A Demonstration of Mitochondrial DNA Editing with CRISPR
Permalink | View Comments (0) | Post Comment | | Posted by Reason

Here I'll point out a technology demonstration of mitochondrial gene editing via CRISPR, something that should be of general interest, though debatable relevance to work on mitochondrial repair at the present time. The development of CRISPR, an efficient low-cost method of genetic editing, has opened a lot of doors. In the course of a few short years since the first practical demonstration, use of CRISPR has made genetic engineering projects accessible and affordable to a vastly greater number of researchers than was previously the case. As an infrastructure advance it is about as transformative as the development of induced pluripotency was for the stem cell research community. Cost and difficulty are very important determinants of the pace of progress in a field, and sharp reductions in both of those for genetic engineering suggests that the next decade is going to be very interesting indeed.

The use of transcription activator-like effector nucleases (TALENs) is one of the candidate next generation genetic engineering technologies that was developed prior to CRISPR, though work continues even now. It is promising, but clearly not starting fires to the same degree that CRISPR is: again, it is all about relative degrees of cost and difficulty. Still, you may recall that it was quite exciting to see TALENs working for mitochondrial DNA back when that was first demonstrated.

Mitchondrial DNA (mtDNA) is distinct from nuclear DNA. It is a circular genome made up of a few leftover genes that is resident in each of the hundreds of mitochondria present in every cell. Mitochondria are the evolved descendants of symbiotic bacteria, and their primary - but far from only - activity is to act as power plants, generating chemical energy store molecules that are used to power cellular activities. They still behave much like bacteria: fusing, dividing, passing molecules and even large portions of their internal structures back and forth between one another. Other processes within a cell monitor the state of mitochondria, and flag damaged ones for destruction, recycling their component parts. Somewhere in all of these interacting processes of generation and destruction, there are ways in which mitochondrial DNA can be come damaged, losing the blueprints for vital protein machinery used in some modes of energy store generation. These damaged mitochondria are in some way privileged, more able to evade destruction at the hands of quality control mechanisms despite their dysfunction. They quickly overtake the entire mitochondrial population of a cell - so quickly that researchers don't have a good view of how exactly the process happens; they only see before and after snapshots. That cell then becomes harmful and dysfunctional, exporting damaged proteins and reactive molecules into the surrounding tissue. The accumulation of such cells over time is one of the contributing causes of degenerative aging.

So as you can see, the ability to edit mitochondrial DNA to fix it is of potential interest. But what can be done here? Can the existence of these dysfunctional cells be fixed for a long enough period of time via a global gene therapy of some sort that directly delivers replacement genes to mitochondria? Or will the continued presence of broken variants just quickly overwhelm any freshly delivered working variants? After all, the damaged variants already achieved that goal in the cells they have taken over, and they are still there in large numbers. There has been sufficient doubt on that front for the research groups involved in efforts to repair damaged mitochondria to adopt other, less direct approaches. These include allotopic expression, in which copies of mitochondrial genes are placed into the cell nucleus, altered in ways that ensure the proteins produced can find their way back to the mitochondria where they are needed. Development of that approach for inherited mitochondrial diseases is at a fairly advanced stage, but it has yet to be applied to aging. With a large fall in the cost and difficulty of mitochondrial gene editing, it may be worthwhile revisiting this picture, however. I'm sure some researchers will do just that in the years ahead.

Efficient Mitochondrial Genome Editing by CRISPR/Cas9

Mitochondria play roles in many important cellular functions. Mitochondria contain their own genome, which encodes 13 proteins that are subunits of respiratory chain complexes, as well as two rRNAs and 22 mitochondrial tRNAs. Due to the critical roles of genes encoded by mtDNA, maintenance of mitochondrial genome integrity is quite important for normal cellular functions. Mitochondrial DNA are, however, constantly under mutational pressure due to oxidative stress imposed by radicals generated by oxidative phosphorylation or an imbalance in the antioxidant defense system in aging or disease processes. Damage to mtDNA, such as point mutations or deletions, contributes to or predisposes individuals to a variety of human diseases.

Despite the huge potential of mitoTALEN-mediated mtDNA editing, more user-friendly and efficient alternative methods are necessary to overcome difficulties in mtDNA modification either for correction of dysfunctional mtDNA or for producing dysfunctional mtDNA in order to create mitochondria-associated disease models.

Here we report a novel approach to generate mtDNA dysfunction with the CRISPR/Cas9 system. Cas9, widely used for genome editing, showed distribution to mitochondria as well as the nucleus. Expression of FLAG-Cas9 with gRNAs designed to target mtDNA resulted in cleavage of mtDNA and alterations in mitochondrial integrity as determined by Western blots for some mitochondrial proteins. Moreover, regular FLAG-Cas9 was modified to contain mitochondrial targeting sequence instead of nuclear localization sequence (NLS) in order to localize it to mitochondria (namely, mitoCas9). MitoCas9 robustly localized to mitochondria; together with gRNA targeting of mtDNA, specific cleavage of mtDNA was observed, demonstrating its functional application for mtDNA editing.

These results together demonstrate the successful application of CRISPR/Cas9 in mitochondrial genome editing and suggest the possibility for in vitro and in vivo manipulation of mtDNA in a site-specific manner.

Christine Peterson on Technology and Longevity
Permalink | View Comments (2) | Post Comment | | Posted by Reason

Christine Peterson is co-founder of the Foresight Institute, one of the oldest of the numerous research and advocacy organizations that emerged from the transhumanist community of the 1980s and 1990s, focused on the development of molecular nanotechnology. Her position on longevity and technology is similar to that of Ray Kurzweil, in that there is to my eyes too much of an emphasis on taking action now via optimization of supplements and diet, something that I think cannot produce sufficient benefits to merit the investment in time required. Further, you'll never in fact know whether or not your investment in time is actually helping, and the size of the best possible result in terms of healthy life gained is still tiny. From my point of view the only way out of the hole we're in with respect to aging is medical research after the SENS model of repairing the cell and tissue damage that causes aging. Everything else is a distraction.

The October 1, 2015 podcast of The Optimized Geek featured Foresight Co-Founder and Past President Christine Peterson: A Glimpse at the Future Lifespan of Humans (55 minutes). Christine explained the development of nanotechnology in three stages. Currently we are moving from the first stage focus on nanomaterials, like stain-resistant pants, into the second phase, dominated by nanoscale devices. The most exciting change change will come with the third stage, in which systems of molecular machines will operate with atomic precision. In responding to a question on what we might see in the next ten years, Peterson suggested that although nanotechnology in that time frame would still be mostly about nanomaterials and simple nanodevices, one of the most interesting applications would be in health, giving the example of more effective diagnosis, imaging, and treatment of cancer through enhanced targeting specificity.

What might advanced nanotechnology look like 30 years from now? Peterson began with the question: What limits do the laws of physics set on what we can build with systems of molecular machines able to build with atomic precision, including inside the human body? One of many applications would be correcting DNA mistakes and mutations cell by cell. Other targets could be damaged proteins and plaques from Alzheimer's, etc. With this level of technology, lifespans would not be limited by aging or traditional diseases, but only by accidents that destroyed the brain, leading to estimated lifespans on the order of 10,000 years. With technology to record the molecular structure of brain, back-up copies of individual brains could be made, eliminating even the 10,000 year limit.

Peterson described "the quantified self" and "biohacking" as taking an engineering approach to making changes and improvements in our bodies. Approaches range from the traditional, like diet, exercise, and stress reduction, to the more exotic, like supplements to improve brain chemistry, or to improve health and longevity. Peterson cautions however, that while taking supplements is easy, figuring out which supplements to take is difficult. Although not of immediate use for those who want to take action now to improve their health and longevity, for those who want to advance research in longevity, Peterson recommended Aubrey de Grey's SENS Research Foundation.

For those who, due to illness or advanced age, will not be able to survive until the future when aging is cured and disease eliminated, Peterson addressed the question of whether there is available today some form of suspended animation to maintain a body until it can be repaired. In the early days of "cryonics", recently deceased bodies were placed at low (liquid nitrogen) temperatures for preservation. Later, certain chemicals were introduced as antifreeze to reduce biological damage caused by freezing. More recent technology has introduced improvements that have been tested on donated organs that are reversible; that is, a viable organ can be recovered from low temperature preservation. Arrangements can be made with cryonics organizations - the largest one is Alcor Life Extension Foundation - to implement for you the best suspended animation technology available at the time that you need it. Peterson shared that she is signed up for it because "I do not see a down side."

Link: http://www.foresight.org/nanodot/?p=6812

Obesity is Harmful, and Studies that Suggest Otherwise Made Overly Simplistic Use of Data
Permalink | View Comments (2) | Post Comment | | Posted by Reason

Researchers here reinforce the point that, yes, being obese is bad for your health, and that a few prior studies that suggested otherwise were mistaken. In any field there are always going to be studies that appear to go against the grain to provide contradictory results. Most of the time these are errors of interpretation; scientific research is hard and complicated, and as a consequence a lot of published work is incorrect in some way. That is why one should never take any single paper in isolation, but look at it in the context of the broader field. In the case of excess fat the broader field has provided a mountain of evidence to show that adding and maintaining more fat tissue causes worse health, greater medical expenditures, and a shorter life expectancy.

It is unfortunate that some factions within our society are willing to cherry pick research to support and propagate the mistaken belief that being overweight is safe and has no effect on health. Everyone who has managed to get themselves into a deep hole wants to be told that they are just fine and haven't caused any harm, but that doesn't make it true.

Researchers set out to solve a puzzle: Why is it that study after study shows obese or overweight people with cardiovascular disease outliving their normal weight counterparts? Would this phenomenon, referred to as the obesity paradox, hold up when approached within different parameters? According to their latest research, the answer is no. When accounting for weight history in addition to weight at the time of survey and when adding in smoking as a factor, obesity is harmful, not helpful, to someone with cardiovascular disease. "There are claims that ... it's good to be obese when you have cardiovascular disease, that if you have fat stores, maybe you'll live longer. It's conceivable that there are health advantages. But we show they are overwhelmed by the disadvantages of being obese, once you control for these two sources of bias."

The researchers started with data from more than 30,400 participants of the National Health and Nutrition Examination Survey between 1988 and 2011. The survey is a nationally representative sample considered the gold standard in the United States. Of those participants, 3,388 had cardiovascular disease. Most research of this type looks only at weight at time of survey. For example, if a participant who long weighed 300 pounds lost one-third of his mass by the time he weighed in, he would be counted at 200 pounds. Not including weight history, however, "would be like classifying a lifelong smoker who quit the day before the survey as a non-smoker, even though we know that if you're a lifelong smoker you carry those risks over even if you stop smoking."

Adding weight history "turns out to have a profound effect on the findings," eliminating the mortality advantage for those who are overweight or obese. Incorporating the second factor, smoking, also contributed to resolving the paradox. Smokers are less likely to be obese, and those who are obese are less likely to smoke. This correlation is much stronger for those with cardiovascular disease, so the researchers limited their pool to lifelong non-smokers. Accounting for weight history makes the obesity paradox disappear. Excluding smokers? That's when being obese equates to significantly higher mortality for those with cardiovascular disease.

The researchers said these results could improve disease treatment, since some clinicians may use the obesity paradox in patient care decisions. "There's every reason to imagine that clinicians are at least confused, and in some cases, are believing that being overweight or obese is a good thing among people with cardiovascular disease, diabetes and other conditions for which a paradox has been demonstrated." Conditions like stroke, kidney disease and high blood pressure, for example. "This may be trickling down into clinical decision making, which is concerning because we don't think it's a real finding."

Link: http://www.upenn.edu/pennnews/news/obesity-does-not-protect-patients-with-cardiovascular-disease

Cryonics is Still the Only Viable Backup Plan
Permalink | View Comments (1) | Post Comment | | Posted by Reason

Front and center, the primary plan for longevity for people in middle age and younger today is to help push through enough of the right medical research. Your body is aging, accumulating damage, but methods of repairing that damage are slowly edging their way towards clinical application. Once in the clinic they will slowly become better. At some point the improvement in repair methodologies will add healthy life expectancy for older people faster than a year with every passing chronological year. Everyone with access to the latest stable medical technology at that point will have beaten the curve: they will no longer suffer and die due to aging. The question is where that point occurs in your life span, indeed whether it occurs in your life span, and that is where activism and funding comes in. You can't make yourself younger (yet), but you can help to speed up the development process: it is certainly moving at far below optimal speed at the present time.

That is the primary plan, and for every primary plan there must be a backup plan. Never bet on just one horse. The backup plan for evading the end that comes with death by aging is cryonics: low-temperature preservation of the fine structure of the brain on clinical death. Cryopreservation organizations will maintain the data of your mind in its physical form for the decades it will take for restoration to active life to become a viable possibility. That will, at minimum, require near complete control over cellular biochemistry and regeneration, as well as a mature molecular nanotechnology industry capable of repairing broken cell structures, removing cryoprotectant from tissues, and similar tasks. None of these goals are impossible or unforeseen, it is just that the necessary technologies don't exist today. Preserved individuals have all the time in the world to wait, of course.

A backup plan is never as good as the primary plan. That is why it is the backup plan. In order to be cryopreserved you have to undergo a very unpleasant set of experiences; you have to age and you have to die, and do so naturally with little help, since our backwards legal systems don't allow for assisted euthanasia in a constructive way that can mesh with cryonics protocols and organizational procedures. Further, in comparison to remaining alive and healthy thanks to the development of working rejuvenation treatments, cryonics will for a long time to come be a leap into the dark with an unknown chance at ultimate success. It is still infinitely better than any of the other possible choices open to the billions who will die too soon to benefit from near future rejuvenation therapies.

Strangely, after four decades of organized operation cryonics remains a tiny, niche, non-profit industry. This is the case for reasons that remain unclear and much debated. Cryopreservation is certainly a far better option than the many strange things people choose to have happen to their bodies following clinical death, usually for no better reason than everyone else does it. Is it little more than the fact that you have to prepare some time in advance to make it cost-effective via life insurance? The reluctance to embrace cryopreservation over the grave and oblivion may have some of the same roots as the reluctance to support research into the treatment of aging as a medical condition and extension of healthy life spans. At root all it would really require for cryonics to grow to become a dynamic and competitive industry is for more people to sign up and express interest.

In recent years the popular press have transitioned from ridicule to balanced respect on the topic of cryonics, and the level of attention has increased. I think at least some of this has to do with growing interest in treating aging as a medical condition, though the relationship may be indirect: people who influence opinions tend to support both life extension and cryonics research and development. In the past decade we've seen a growing acceptance of the transhumanist ideals for longevity and the defeat of death that were first discussed realistically and robustly over the course of the 1960s to the 1980s. Many more people are now on the inside of what was once a small intellectual circle, and visionary thinking from that time is now taken as a foregone conclusion for technological development. That said, journalists are ever journalists and still largely miss the very important difference between freezing, which is something that cryopreservation seeks to avoid, and vitrification, which is the goal of modern procedures. Freezing produces ice crystals which are highly damaging to tissues, whereas vitrification minimizes that outcome.

Dying is the last thing anyone wants to do - so keep cool and carry on

Call the headquarters of Alcor in Scottsdale, Arizona, and you are greeted by a recorded message. "If you would like to report the death or near-death of an Alcor member," says a chirpy midwestern voice, "please press two." The Alcor Life Extension Foundation - to give it its full title - has an unexceptional grey concrete exterior that resembles a regional bank branch. Inside, however, are the bodies or brains of 138 dead people, stored in vats of liquid nitrogen in the hope that, at some point in the future, advances made in science will be capable of bringing them back to life.

This is cryonics - the preservation of animals and humans at extremely low temperatures. And in America, business is booming. Last month, Alcor took receipt of its 138th patient: Du Hong, a Chinese science-fiction writer who died of pancreatic cancer at the age of 61 and whose family contacted Alcor shortly before her death to have her brain preserved. Brain-freezing starts at $100,000 and is cheaper than the full-body option, which costs more than twice that amount. Alcor, which describes itself as a not-for-profit organisation, insists that all fees go directly back into running costs.

Brain Freeze: Those looking to cheat death turn to cryonics - being frozen in liquid nitrogen - to one day live again

"I believe that my identity is stored inside my physical brain," says Carrie Wong, president of the Lifespan Society of British Columbia, an advocacy group that works to promote and protect access to cryonic preservation. "So if I can somehow preserve that, maybe at a future time technology and medical science will advance to such a point that it may be possible to repair the damage of freezing me in the first place and also what killed me back then," says the 27-year-old, who concedes such a feat could be hundreds of years in the future. "It's not possible now, but nobody can really argue it's not possible in the future because that's arguing about what future technology is capable of."

The Cryonics Institute, a non-profit organization founded in 1976 by Robert Ettinger, operates a preservation facility near Detroit, where about 100 pets and 135 humans are suspended in tanks called cryostats. "The actual cryostats are just giant thermos bottles with liquid nitrogen, there's no electricity to fail," says president Dennis Kowalski, a 47-year-old Milwaukee firefighter and paramedic who became interested in cryonics in his 20s.

About 1,250 people, including a number of Canadians, are signed up for CI's service. Membership costs US$28,000, which is typically paid for through life-insurance policies. While acknowledging that he and others who intend to be frozen are often "looked at as a bunch of kooks," Kowalski views cryonics as being like a clinical experiment - and one that beats the alternative. "I'll be the first to admit it may not work. And everyone who's signed up should understand cryonics may not work and there are no guarantees."

A Reddit AMA with the BioViva CEO
Permalink | View Comments (23) | Post Comment | | Posted by Reason

BioViva is a small group that recently announced they have moved ahead with a human test of telomerase and myostatin-related gene therapies as a potential method to modestly slow the effects of the aging process. Their initial goals are to get things moving in this part of the field by taking this step forward, observing the results, and raising funding for further development efforts to try to lower the costs of this sort of approach. The BioViva CEO Liz Parrish, who is also the initial test subject, recently hosted an AMA (ask me anything) event at Reddit's /r/futurology community. Her comments below are lightly edited for continuity, since they are pulled from numerous distinct answers to questions posted by the community:

I am patient zero. I will be 45 in January. I have aging as a disease. To take on this role myself was the only ethical choice. I am happy to step up. I do feel we can use these therapies in compassionate care scenarios now but we will have to work them back into healthier people as we see they work as preventive medicine.

The genes targeted are human telomerase reverse transcriptase (hTERT) and follistatin (FST). In animal models neither FST nor hTERT have increased the risk of cancer. We expect to see the same result on myself, and to that effect we are measuring all known cancer biomarkers. The gene therapies on my body are to measure the effects on humans. There is plenty of animal research to support these gene therapies but no one was conducting human tests. We are using both visual biomarkers, MRI and a panel of blood and tissue testing including work on telomere length and epigenetic testing. We are collecting as much data as we can, but unfortunately we currently don't have the coverage rate for this therapy, how much of the tissue of the body is affected. Depending on the tissue and vector used we ultimately expect to see similar rates of transfection as seen in mice, which is somewhere between 5 to 60%.

We are working as hard as we can to bring it to the world as quickly and safely as possible. We will will evaluate monthly and within 12 months we will have more data. If the results are good we hope to have something to the general public, that is cost acceptable, in 3-5 years. Our goal is to build laboratories that will have the mission of a gene therapy product at a reduced cost. Gene therapy technology is much like computing technology. We had to build the super computer which cost $8 million in 1960. Now everyone has technologies that work predictably and at a cost the average person can afford. We need to do the same with these therapies. What you will get in 3-5 years will be vastly more predictable and effective that what we are doing today and at a cost you or your insurance can cover .

We need a lab that works solely to bringing those costs down. We would need about $1 - 1.5 million to build one lab to focus on this. We can expand as needed. I would love to crowdfund this project but I do not know how to get good results at that scale - I think the price tag is high for that modality. We are raising investment to do offshore clinical trials. Many USA companies do this. If we can cut costs we will be able to bring back a treatment that people can afford.

Link: https://www.reddit.com/r/Futurology/comments/3ocsbi/ama_my_name_is_liz_parrish_ceo_of_bioviva_the/

James Bedford Becomes the Longest Surviving Human
Permalink | View Comments (2) | Post Comment | | Posted by Reason

James Bedford was the first person to be cryopreserved following death, and unlike the others from that early era of cryonics he remains preserved today, nearly fifty years later, at the Alcor facility. It is an open question as to the degree to which the crude preservation methodologies of the time damaged the fine structure of his brain due to ice crystal formation, making restoration a far more complex project, requiring far more advanced future technologies. Even taking that into account restoration is a theoretical possibility, a project that lies within the bounds of the laws of physics as we understand them, which is more than can be said for all of Bedford's peers. They are gone to the grave and oblivion, beyond any hope of a renewed life in the future.

Jeanne Louis Calment is listed as the longest-living (verified) human being in history. She was born on February 1875 and died on 4 August 1997, at the age of 122 years, 164 days. As of October 2, 2015, Ms. Calment's record has been broken by cryonaut Dr. James Bedford, who is maintained in cryopreservation by the Alcor Life Extension Foundation.

Bedford was born on April 20, 1893. As of today, October 6, 2015, he has survived for 122 years, 167 days. It is true that Bedford is not currently alive. But neither is he dead. When Alcor transferred him from an old, customized vessel back in 1991, it was clear that the original ice cubes created at the time of preservation were intact. We have no good information on the quality of the ultrastructural preservation of his neural tissue. But we can say that he has remained cryopreserved since 1967, and so deserves the title of longest-surviving human being in history!

Link: http://www.alcor.org/blog/james-bedford-first-cryonaut-is-now-the-longest-surviving-human-being-ever/

Recent Research on Aging-Related Genes and Proteins
Permalink | View Comments (1) | Post Comment | | Posted by Reason

Below find links to a few recent papers relating to the genetics and epigenetics of aging. Aging is a byproduct of the normal operation of cellular metabolism, due to damage generated and not repaired. Many genes will have some impact on the progression of aging because they govern the operation of metabolism and thus influence the pace at which unrepaired damage accumulates. As time progresses and the damage of aging builds up, cells react to that damage with changes to the epigenetic regulation of the production of proteins. Thus old individuals have more of some proteins and less of others in circulation and present in various tissues, changing the way in which cells and tissues function. Some of this is compensation, and aging would be faster and worse without it, but some of it is just more dysfunction piled on top of that caused directly by damage to cells and their component parts.

Much of the aging research field is involved in cataloging: firstly finding genes associated with the pace of aging by dint of altering them one by one in short-lived and well-characterized species such as yeast or nematode worms, and secondly finding genes whose output of proteins changes with age by precisely measuring the molecules present blood and other bodily fluids at various different ages. Gathering information about how exactly aging progresses at the detail level still has a higher priority for most researchers in comparison to moving beyond that to try to treat aging.

There are some necessary tools that will emerge from cataloging efforts, however. One is a good biomarker of biological age, a measurement that must be cheap and easy to carry out given simple patient samples such as skin or saliva, and comprehensive enough to pick up the beneficial effects of a partial rejuvenation therapy soon after it is applied. For rejuvenation based on repair of cell and tissue damage after the SENS model, researchers can always identify how much of the specific form of damage has been repaired by their treatment, but there is still the need to link that to some reliable and accepted measure of overall biological age for the organism as a whole. Without that biomarker the only way to prove that rejuvenation has happened is to wait and see: run the life span study, which even in mice requires years and millions of dollars, never mind in longer-lived mammals. The need for life span studies as proof is a real drag on the pace of progress.

Identification of ageing-associated naturally occurring peptides in human urine

In a first small scale study, we investigated the urinary proteome in a cohort of 324 healthy individuals between 2 to 73 years of age showing the feasibility to obtain high resolution molecular information from readily available body fluids such as urine. Meanwhile, we have accumulated multiple high-resolution urine peptidomics datasets that enable the investigation of ageing-associated changes in a large cohort. In the present study, we therefore investigated the unique urinary proteome profiles of 11,560 individuals in an attempt to identify specific ageing-associated alterations and investigate pathological derailment of normal ageing. This showed that perturbations in collagen homeostasis, trafficking of toll-like receptors and endosomal pathways were associated to healthy ageing, while degradation of insulin-like growth factor-binding proteins was uniquely identified in pathological ageing.

Length of paternal lifespan is manifested in the DNA methylome of their nonagenarian progeny

The heritability of lifespan (age at death) has been estimated to be approximately 20-30%, and it has been shown to increase with advancing age. Healthy aging is also heritable, and the offspring of long-lived parents show delayed onset of aging-associated diseases. Much of the research studying the heritability of lifespan has focused on extreme age (nonagenarians, centenarians, supercentenarians), but recently it has been shown that every decade of parental age after the age of 65 reduces the mortality and incidence of cancer of their offspring. Even though the heritability of the lifespan is acknowledged, only one genomic locus (on chromosome 3) and a few genetic variants, such as in APOE and FOXO3, have consistently been shown to be associated with longevity. To explain this discrepancy, the inheritance of epigenetic features, such as DNA methylation, have been proposed to contribute to the heritability of lifespan.

We investigated whether parental lifespan is associated with DNA methylation profile in nonagenarians. A regression model, adjusted for differences in blood cell proportions, identified 659 CpG sites where the level of methylation was associated with paternal lifespan. However, no association was observed between maternal lifespan and DNA methylation. The 659 CpG sites associated with paternal lifespan were enriched outside of CpG islands and were located in genes associated with development and morphogenesis, as well as cell signaling. The largest difference in the level of methylation between the progeny of the shortest-lived and longest-lived fathers was identified for CpG sites mapping to CXXC5. In addition, the level of methylation in three Notch-genes (NOTCH1, NOTCH3 and NOTCH4) was also associated with paternal lifespan.

The role of Hsp70 in oxi-inflamm-aging and its use as a potential biomarker of lifespan

The heat-shock protein 70 (Hsp70) acts as a cellular defense mechanism its expression being induced under stressful conditions. Aging has been related to an impairment in this induction. However, an extended longevity has been associated with its increased expression. According to the oxidation-inflammation theory of aging, chronic oxidative stress and inflammatory stress situations (with higher levels of oxidant and inflammatory compounds and lower antioxidant and anti-inflammatory defenses) are the basis of the age-related alterations of body cells. Since oxidation and inflammation are interlinked processes, and Hsp70 has been shown to confer protection against the harmful effects of oxidative stress as well as modulating the inflammatory status, it could play a role as a regulator of the rate of aging.

Mapping the Genes that Increase Lifespan

Following an exhaustive, ten-year effort, scientists have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. "This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is. It also sets up a framework to define the entire network that influences aging in this organism." Researchers began the painstaking process by examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing. "We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides. We had several microscopes running all the time."

These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control. "Calorie restriction has been known to extend lifespan for a long time. The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes."

A Role for LAP2α in Progeria
Permalink | View Comments (0) | Post Comment | | Posted by Reason

It remains an open question as to the degree to which the mechanisms that cause progeria are relevant in normal aging. They are present at very low levels in old people, a very different picture from the upheaval and dysfunction taking place in the cells of progeria patients. Are those low levels meaningful over the course of a normal human life span, and in comparison to the known causes of degenerative aging? Time will tell, but it can't hurt to keep an eye on progress in progeria research, which seems to be on the verge of a more effective class of therapies:

Though researchers identified the abnormal protein behind progeria - progerin - the exact way in which it causes the accelerated aging remains elusive. Progerin, a protein present in very high concentration in progeria cells, is known to be responsible for many of the characteristics of the disease. It is a mutant version of lamin A, a protein crucial for the stability of the nucleus and involved in many essential nuclear functions. "A few years ago, we and others found that progeria cells have much less LAP2α than normal cells. LAP2α is a protein that interacts with lamin A to regulate cell proliferation, the process that produces new cells. Interestingly, LAP2α levels also decrease during normal aging. The cells that produce progerin had really low LAP2α levels compared to normal cells. But when we re-introduced LAP2α we could completely rescue the proliferation defect of the progeria cell line. The same actually happened in cells from patient samples."

Further experiments revealed a real surprise: LAP2α functions very differently in progeria cells compared to normal cells. Usually it binds to a distinct nuclear pool of lamin A and slows proliferation, so low LAP2α levels result in hyperproliferation. But in progeria the opposite is the case, cells proliferate much slower and prematurely enter the cellular aging process. The reason for this is that progeria cells do not have the nuclear lamin A pool. This hinted that LAP2α uses a different route to exercise its function in progeria cells. In the end, data from previous experiments gave the researchers the clue to solve the puzzle. "Cells are surrounded by material that structurally supports them. It is called extracellular matrix or in short ECM. It was reported before that progerin negatively affects the production of ECM proteins, leading to a disrupted cellular environment and slower proliferation. Now we connected this to the low LAP2α levels and when we reintroduced LAP2α into progeria cells they again produced normal ECM and proliferated normally and didn't enter the cellular aging process."

The study's insights why and how progerin impairs the production of ECM proteins and normal proliferation opens new avenues towards the development of more specific therapeutic strategies for the treatment of progeria. As the premature aging disease resembles in many aspects normal aging, the results also allow drawing conclusions on the cellular processes during normal aging.

Link: http://www.meduniwien.ac.at/homepage/1/news-and-topstories/?tx_ttnews[tt_news]=6044

Eliminating Rejuvenation in Cellular Reprogramming
Permalink | View Comments (0) | Post Comment | | Posted by Reason

Researchers here demonstrate a method of generating reprogrammed cell lines from old patients that retain the age-related changes and damage in the cells, a useful tool for further research. The technique of induced pluripotency has in recent years been used to generate cells of arbitrary specific types from, for example, a patient skin cell sample: the skin cells are reprogrammed to be pluripotent, and then differentiated into the desired cell type. Reprogramming to pluripotency has been shown to rejuvenate some of the aspects of old cell lineages, such as by clearing out damaged mitochondria, and removing age-related epigenetic markers, possibly reflecting other forms of repair. This may be related to the early stage of embryonic development in which age-related damage is abruptly repaired, the cells reset to a youthful state. This is all very interesting to some factions of the research community, but frustrating for those scientists who are trying to build patient-matched models of old tissue to better understand what is going wrong in age-related diseases.

For the first time, scientists can use skin samples from older patients to create brain cells without rolling back the youthfulness clock in the cells first. The new technique, which yields cells resembling those found in older people's brains, will be a boon to scientists studying age-related diseases like Alzheimer's and Parkinson's. "This lets us keep age-related signatures in the cells so that we can more easily study the effects of aging on the brain. By using this powerful approach, we can begin to answer many questions about the physiology and molecular machinery of human nerve cells - not just around healthy aging but pathological aging as well."

Over the past few years, researchers have increasingly turned to stem cells to study various diseases in humans. For example, scientists can take patients' skin cells and turn them into induced pluripotent stem cells, which have the ability to become any cell in the body. From there, researchers can prompt the stem cells to turn into brain cells for further study. But this process - even when taking skin cells from an older human - doesn't guarantee stem cells with 'older' properties. "As researchers started using these cells more, it became clear that during the process of reprogramming to create stem cells the cell was also rejuvenated in other ways."

Researchers decided to try another approach, turning to an even newer technique that lets them directly convert skin cells to neurons, creating what's called an induced neuron without passing through a pluripotent state. They collected skin cells from 19 people, aged from birth to 89, and prompted them to turn into brain cells using both the induced pluripotent stem cell technique and the direct conversion approach. Then, they compared the patterns of gene expression in the resulting neurons with cells taken from autopsied brains. When the induced pluripotent stem cell method was used, as expected, the patterns in the neurons were indistinguishable between young and old derived samples. But brain cells that had been created using the direct conversion technique had different patterns of gene expression depending on whether they were created from young donors or older adults. For instance, levels of a nuclear pore protein called RanBP17 - whose decline is linked to nuclear transport defects that play a role in neurodegenerative diseases - were lower in the neurons derived from older patients.

Link: http://www.salk.edu/news/pressrelease_details.php?press_id=2119

The Arcane
Permalink | View Comments (2) | Post Comment | | Posted by Reason

Here I am going to ramble a little about patterns of human behavior. "Arcane" is one of those words sorely abused by generations of people involved in the most fanciful of modern pastimes, which is to say the creation of alternative magical and religious beliefs and practices, both in earnest and for fun. As a consequence it has gathered a broad wake of connotations and cultural baggage. Cut all that away and it has an unbiased, simple, and straightforward meaning, however. To be arcane is to be obscure, to be hidden, to be known only to a few.

We humans have evolved a strong urge to pattern recognition. It is a key part of our intelligence as it applies to the business of surviving the rigors of natural selection. Clearly the benefits of identifying and acting on real patterns far outweighed the disadvantages of incorrectly seeing patterns that are not real. How else to explain magical thinking, the tendency for people to fit everything they observe into simple models of cause and effect regardless of accuracy, and then search for the truth later, if at all? The world about us is so very complex that there will always be things that any given group of people cannot understand or model accurately with the resources at their disposal, but put in that situation they will build the models anyway, because that is more comfortable than acknowledging ignorance. So we have religion, magical traditions, the ridiculous marketing that emerges from the snakeoil "anti-aging" marketplace, and generations of people attaching extra saddlebags of meaning to workhorse words such as "arcane," "esoteric," and the like.

Every present culture has very deep roots, stretching back at least centuries into eras in which it was universally accepted that an arcane world lies underneath the mundane, steering it, providing the rules that make sense of what seems senseless. In search of patterns, any patterns, people looked for guidance to whomever was bold enough to claim to see into the arcane world, and since we are a hierarchical species, like our fellow primates, that form of leadership was institutionalized into power structures very early on. Thus we have a history of shamans, priesthoods, temples, the Hero's Journey, and the endless, ever more baroque theology that commenced as soon as things advanced to the point of fighting with words and concepts rather than weapons. All of that lies underneath the thin veneer of modernism, a bone mountain, the legacy of the dead.

Now, here is an interesting thing about modern science and technology: its complexity and importance has in effect created a real arcane world that lies alongside the mundane, steering its future, determining who will live and who will die, what changes and what persists, how the rules of everyday life will differ tomorrow. The present state of technology is the greatest determinant of how we live our mundane lives, and technological progress is the greatest determinant of what tomorrow will bring. Yet few people choose to undertake the work needed to peer from their daily grind into the arcana of technology, even in this age of enormously rapid change, in which the formative lives of each new generation are appreciably different from those of their parents.

Medicine and medical research, especially into aging, shape the rules that will determine the portents for the rest of our lives. How long will we live, will we suffer, what must we do to have the best odds of success? Two thousand years ago people went to priests and burned offerings. A thousand years ago they petitioned physicians who had more in common with priests than with today's practitioners. Today they go clinics and understand about as much of the underpinnings of what they are told to do, for all that it is a lot more effective. The behaviors and organizations laid down to deal with the imaginary arcana of mysticism and religion continue for the real arcana of technology. Very few people go beyond talking to researchers to lift the veil and seek to understand why medicine is the way it is, why the answers to their questions are what they are. They accept the patterns that are explained in shorthand, and are comforted by them, right or wrong. That the patterns offered are better and more effective because of the changing tides of the arcane world of medical research is almost beside the point.

It is always too easy to castigate, however. We who do look further, who place ourselves with a foot in the arcane and a foot in the mundane, drifting from day to day activities on the one hand to presenting the logical outcome of human agelessness resulting from effectively treating aging as a medical condition on the other - we can forget just how distantly removed from all this we once were, or how much of an accident it is that we are where we are today. Ponder just how little thought you gave to medicine and where it came from when you were young, immersed in the mundane: back when you thought aging was set in stone, and the sum of the world was school, shopping, relationships, the changing of the seasons, a job, a hobby. The sum of an unremarkable, unique life. That is most people, unaware of what actually sways their futures.

All of this is why you see similar patterns of human organization at the high level emerging at the boundary of medical science and the world at large as at the boundary of organized religion and the world at large. The data is vastly different, and the importance vastly different. But the same underlying incentives and facets of human nature are at work, driving the small decisions that snowball into organizations and initiatives. For preference I'd like to see this change. The arcane world of medical research, and particularly that related to ending frailty and disease in aging, cannot continue to be as arcane as it is today if we are to see the growth we need in funding and support. The scale of applied resources and pace of progress that is justified by the grand panoply of suffering caused by disease and aging is hard to sustain when no-one thinks about medicine until they are sick. Research and development of new therapies is slow, and leaving education and support for that process until it is needed is leaving it far too late to make a difference.

If we could just bootstrap medicine to much the same position in the public eye as the automobile or the personal computer, where there is some breakdown of the veil between the arcane world of progress and development and the mundane world of use, even that would be a great gain. Unfortunately doing this is an uphill battle against our own evolutionary history and evolved preferences: threatened by complexity, and worse, by the time needed to make a dent in that complexity, most people retreat and direct their limited attention elsewhere. It is a hard sell to persuade anyone to outlay their precious time to understand something that will be important a decade or two from now. In effect those of us closer to the inside of the veil of the arcane for medical research are something like reverse Cassandras: knowing that wondrous, golden futures lie ahead, if only people will listen, understand, and help. More are taking notice with each passing year, but it still far more slowly than they might. Changing the world is not easy.

AC5 Knockout in Mice Increases Exercise Performance as Well as Extending Life
Permalink | View Comments (0) | Post Comment | | Posted by Reason

Here I'll point out some of the latest work on adenylate cyclase 5 (AC5), a longevity gene in mammals, which is now shown to boost exercise performance as well as longevity in mice. It is an open question as to the degree to which the longevity effects are secondary to the exercise effects. The authors of this paper note that there has been little study of exercise effects for most of the other methods of enhancing longevity in laboratory mice, which is an interesting oversight. Perhaps this will change with a growing interest in the development of exercise mimetic drugs.

Disruption of AC5, such as through gene knockout, is one of the many methods shown to modestly slow aging and extend healthy life in mice. As for all of these approaches, much work is yet needed to understand exactly how it works under the hood. The present high level understanding of single gene longevity enhancements in laboratory animals varies from sketchy theory to fairly robust outline, and getting any further than that is proving to be a slow, expensive, and time-consuming business. Every mechanism influences every other mechanism inside a cell, nothing happens in isolation, and so understanding any one life-extending genetic alteration blurs at the edges into the much, much larger project of understanding the enormous complexity of cellular biochemistry as a whole.

The major finding of this investigation is that disruption of AC5, which actually decreases sympathetic tone, increases exercise performance. This is novel, as the most common mechanism mediating enhanced exercise is via increased sympathetic stimulation and catecholamines, resulting in increased AC activity and augmented cardiac output. This was not the mechanism in AC5 knockout mice, where AC activity is actually reduced, and there was no greater increase in cardiac output during exercise compared with WT mice, based on direct measurements of ascending aortic blood flow with implanted ultrasonic flow probes and heart rate in chronically instrumented mice. Further confirming the lack of a cardiac mechanism, the cardiac-specific AC5 knockout did not exhibit enhanced exercise. Accordingly, the mechanism resided at the level of the exercising skeletal muscles, which was confirmed, when we found that exercise performance was also elevated in the skeletal muscle-specific AC5 knockout.

Another key finding of the current investigation was demonstrating that protection against oxidative stress, by increased MnSOD levels and activity in AC5-deficient skeletal muscles, is also involved in the mechanism of enhanced exercise capacity in AC5 knockout mice, as exercise capacity of AC5 knockout mice was significantly attenuated in AC5 knockout / MnSOD heterozygous knockout bigenic mice. One question that arose is whether these effects of enhanced exercise in AC5 KO mice are simply due to a decrease in AC, which might be evoked in a knockout from any of the 9 AC isoforms, or are they due to unique signaling in AC5. To address this question, we examined exercise in 10 AC6 KO mice and 7 wild type controls. The AC6 KO mice did not show increased distance or speed with exercise compared to their wild type. Therefore, the enhanced exercise was not simply due to a reduction in AC, but was rather unique to the AC5 KO and its signaling pathway noted above.

Exercise plays an essential role in longevity, in general, and healthful aging, in particular, as it protects not only against obesity, diabetes, and cardiovascular disease, but also reduces the risk of cancer and improves bone health and even mental diseases that impair aging. Therefore, the demonstration of improved exercise performance in the AC5 knockout model is particularly germane, as this is also a model for longevity, and protects against cardiovascular stress, diabetes, and obesity. In view of the important link between exercise and longevity, it is surprising that of 20 mouse models we reviewed, only two studied exercise and found it to be increased.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12401/

Lab-Grown Intestinal Tissue Regenerates Gut Lining in Dogs
Permalink | View Comments (0) | Post Comment | | Posted by Reason

Over the last five years considerable progress has been made in the tissue engineering of intestines. Researchers have created sections of intestine, grown intestine organoids, and regenerated damage to intestines in laboratory animals. Here is the latest example:

Working with gut stem cells from humans and mice, scientists have successfully grown healthy intestine atop a 3-D scaffold made of a substance used in surgical sutures. The tube-shaped scaffold was a big first step on the quest to develop an implantable replacement intestine. But the new work pushes that effort further because it shows how stem cells, when mixed with immune and connective tissue cells, can grow into normal gut tissue around the scaffold and function inside a living mammal. Researchers caution that a fully functioning replacement intestine for humans is far off, but they say their results have laid the critical groundwork to do so. "Our experiments show that the architecture and function of our lab-made intestine strikingly resemble those of the healthy human gut, giving us real hope that our model could be used as the backbone for replacement intestine."

In an initial set of experiments researchers took stem cells from the colons of babies undergoing intestinal surgeries and from mice, then added immune cells called macrophages, the body's scavengers that seek out and engulf debris along with foreign and diseased cells. To this mix, they added cells called fibroblasts, whose function is to form collagen and other connective substances that bind tissues and organs together. The idea, the scientists say, was to create a mixture that closely mimics the natural composition of the gut. In another set of experiments, researchers added probiotic bacteria to the newly created intestinal tissue. Doing so further amplified the growth and differentiation of new gut cells, specifically the growth of Paneth cells responsible for production of infection-fighting proteins that guard against intestinal infections.

Next, researchers implanted the newly created intestine into the bellies of mice. In a matter of days, the implanted intestine began producing new intestinal stem cells and stimulated the growth of new blood vessels around the implant. That observation, researchers say, affirmed the ability of the 3-D intestine to spur the growth of new tissue not only in lab dishes, but also in living organisms. In a final step, the investigators implanted pieces of the newly created intestine - about 1.6 inches in length - into the lower portion of dog colons lacking parts of their intestinal lining. For two months, the dogs underwent periodic colonoscopies and intestinal biopsies. Strikingly, the guts of dogs with implanted intestines healed completely within eight weeks. By contrast, dogs that didn't get intestinal implants experienced continued inflammation and scarring of their guts.

Link: http://www.hopkinsmedicine.org/news/media/releases/lab_grown_3_d_intestine_regenerates_gut_lining_in_dogs

A View of the Importance of Neurogenesis
Permalink | View Comments (3) | Post Comment | | Posted by Reason

Neurogenesis is name given to the creation of new neurons in the central nervous system, and particularly the brain. Only within the last thirty years, quite recently in the grand scheme of things, have researchers proved that neurogenesis occurs at a low level in adults, that the brain is not a fixed set of long-lived and non-dividing cells, but is augmented with new arrivals on an ongoing basis. Once verified, this became a topic of considerable interest for the growing fields of regenerative medicine and stem cell research. Can the rate of neurogenesis be safely increased, and will this produce benefits for patients suffering neurodegenerative conditions, or postpone the onset of such conditions? Can investigation of neurogenesis be used to guide improvements in first generation stem cell therapies based on transplanted cells?

With more research into the biology of the brain, aided by the rapid improvement in the tools of biotechnology since the 1990s, there is an increased realization of the importance of adult neurogenesis. Few evolved processes exist without serving multiple ends, and this one is no exception in that regard. More than a mere repair and replacement mechanism, neurogenesis in adults is necessary to the correct functioning of the brain. Couple that to the discovery that rates of neurogenesis decline with age, and the processes of slow growth and change in the brain become ever more attractive as an area of medical research. It is worth noting that some of the recent work emerging from parabiosis studies, in which alterations are made to levels of some of the molecular signals in the circulatory system, have shown preliminary signs of being able to reduce the age-related decline in neurogenesis.

The article linked below is a good read, and goes some way to providing the high-level context and background to explain why research into neurogenesis is so important to those parts of the life science community focused on aging, age-related diseases of the brain, neurobiology, and regenerative medicine. Clearly there is a lot more to be done before an initial set of therapies emerge via the traditional drug development approach, and those therapies will likely be pretty marginal at the outset if history is any guide, but it is an interesting field to watch.

Brain Gain: Young Neurons in the Adult Human Brain are Likely Critical to its Function

At a lab meeting in the mid-1990s a neuroscientist told his team that he wanted to determine whether new neurons are produced in the brains of adult humans. At the time, adult neurogenesis was well established in rodents, and there had been hints that primate brains also spawned new neurons later in life. But reports of neurogenesis in the adult human brain were sparse and had not been replicated. Soon enough, a clear picture emerged: the human hippocampus, a brain area critical to learning and memory and often the first region damaged in Alzheimer's patients, showed evidence of adult neurogenesis. In November 1998, the group published its findings. "When it came out, it caught the fancy of the public as well as the scientific community. It had a big impact, because it really confirmed neurogenesis occurs in humans."

Fifteen years later, in 2013, the field got its second (and only other) documentation of new neurons being born in the adult human hippocampus - and this time learned that neurogenesis may continue for most of one's life. Neuroscientistists took advantage of nuclear bomb tests carried out during the Cold War. Atmospheric levels of carbon-14 have been declining at a known rate since such testing was banned in 1963, and researchers were able to date the birth of neurons in the brains of deceased patients by measuring the amount of carbon-14 in the cells' DNA.

In the late 1990s and early 2000s, researchers delved into the cell biology of neurogenesis, characterizing the populations of stem cells that give rise to the new neurons and the factors that dictate the differentiation of the cells. They also documented significant differences in the behavior of young and old neurons in the rodent brain. Most notably, young neurons are a lot more active than the cells of established hippocampal networks, which are largely inhibited. "For a period of about four or five weeks, while the newborn neurons are maturing, they're hyperexcitable. They'll fire at anything, because they're young, they're uninhibited, and they're integrating into the circuit."

To determine the functional role of the new, hyperactive neurons, researchers began inhibiting or promoting adult neurogenesis in rodents by various means, then testing the animals' performance in various cognitive tasks. What they found was fairly consistent: the young neurons seemed to play a role in processing new stimuli and in distinguishing them from prior experiences. This type of assessment is called pattern separation. While some researchers quibble over the term, which is borrowed from computational neuroscience, most who study hippocampal neurogenesis agree that this is a primary role of new neurons in the adult brain. The basic idea is that, because young neurons are hyperexcitable and are still establishing their connectivity, they are amenable to incorporating information about the environment. If a mouse is placed in a new cage when young neurons are still growing and making connections, they may link up with the networks that encode a memory of the environment.

While studying the function of hippocampal neurogenesis in adult humans is logistically much more difficult than studying young neurons in mice, there is reason to believe that much of the rodent work may also apply to people - namely, that adult neurogenesis plays some role in learning and memory. "Given that the dentate gyrus is so highly conserved and that the mechanisms of its function are so similar between the species - and given that neurogenesis is there in humans - I would predict that the general principle is the same." And if it's true that hippocampal neurogenesis does contribute to aspects of learning involved in the contextualization of new information - an ability that is often impaired among people with neurodegenerative diseases - it's natural to wonder whether promoting neurogenesis could affect the course of Alzheimer's disease or other human brain disorders. Epidemiological studies have shown that people who lead an active life - known from animal models to increase neurogenesis - are at a reduced risk of developing dementia, and several studies have found reduced hippocampal neurogenesis in mouse models of Alzheimer's. But researchers have yet to definitively prove whether neurogenesis, or lack thereof, plays a direct role in neurodegenerative disease progression.

Of course, the big question is whether researchers might one day be able to harness neurogenesis in a therapeutic capacity. Some scientists say yes. "I think the field is moving toward that. Neurogenesis is not something de novo that we don't have at all - that would be much harder. Here, we know it happens; we just need to enhance it."

Study Suggests More Moderate Exercise is Better
Permalink | View Comments (2) | Post Comment | | Posted by Reason

Researchers here crunch the numbers to suggest that people who exercise for longer are better off in terms of risk of suffering age-related cardiovascular disease. One of the emerging themes in epidemiology in recent years is an attempt to pin down the dose-response curve for exercise. How is long term health and life expectancy affected for different levels of exercise, and do these differences reflect correlation or causation? Is it a matter of people obtaining health benefits through exercise or a matter of more healthy people tending to exercise more? These are hard questions to answer for human populations, but as technology lowers the cost of obtaining and using large data sets, ever more research groups are taking a stab at it. As with all such statistical studies, it is wise to wait for more data and the work of different teams before taking anything published by one group at face value, however:

Doubling or quadrupling the minimum federally recommended levels of physical activity lowered the risk of developing heart failure by 20 percent and 35 percent, respectively, according to researchers. "Walking 30 minutes a day as recommended in the U.S. physical activity guidelines, may not be good enough - significantly more physical activity may be necessary to reduce the risk of heart failure." The researchers found that the current U.S. physical activity guidelines recommendation of a minimum of at least 150 minutes of moderate intensity physical activity a week was associated with only a modest reduction in heart failure risk, and suggest that higher levels of physical activity, up to twice the minimum recommended dose, is needed to reduce the risk of heart failure.

They also found a "dose-dependent" inverse association between physical activity and heart failure, that is, higher levels of physical activity were associated with a lower risk of heart failure. This relationship was consistent across all age, sex, race, and geographic location based subgroups studied. Although the role of physical activity in coronary heart disease - the narrowing of the arteries that causes heart attacks - has been comprehensively studied, this study focused exclusively on the quantitative relationship between the amount, or specific "dose" of regular physical activity and the risk of heart failure.

The researchers pooled data from 12 studies from United States and Europe that collectively included 370,460 individuals with varying levels of physical activity at baseline and 20,203 heart failure events over a mean follow-up of 15 years. Physical activity was measured by self-reported levels of activity by study participants using standard questionnaires. "Future physical activity guidelines should take these findings into consideration, and potentially provide stronger recommendations regarding the value of higher amounts of physical activity for the prevention of heart failure."

Link: http://blog.heart.org/physical-activity-more-is-better-for-heart-failure-prevention/

CRISPR Gene Editing and Xenotransplantation
Permalink | View Comments (2) | Post Comment | | Posted by Reason

The present best approach to enabling xenotransplantation of pig organs into human patients is decellularization: strip all the cells and repopulate the extracellular matrix scaffold of the organ with human cells. However, with the existence of cheap and efficient genetic alteration based on CRISPR it may be possible to edit all of the genes in pig cells that produce problem proteins instead of replacing these cells. My first thought on this is that decellularization is still a better option; after any reasonable number of genetic edits on pig cells the result remains an organ built out of edited pig cells, not human cells, and not matched to the patient. Still, this is an interesting demonstration of the cost-effectiveness of CRISPR, making genetic alterations in much larger batches than have been achieved to date:

For decades, scientists and doctors have dreamed of creating a steady supply of human organs for transplantation by growing them in pigs. But concerns about rejection by the human immune system and infection by viruses embedded in the pig genome have stymied research. By modifying more than 60 genes from pig embryos - ten times more than have been edited in any other animal - researchers believe they may have produced a suitable non-human organ donor.

The researchers used CRISPR gene-editing technology to inactivate 62 porcine endogenous retroviruses (PERVs) in pig embryos. These viruses are embedded in all pigs' genomes and cannot be treated or neutralized. It is feared that they could cause disease in human transplant recipients. They also modified more than 20 genes in a separate set of embryos, including genes encoding proteins that sit on the surface of pig cells and are known to trigger the human immune system or cause blood clotting. Eventually, pigs intended for organ transplants will have both these modifications and the PERV deletions.

A biotech company founded to produce pigs for organ transplantation, eGenesis in Boston, is now trying to make the process as inexpensive as possible. The team released few details about how they managed to remove so many pig genes. But both sets of edited pig embryos are almost ready to implant into mother pigs. eGenesis has procured a facility at Harvard Medical School where the pigs will be implanted and raised in isolation from pathogens.

Link: http://www.nature.com/news/gene-editing-record-smashed-in-pigs-1.18525