or not the encoded proteins are produced. The methylation status of genes changes constantly in response to circumstances, differently in every tissue, one small portion of the countless interacting feedback loops that drive the behavior of cells. The cell and tissue damage of aging is the same for everyone, however, and so are the reactions to that damage, even though happenstance, lifestyle choices, and genes conspire to create some variation in the pace at which aging progresses. Thus there are patterns of DNA methylation that are distinctive for people at a given point in the progression of degenerative aging, and those patterns can be picked out of the constant changes that occur due to other environmental factors. Some of these patterns better reflect chronological age, others better reflect biological age, but there is much left to be done to expand and improve upon the existing discoveries in this field.

Why is this important? Primarily for economic reasons. At present it costs a great deal of time and money to assess whether or not a potential therapy that might produce a slowing or reversal of aging in fact works. Researchers have to run life span studies, and as the focus moves from lower animals into mice the cost per study rises to millions of dollars and the time taken rises to years. Yet without those studies, obtaining the proof and support to justify further development is impossible. You might look at the progress towards senescent cell clearance, one of the SENS approaches to rejuvenation biotechnology, over the past decade as an example. Despite the established body of evidence for the role of senescent cells in aging, that line of research didn't start to pull in meaningful support until researchers managed, against all the odds, to raise enough funding to run a study in mice and demonstrate extended life span through removal of senescent cells. Now, five years after those results were published, there are funded startups and numerous research groups working on building a variety of senescent cell clearance therapies. Looking ahead for the field of aging research as a whole, imagine that these lengthy and expensive mouse life span studies could be replaced with very short studies that assess a biomarker of aging, apply the therapy, wait a few weeks, then assess the biomarker again. That would dramatically reduce the cost, get many more research groups into the field, and allow many more approaches to be proved or disproved fairly rapidly. The iterative process of research and development would speed up considerably.

So, to the degree that DNA methylation is a path to a good biomarker of biological age, one that will change quickly and predictably when a real, actual, working rejuvenation therapy is applied, we should all be cheering progress in DNA methylation research. The present DNA methylation clocks are not as accurate as researchers would like them to be, however. There is definitely room for improvement, and all such improvement will - in the end - be reflected in the bottom line: the cost of running studies to assess potential treatments for aging, and thus the cost of progress in the treatment of aging as a whole. Greater reductions in costs will bring larger increases in the output of the research and development communities. The more progress here the better, as no-one is getting any younger yet. All of that said, I should note that the publicity materials here make what is to my eyes a complete hash of the meaning and significance of this research, so you might want to just skip straight to the paper.

Youthful DNA in old age

The DNA of young people is regulated to express the right genes at the right time. With the passing of years, the regulation of the DNA gradually gets disrupted, which is an important cause of ageing. A study of over 3,000 people shows that this is not true for everyone: there are people whose DNA appears youthful despite their advanced years. The researchers charted the regulation of the DNA of over 3,000 people by measuring the level of methylation at close to half a million sites across the human DNA. They were looking for sites where the difference in regulation increased between people as life progressed. Unexpectedly, these sites were closely linked to the activity of genes that were known from studies in worms and mice to play a central role in the ageing process. Not everyone in the study showed equal evidence of an age-related dysregulation of the DNA. Some elderly people had DNA that was regulated as if they were still 25 years old. In these individuals, genes characteristic of the ageing process were much less active. The next step will be to find out whether such people stay healthier for longer. "Obviously, health depends on more than just the regulation of our DNA. But we do think that the dysregulation of the DNA is a fundamental process that could push the risk of different diseases in the wrong direction. In cancer cells, we found changes in the regulation of the DNA at the same sites as if the differences occurring with ageing were a precursor of the disease. We therefore want to study whether a dysregulated DNA increases the risk of different forms of cancer and, conversely, a "youthful" DNA is protective."

Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

Studies of model organisms such as yeast, nematodes, and mice have shown that the accumulation of cellular damage is a fundamental cause of ageing across species. Epigenetic dysregulation is thought to play a key role in this process. Numerous human population studies have now shown that changes in DNA methylation of CpG dinucleotides, a key epigenetic mechanism, are strongly associated with chronological age. Although these epigenetic changes are in part a by-product of age-related changes in the cellular composition of the studied tissue, many age-related differentially methylated positions (aDMPs) observed in blood samples are independent of cell composition, and aDMPs have proven to be a useful tool to predict chronological age. However, aDMPs may not be the most informative marker of the ageing process since they were discovered as close correlates of chronological age instead of biological age. Moreover, only a small proportion of aDMPs are associated with expression changes, suggesting that their functional implication may be limited. In contrast, DNA methylation changes that increasingly diverge from chronological age may reflect the increasing inter-individual variation in health that occurs with increasing age. Initial studies, although small or lacking a genome-wide view, indicated that an increasing variability of DNA methylation with age indeed exists.

In the current study, we charted the occurrence of age-related variably methylated positions (aVMPs) across the genome. We evaluated the methylation at 429,296 CpG sites for increased variability with age in whole blood samples from 3295 individuals aged 18 to 88 years. We discovered and validated 6366 age-related variably methylated positions (aVMPs). While aVMPs were commonly associated with the expression of (neuro)developmental genes in cis, they were linked to transcriptional activity of genes in trans that have a key role in well-established ageing pathways such as intracellular metabolism, apoptosis, and DNA damage response. Of interest, tumors were found to accumulate DNA methylation changes at CpG sites of aVMPs, thus supporting the long-standing notion that ageing and cancer are in part driven by common mechanisms.

Our data show that the genomic regions accumulating variability in ageing populations are highly specific and reproducible. Hence, although the increase in variability may have a stochastic component, the regions affected by this phenomenon are well-defined and not stochastic. Intriguingly, associations of aVMP methylation with gene expression in trans extended to genes known to play a role in ageing. In older individuals who had an aged DNA methylation profile as compared with young individuals, we observed a downregulation of genes involved in metabolism. The upregulation of ageing pathways, as observed in old individuals with an aged methylome, has been reported previously in hematopoietic stem cells in mice and humans, for which macromolecular or DNA damage may be the driving force. Of note, many of the trans-genes we identified are involved in the DNA damage response and are frequently mutated in various cancers. Hence, genomic stress, due either to hyperproliferation or DNA damage, may drive upregulation of well-established ageing pathways, downregulation of intra-cellular metabolism, and altered regulation by proteins associated with increased variability of DNA methylation. In contrast to aDMPs, aVMPs show a striking variability in DNA methylation at higher ages. Two individuals of the same age may display highly distinct methylation patterns across aVMPs, where one of them may have a DNA methylation profile at aVMPs that is similar to that of young individuals. Therefore, aVMPs fulfill a primary prerequisite for a biomarker of biological age.

One observation that has emerged in recent years from large epidemiological studies of health and longevity is that greater time spent sitting correlates with a higher risk of death and thus shorter life expectancy. This even seems to be independent of amount of exercise carried out while not sitting, though that aspect of the findings needs further reinforcement to rise to the level of evidence for the more general association between level of inactivity and mortality rates. As for most statistical human studies it is a challenge to move from correlation to understanding the directions and mechanisms of causation, though as ever we can reference the numerous animal studies in which it is shown that increased activity is very definitely a cause of reduced mortality. This latest paper to look at the "chair effect" is more food for thought on the topic. The national differences suggest that this, like most correlations, reflects the operation of numerous interacting environmental factors:

Exercising and not spending so much time on the couch tend to be some of these good intentions. 31% of the worldwide population does not meet the current recommendations for physical activity according to several studies. In addition, a lack of exercise is associated with major noncommunicable diseases and with deaths of any cause - inactivity is the culprit behind 6% to 9% of total worldwide deaths. Today's lifestyle has an impact on these numbers. In fact, various studies over the last decade have demonstrated how the excessive amount of time we spend sitting down may increase the risk of death, regardless of whether or not we exercise. A new study now estimates the proportion of deaths attributable to that 'chair effect' in the population of 54 countries, using data from 2002 to 2011. "It is important to minimise sedentary behaviour in order to prevent premature deaths around the world, cutting down on the amount of time we sit could increase life expectancy by 0.20 years in the countries analysed."

The results reveal that over 60% of people worldwide spend more than three hours a day sitting down - the average in adults is 4.7 hours/day - and this is the culprit behind 3.8% of deaths (approximately 433,000 deaths/year). The highest rates were found in Lebanon (11.6%), the Netherlands (7.6%) and Denmark (6.9%), while the lowest rates were in Mexico (0.6%), Myanmar (1.3%) and Bhutan (1.6%). Spain falls within the average range with 3.7% of deaths due to this 'chair effect'. The authors calculate that reducing the amount of time we sit by about two hours (i.e., 50%) would mean a 2.3% decrease in mortality (three times less), although it is not possible to confirm whether this is a causal relationship. Even a more modest reduction in sitting time, by 10% or half an hour per day, could have an immediate impact on all causes of mortality (0.6%) in the countries evaluated.

Link: http://www.agenciasinc.es/en/News/Sitting-for-long-periods-of-time-is-the-cause-of-4-of-deaths-worldwide

If cancer results from mutation, then why don't species with more cells have more cancer? That is clearly not the case. Whales, for example, have a lower rate of cancer than humans despite having something like a thousand times as many cells as we do. Mice have a much higher rate of cancer than we do. This is Peto's paradox in a nutshell, and the observation is the basis for a range of fundamental research that seeks to understand large variations in cancer rates across mammalian species, and then perhaps do something with that understanding. This paper looks at the evolutionary origins of this variation between species of differing sizes:

Multicellularity is risky. Every cell could, in principle, escape the checks and balances of healthy organisms that keep individual cells from proliferating in an uncontrolled manner and cause cancer. If having many cells is risky, then having even more cells should be even riskier. If the hazard rate increases with age, then a longer life should progressively increase cancer risk. Hence, large, long-lived organisms are expected to suffer a higher lifetime cancer risk than small, short-lived organisms. This does not seem to be the case; an apparent contradiction known as Peto's paradox. There is significant recent interest in Peto's paradox and the related problem of the evolution of large, long-lived organisms in terms of cancer robustness. Peto's paradox, however, is circular. The paradox relies on assuming a certain lifespan, after which the cancer risk during that lifetime is evaluated. This seems the wrong procedure. Lifespan is a function, among others, of cancer robustness: organisms are long-lived because they are cancer robust. If not, then they would be short-lived. One cannot next expect that they are not cancer robust and should therefore have a higher lifetime cancer risk, based on the very same lifespan that derives from high cancer robustness. Similarly, large organisms exist because they are cancer robust; one cannot next expect that they are not.

Because no set of competing risks is generally prevalent, it is instructive to temporarily dispose of competing risks and investigate the pure age dynamics of cancer. In addition to augmenting earlier results, I show that in terms of cancer-free lifespan large organisms reap greater benefits from an increase in cellular cancer robustness than smaller organisms. Conversely, a higher cellular cancer robustness renders cancer-free lifespan more resilient to an increase in size. This interaction may be an important driver of the evolution of large, cancer-robust organisms. Large, long-lived animals can exist if and only if they are cancer robust; one cannot next expect them to have a higher lifetime cancer risk because they are not cancer robust. The observation that (cells of) large, long-lived organisms must be more cancer robust than (those of) small, short-lived organisms is shrewd and of great importance, but should have been the endpoint. The expectation that large, long-lived animals should have a higher lifetime cancer risk than small, short-lived organisms is an unnecessary and faulty extra step, as is the resulting paradox when that prediction remains unconfirmed. Given that whales live up to 200 years and weigh up to 200,000 kg, their cancer dynamics differ from those of humans, and the "promise of comparative oncology" stands.

Link: https://dx.doi.org/10.1098/rspb.2016.1510

I see that the Zuckerbergs have set themselves the ambitious goal of ending disease over the course of this century. Don't forget that these are the spokespeople for an organization, not a few individuals making choices. Billionaires are effectively each the head of their own small state with its own politics and varied goals, the center of circles of delegation and machination, and frequently have less freedom to direct resources than you might think they do. Nonetheless:

Chan Zuckerberg Initiative announces $3 billion investment to cure disease

The Chan Zuckerberg Initiative just announced a new program informally called Chan Zuckerberg Science to invest $3 billion over the next decade to help cure, prevent, or manage all disease. The money will bring together teams of scientists and engineers "to build new tools for the scientific community." Part of the $3 billion will go to a $600 million investment in Biohub, a new physical location that which will unite researchers from Stanford, Berkeley, and UCSF with elite engineers to find new ways to treat disease. The majority of deaths are caused by heart disease, infectious disease, neurological disease, and cancer, so those are the areas where the program will concentrate its efforts. Mark Zuckerberg showed visible gusto, noting how our country spends 50x more on treating people who are sick than curing diseases so people don't get sick. "We can do better than that!" he exclaimed. To change this, Zuckerberg explained there must be a shift towards long-term thinking for research that requires more funding than typical academic grants can sustain. That's where his $45 billion fortune comes in.

Ambitious goals are good; far too few people with significant resources also choose to aim high, and the simple possession of wealth certainly doesn't magically grant vision. It is welcome to see that at least some of the wealthy of the world are waking up to the fact that this is an age of biotechnology in which the sky is the limit. The cost of medical research and development has plummeted over the past three decades. Yes, it is true that the straitjacket of regulation ensures that it is ever more costly to actually deploy medicine to the clinic, and that all to many promising lines of research never even get to that point since they couldn't be profitable. That fact serves to hide the reality from casual observers, which is that the actual research itself has become very cheap, and the state of the art in the lab is moving ever further ahead from the state of the art in the clinic. Any line of work using the tools of the biotechnology industry has experienced the same curve in costs and capabilities over the past few decades as computing and telecommunications, the result of advances in materials science and processing power. This is a time to aim high.

You might recall that Sean Parker is funding cancer immunotherapy at a fairly large scale, and then there is the Gates Foundation, funding work on a number of infectious diseases, Paul Allen's large-scale funding for mapping a range of human biochemistry, the Google founders' Calico Labs venture, Larry Ellison's past funding for aging research, and so forth. Where disease and the cause of disease is the target most of these are neither ambitious nor visionary exercises, however. While they bring a large amount of money to the table, very few manage to blaze a new path with that funding. They largely follow the current mainstream strategy, fund later stage scientific work, more development than research, and tend to only incrementally improve outcomes. The Ellison Medical Foundation essentially become a small arm of the National Institute on Aging, for example, and we can point to nothing that changed greatly as a result of those years of additional budget. There is a good chance, given the way things tend to go, that Calico and the Parker Institute for Cancer Immunotherapy will end up at the same destination - incremental increases in funding for existing projects, no meaningful change in strategies that have produced only small gains over the years, no bold steps, no radical advances. It often seems that the more funding one can bring to bear, the more one is constrained to do nothing new with it. To be sure more funding for research is better than less funding for research, but there is a very large difference between investing intelligently and taking calculated risks for a shot at large gains in medical capabilities and simply investing in the current mainstream, whatever that might be. Real, radical progress and the foundation for the next generation of medicine tends to come from the fringes of a field, not the established institutions.

The Zuckerberg vision is a good one, but we shall see how that translates to reality in the years ahead. There is only one way to bring an end to heart disease and the other diseases of aging, and that is to control the causes of aging - to repair or make irrelevant the molecular damage that gives rise to degeneration, decline, and disease, as outlined in the SENS proposals. I will be pleasantly surprised to see that approach showing up anywhere in practice in this venture, however, as it isn't yet reflected in the mainstream consensus on strategy in the research community. The bold visions of past ventures largely gave way to work that was prosaic and mediocre in ambition, subsumed by the short-term targets of small, incremental gains. So on the one hand I'm not optimistic that this, rather than any other past or existing venture, will be the one to break the mold. On the other hand there's a lot to cheer about when people with access to world-changing levels of resources acknowledge that ending disease is a viable goal for this age of biotechnology, and set their sights on it, in word at least. That is a part of the persuasion that must continue to happen in order to bring ever more resources to bear on progress in medicine, and in order to have a decent chance at realizing the potential of medical science to bring an end to all of the presently common causes of death. The more funding that there is in general, the more of that funding that we can persuade to go towards SENS-like strategies that stand a real chance of producing radical improvements in health and longevity, rather than the mainstream research strategies that largely cannot achieve such goals soon enough to matter.

Most research into the mechanisms of aging starts with cells and then moves to short-lived species such as flies or nematode worms - easier to manage than mice, and the short life spans mean that more work can be carried out for a given amount of funding and time. Only later do more promising projects move to the use of mice. At each stage of the process, from cells to worms, from worms to mice, from mice to people, many research results fail to prove relevant. Worms are not mice, and mice are not people. There are significant differences, for all that many of the most fundamental aspects of aging and cellular biochemistry are remarkable similar in all of these species. The paper here, the full text in PDF format only I'm afraid, is an interesting attempt to put some numbers to the degree to which nematodes and mice are different in the matter of aging and interventions that slow aging.

Given the existence of subtle but important differences that can produce the results outlined here, then it may well be the case that the development of reliable biomarkers of aging should be prioritized to a greater degree and work in nematodes and the like largely abandoned in favor of short mouse studies that assess effects on aging through the use of biomarker tests. The discussion below should be considered in the context of the comparatively small changes in life span achieved by most interventions, where it is reasonable to ask how that change came about and whether it was due to an influence on aging or some other factor. The future of the field, assuming that SENS rejuvenation research prospers, is to create increases in life span and health span so large that there is no room for debate as to what is taking place.

It has been argued that an extension of lifespan may not necessarily be concrete evidence of a retardation of the aging process. In this view, a lifespan-extending intervention may simply remedy deficiencies in the environment or in the genetic make-up of one particular strain. The intervention would therefore extend lifespan by correcting specific flaws rather than altering the aging process. These considerations create a conundrum: if lifespan is not a reliable measure of aging, how can we confirm that a particular manipulation truly affects the aging process? One approach is to assess physiological phenotypes which are known to deteriorate with age, such as cognition or the functioning of the cardiovascular or immune systems, in order to detect similarities or discrepancies with the patterns observed in control strains. An alternative criterion is to consider whether a particular manipulation changes how mortality rates increase with age. This is based on the hypothesis that the increased incidence of the age-related pathological changes that characterizes the aging process is reflected in changing mortality rates.

In the Gompertz model of mortality, 'G' describes the rate at which mortality rates accelerate with age and 'A' represents the initial mortality rate at time 0. 'A' is strictly theoretical as a mortality rate, since there can be no actual mortality at time 0. Instead, it can be determined by extrapolation from mortality rates at greater ages, and does not necessarily correspond to true mortality rates at birth or during youth. Decreasing 'A' extends lifespan by shifting the inflection point of the curve rightwards, such that it occurs proportionally later in age, relative to maximum lifespan. There is no change in the apparent "slope" of the curve. In contrast, decreasing 'G' extends lifespan by decreasing the slope. 'A' has been described as measuring the vulnerability to disease unrelated to the onset of aging, or the effect of the environment on mortality. Changes to 'A' will alter mortality rates evenly across the lifespan of the population. In contrast, since the parameter 'G' can be considered a rate constant for the age-related increase of mortality of a sample or population, it is often given a pre-eminent role as an indicator of the "rate of aging". This is a logical hypothesis, since an increased or decreased 'G' would likely reflect the rate at which physiological conditions are declining with age. Therefore it is often assumed that interventions that extend lifespan by slowing aging, rather than by alleviating some age-independent pathology, will be associated with a decreased 'G'.

Since a substantial number of studies reporting changes in mouse lifespan resulting from genetic manipulations have now been published, we hypothesized that a correlation-based approach may be a more powerful technique to search for patterns in Gompertz parameter shifts. For example, a negative correlation between lifespan and 'G' across long-lived lines of mice would suggest that their extended longevity was due to a decreased rate of aging. By the straightforward method of plotting Gompertz parameters against lifespan we found that most of the genetically-driven variability in lifespan between normal- or long-lived groups of mice was due to changes in 'A', not in 'G'. In fact, 'G' remained remarkably invariant for different groups of wild-type mice as well as for mice with genetic variations that extend lifespan. The only exceptions to this trend were some interventions which acutely shortened lifespan. We also found this to be true for a collection of inbred mice strains studied under uniform conditions as part of the Mouse Phenome Database. Thus, with the exception of some severe lifespan-shortening interventions, lifespan in laboratory mice is largely determined by factors that affect initial vulnerability, rather than age-dependent mortality rate acceleration. In contrast to mice, we found lifespan to be associated with changes in 'G', not 'A', among long-lived C. elegans mutants. This was true as a trend across long-lived mutants, and was also observed by analysing changes to Gompertz parameters among numerous replicate studies of the well-characterized daf-2, isp-1, and eat-2 mutants.

Link: http://dx.doi.org/10.1534/genetics.116.192369

The tissue engineering community is making rapid progress in discovering techniques to reliably grow functional tissue structures from cells. The challenge of producing blood vessel networks remains, however, so these tissues are small in size. Any larger and the inner cells would not receive sufficient oxygen and nutrients. This is not to say that these organoids are useless - far from it. They will revolutionize many areas of research by replacing the use of animal models and greatly speeding up activities such as drug discovery and testing. Further, for many tissues the transplantation of multiple organoids to be integrated into an existing organ is a potentially viable approach to improving function and treating degenerative conditions: consider that many organs function as filtration devices or chemical factories, and these functions are only loosely connected to the present shape and location of the organ. To mention one example from recent years, there is nothing to prevent liver, pancreas, and thymus organoid tissue from usefully functioning inside lymph nodes rather than their usual location. Lungs are a less flexible situation, but it is still the case that organoids may be the basis for a useful transplantation strategy in addition to benefiting research efforts:

By coating tiny gel beads with lung-derived stem cells and then allowing them to self-assemble into the shapes of the air sacs found in human lungs, researchers have succeeded in creating three-dimensional lung organoids. The laboratory-grown lung-like tissue can be used to study diseases including idiopathic pulmonary fibrosis, which has traditionally been difficult to study using conventional methods. "While we haven't built a fully functional lung, we've been able to take lung cells and place them in the correct geometrical spacing and pattern to mimic a human lung." The researchers started with stem cells created using cells from adult lungs. They used those cells to coat sticky hydrogel beads, and then they partitioned these beads into small wells, each only 7 millimeters across. Inside each well, the lung cells grew around the beads, which linked them and formed an evenly distributed three-dimensional pattern. To show that these tiny organoids mimicked the structure of actual lungs, the researchers compared the lab-grown tissues with real sections of human lung. "The technique is very simple. We can make thousands of reproducible pieces of tissue that resemble lung and contain patient-specific cells."

Moreover, when researchers added certain molecular factors to the 3-D cultures, the lungs developed scars similar to those seen in the lungs of people who have idiopathic pulmonary fibrosis, something that could not be accomplished using two-dimensional cultures of these cells. Idiopathic pulmonary fibrosis is a chronic lung disease characterized by scarring of the lungs. The scarring makes the lungs thick and stiff, which over time results in progressively worsening shortness of breath and lack of oxygen to the brain and vital organs. After diagnosis, most people with the disease live about three to five years. Though researchers do not know what causes idiopathic pulmonary fibrosis in all cases, for a small percentage of people it runs in their families. To study the effect of genetic mutations or drugs on lung cells, researchers have previously relied on two-dimensional cultures of the cells. But when they take cells from people with idiopathic pulmonary fibrosis and grow them on these flat cultures, the cells appear healthy. Using the new lung organoids, researchers will be able to study the biological underpinnings of lung diseases including idiopathic pulmonary fibrosis, and also test possible treatments for the diseases. To study an individual's disease, or what drugs might work best in their case, clinicians could collect cells from the person, turn them into stem cells, coax those stem cells to differentiate into lung cells, then use those cells in 3-D cultures. Because it's so easy to create many tiny organoids at once, researchers could screen the effect of many drugs.

Link: http://newsroom.ucla.edu/releases/ucla-researchers-use-stem-cells-to-grow-3-d-lung-in-a-dish

If you have an interest in telomerase research, and anyone following developments in the science of aging really should pay attention to telomerase research, then you might find a recent special issue of Genes to be worth reading. It collects a dozen or so papers on the subject, adding to a growing number of reviews, calls to action, and discoveries published in the last couple of years in the field of telomere and telomerase biology. You might look at a very readable review from Maria Blasco's lab, published earlier this year, for example. The researchers there are leaders in telomerase gene therapy, and have demonstrated benefits and a slowing of aging in mice via this path. It remains to be seen how well it will translate to humans, though there are certainly people out there willing to try.

It is possible to describe cancer and aging as two sides of the same coin; the evolved systems that act to suppress cancer also suppress tissue maintenance, and the decline in stem cell activity with age that causes a slow decay of tissue function is a trade-off, balancing death by cancer against death by frailty and organ failure. Cellular replication and growth is the commonality in cancer and maintenance: one is uncontrolled growth, the other controlled growth. One of the most important mechanisms in our cellular biochemistry is the Hayflick limit, and telomeres are a part of the system that creates that limit. Telomeres are lengths of repeated DNA that cap the ends of chromosomes. Every time a cell divides some of that length is lost. When telomeres become too short, a cell halts replication and either destroys itself or becomes senescent and is soon thereafter destroyed by the immune system. Healthy tissues are in a state of balance between loss of cells to the Hayflick limit and the delivery of new cells with long telomeres, created by stem cells. How do stem cells constantly create new daughter cells with long telomeres? They use telomerase to maintain long telomeres: the primary function of telomerase is to add more of the repeating telomeric DNA sequences to the ends of chromosomes.

This ornate situation has evolved because it ensures that cancer incidence is kept low enough for it not to impede evolutionary success. The majority of cells have a limited ability to replicate, and only a small number of cells have unlimited replication rights. This greatly reduces vulnerability to cancerous mutations. Still, cancer happens, and it occurs when cells mutate in one of the few ways that can unlock telomerase or alternative lengthening of telomeres activity, or when stem cells mutate in ways that break their regulatory programs. For cancer researchers, interfering in telomere lengthening is the road to the grail of a universal cancer therapy, a single way to shut down all of the hundreds of types of cancerous tissue. On the other side of the coin, for aging, increased telomerase activity is thought to be a way to spur greater tissue maintenance in older individuals, though the processes by which this happens are many, varied, and much debated, just as the full list of mechanisms of action for stem cell therapies is a matter still under investigation. There is some thought that an increased level of telomerase activity will increase cancer risk, as damaged cells will be allowed to replicate far more often than they have evolved to replicate. Though by the same token, stem cell therapies should be similarly risky. So far the benefits look to outweigh the harms. It may be that our evolutionary point of balance has a fair amount of wiggle room.

Special Issue "Telomerase Activity in Human Cells"

The activity of the reverse transcriptase telomerase is a canonical function to maintain telomeres, the ends of linear chromosomes. Telomeres shorten in the absence of telomerase, causing senescence and ageing. In contrast to other organisms, telomerase activity is downregulated early in development in many somatic human tissues. However, some cell types, such as lymphocytes, adult stem cells, and endothelial cells retain, or can upregulate, telomerase activity. Importantly, this activity is strongly controlled by physiological conditions. In contrast, telomerase activity is continuously expressed at a high level in the majority of cancer cells, contributing to their indefinite proliferation potential. Although telomerase activity has been vigorously investigated over the last few decades, many questions still remain open regarding the mechanisms of physiological regulation in normal cells, as well as its up-regulation during tumourigenesis. The complex regulation at the levels of transcription, splicing, and posttranscriptional activation certainly contribute to that. Recently, interventions into its activation to counteract telomere shortening in healthy tissues, as well as its inhibition as tumour therapy, have been suggested and trials have been started with no final breakthrough yet. Thus, we still need to better understand the biology and regulation of telomerase activity in order to interfere with it successfully.

Telomerase Regulation from Beginning to the End

The vast body of literature regarding human telomere maintenance is a true testament to the importance of understanding telomere regulation in both normal and diseased states. In this review, our goal was simple: tell the telomerase story from the biogenesis of its parts to its maturity as a complex and function at its site of action, emphasizing new developments and how they contribute to the foundational knowledge of telomerase and telomere biology. Telomeric integrity has implications in both cancer and aging, as telomere attrition serves as a key checkpoint in the control of cell proliferation by triggering replicative senescence. There are two broadly defined mechanisms of telomere maintenance in humans: telomerase-mediated maintenance and ALT (alternative lengthening of telomeres). However, the complexity of each of these mechanisms becomes more evident with every new publication in the field of telomere biology. Approximately 80% of cancers are immortalized by constitutive activation of telomerase to maintain telomeres throughout rapid cellular proliferation. Additionally, defects in telomerase and other telomere maintenance components cause premature aging syndromes like dyskeratosis congenita (DC), due to progressive telomere shortening and subsequent proliferative blocks. As such, greater knowledge of telomerase regulation and its contribution to telomere homeostasis will contribute to our understanding of human disease and natural cellular processes alike.

The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

Many chronic conditions in humans are associated with chronic inflammation, immune system impairment and accelerated aging. In addition, abnormalities in telomere/telomerase system of these patients have been reported in many of these disorders. Since telomerase, an enzyme directly associated with aging, is inactive in most cell types in a mature organism and active in immune system cells, one can easily hypothesize that the immune system dysfunction/accelerated aging observed in chronic conditions is connected with telomeres and telomerase biology. Indeed, a connection of this nature seems to exist since shortened telomeres, observed in aged cells, cause an inflammatory cascade whereas, at the same time, NF-κB, a master regulator of inflammation, seems to directly induce telomerase transcription as stated above. Moreover, many researchers documented correlations between lower telomerase activity and/or shorter telomeres in immune system cells and elevated cytokines in blood serum from patients with chronic disorders. One should also bear in mind that, although aging is a multifactorial and complex procedure, healthy aging and longevity are believed to be associated with longer telomeres and lower inflammation profiles among older individuals. Despite all of the above, and despite the accumulating data of a strong interconnection between telomerase regulation/activity and inflammation, the mechanistical details and the molecular pathways of this connection have not been uncovered yet.

Telomerase: The Devil Inside

Emerging evidence over the last decade supports the idea that telomere length-independent functions of telomerase are also important for its function, both in normal and tumor cells. Interestingly, current research also revealed that telomeres may sense cellular stress (such as genotoxic stress, oncogenic or aneuploidy-inducing mutations) that result from harmful mutations that lead to genome instability and induce senescence in cells with intact checkpoints. Although the mechanistic details of the 'sensing' process are yet to be revealed, this new function of telomeres, thought to be a result of accumulating replication stress at the telomeres, seems to be independent of telomere length. In this context, telomerase relieves this cellular protective mechanism by mitigating telomere replication stress and this function of telomerase apparently is separate from its telomere elongation activity. In light of the recent discoveries hinting at novel, telomere length-independent roles of telomeres and telomerase, attempts at modulating telomerase activity to improve organ function and longevity must be seriously reconsidered. In this line, interfering with telomerase activity and its extracurricular functions for cancer therapy seems to be an attractive strategy again but new concepts need to be taken into account.

Role of Telomerase in the Cardiovascular System

Aging is one major risk factor for the incidence of cardiovascular diseases and the development of atherosclerosis. One important enzyme known to be involved in aging processes is telomerase reverse transcriptase (TERT). It has been proposed for a long time that telomerase activity is absent from human somatic cells. However, there is accumulating evidence that substantial telomerase activity is present in differentiated, non-dividing somatic cells of the cardiovascular system. This is of particular importance since cardiovascular diseases (CVD) are still the leading cause of death worldwide. All of these diseases have a primary defect in the heart or in the blood vessels, and there is emerging evidence that telomerase has a protective effect against CVD. Understanding this enzymes' functions in these tissues could, in the long run, help to reveal the therapeutic potential of activating TERT in cardiovascular diseases.