Fight Aging!

Later this year I will be running a SENS research charitable fundraiser in collaboration with various allies in the community. At this time I am in search of a few good people and organizations to stand with me and others in assembling a matching fund to raise additional donations from the grassroots supporters of longevity science.

I am far from the only person to recognize that the Strategies for Engineered Negligible Senescence (SENS) is perhaps the most important early-stage research program in medicine today. SENS is so far the only coherent, well-planned vision for producing rejuvenation treatments that has managed to establish traction and growth in the research community, while gaining the support of noted researchers and philanthropists. The SENS Research Foundation exists to shepherd this research, and is the hub of an enthusiastic network of supporters and scientists.

We are Responsible for Creating Progress

If we want to see real progress towards an end to age-related disease in our lifetimes, and years from now benefit from treatments that reverse the degeneration and frailty of old age, then we must put our support behind SENS. In the world of research funding, all of the most novel and promising science is funded in its early years by philanthropy, by people of vision and modest means who step up by their thousands to show that they understand what it means to change the world one step at a time.

Who are those people? That would be us. The big organizations and high net worth folk with big checkbooks never show up until later, years after they would have been most useful, and they only turn up because they see that people like us are making noise and changing the world. Ultimately, we are responsible for seeding the future that we wish to see, guiding later large-scale investments by the light we shine on the best path forward.

Help Us to Create a Matching Fund for 2014

As always I only ask no more than I can do myself: I will be putting $15,000 on the table, and each of the other members of the matching fund will be doing the same. This year I hope to be able to do better than last year, when I, Jason Hope, and the Methuselah Foundation joined forces to raise $60,000 for rejuvenation biotechnology research.

Do you already make sizable 501(c)(3) charitable donations to the SENS Research Foundation and would like to see your efforts attract more funding? Then you should join in and help us to build this matching fund. Please do contact me if this is the case.

Do you know someone who could make a difference by joining in and can put $15,000 towards breakthrough medical science? Then ask. Do you have connections to organizations that might be interested in funding SENS research? Then think about giving me an introduction. What is the worst that can happen? There are far more terrible things in this world of ours than gaining a reputation as an advocate who sometimes asks people to fund progress in medical science.

The thymus is a gateway for the production of new T cells, the immune cells responsible for destroying pathogens and precancerous or senescent cells. The thymus is highly active in childhood, churning out a large supply of these immune cells as it builds up and supports the immune system. But upon adulthood the thymus atrophies quickly, reducing that supply to a trickle, and effectively imposing a cap on the number of T cells present in the body at any one time. Unfortunately the evolved mechanisms of the immune system, while very effective in the destruction of most intruders, interact with the presence of persistent herpesviruses - largely cytomegalovirus - to gradually convert useful killer T cells into useless memory T cells fixated on these viruses. Over the years the immune system becomes ever more dysfunctional simply through trying to do its job.

Removing these memory T cells is one possible approach to this issue, to spur the body to generate a replacement set of fresh new cells. Another approach is to increase the supply of new cells, and there are a number of options here ranging from periodic infusions of T cells grown from a patient's own stem cells to restoring the thymus to youthful levels of activity. Here is one example of an attempt to regenerate some of the functions of the thymus:

T cell deficiency related to disease, medical treatment, or aging represents a major clinical challenge and is associated with significant morbidity and mortality in cancer and bone marrow transplantation recipients. This study describes several innovative and clinically relevant strategies to manipulate thymic function based on an interventional radiology technique for intrathymic injection of cells or drugs.

We show that intrathymic injection of multipotent hematopoietic stem/progenitor cells into irradiated syngeneic or allogeneic young or aged recipients resulted in efficient and long-lasting generation of functional donor T cells. Persistence of intrathymic donor cells was associated with intrathymic presence of cells resembling long-term hematopoietic stem cells, suggesting a self-renewal capacity of the intrathymically injected cells. Furthermore, our approach enabled the induction of long-term antigen-specific T cell-mediated anti-tumor immunity following intrathymic injection of progenitor cells harboring a transgenic T cell receptor gene.

The intrathymic injection of interleukin 7 prior to irradiation conferred radioprotection. In addition, thymopoiesis of aged mice improved with a single intrathymic administration of low-dose keratinocyte growth factor, an effect that was sustained even in the setting of radiation-induced injury. Taken together, we established a preclinical framework for the development of novel clinical protocols to establish life-long antigen-specific T cell immunity.

Link: http://dx.doi.org/10.1182/blood-2013-10-535401

Researchers have identified correlations between duration of sleep and cognitive decline with aging. There is at this point very little that can be said about mechanisms and the direction of causation, even speculatively, though the authors of this paper make an attempt at that:

Analysis of sleep and cognitive (brain function) data from 3,968 men and 4,821 women who took part in the English Longitudinal Study of Ageing (ELSA), was conducted. Respondents reported on the quality and quantity of sleep over the period of a month. In adults aged between 50 and 64 years of age, short sleep (less than 6hrs per night) and long sleep (more than 8hrs per night) were associated with lower brain function scores. By contrast, in older adults (65-89 years) lower brain function scores were only observed in long sleepers.

In this study, we did not find any significant interaction with gender. We found a significant decrease in amnestic and non-amnestic cognitive function in long sleepers, but this only reached significance in the older group. In our younger group, amnestic scores were significantly lower in short sleepers, whereas non-amnestic scores were lower in long sleepers. Our results show that an inverted U-shaped relationship exists in younger adults, where the amnestic scores for short sleepers were significantly lower than those for optimal sleepers, and whilst the amnestic scores for the long sleepers were reduced, this difference was not statistically significant. These findings could be interpreted in the context of recent findings in mice, which suggest that sleep deprivation causes irreversible damage to the brain which could impair cognitive function, particularly alertness. However, if this is the case, it is not clear why the effect of short sleep is not evident in the older group. That is, in the older adults, there was no observed effect in short sleepers but the amnestic scores in long sleepers were significantly lower than those for optimal sleepers.

In a study in men only, [previously published researcher] suggested that disturbed sleep is strongly associated with decline in executive function (or non-amnestic function), and less so for global cognition, whereas we found the opposite to be true in older adults. Indeed in our older group, the highest cognitive function scores (both amnestic and non-amnestic) were seen in those individuals with the greatest reported disturbances in sleep. In younger individuals however, there was no significant association between cognition and sleep quality, indicating that until we reach the age of around 65 years, there may be no association between sleep quality and cognitive function. The reason for these differences is unclear and prospective analyses of the effects of sleep quality on the decline in cognition could help rule out possible influences of reverse causality due to pre-existing ill-health or other confounders.

The suggestion that cognitive function increases with increasing sleep disturbance in older individuals appears to be counterintuitive. It may reflect the fact that those individuals who are more cognitively able are better at recording sleep disturbance data. Alternatively, it may indicate that in an elderly population, individuals who are more cognitively active may process the day's events and/or experience more worry or anxiety than those who are less cognitively active, and hence this may lead to an associated increase in self-reported frequency of sleep disturbance. Confounding effects of medications may also be more important in an older group. Likewise, in those participants with memory problems, we cannot exclude the possibility that their responses might have been erroneous to some extent due to their memory impairment.

Link: http://dx.doi.org/10.1371/journal.pone.0100991

The Immortality Project has been around for a couple of years, a modestly sized fund for academics that intends to make awards spanning everything from the hard life sciences to philosophy and theology. The central theme is in fact immortality, in any of its varying meanings, though it is pretty clear that the driving impulse here is religious rather than scientific. In that it is perhaps an unwelcome echo of an earlier age, something you'd expect to see undertaken by contemporaries of Isaac Newton, those with only one foot set into the Age of Enlightenment, and for all the wrong reasons.

I'm still of the mind that this project is something of a poisoned chalice. It does fund actual science, such as investigations into the biology of hydra with an eye to determining whether physical immortality exists in the natural world. There are few species such as hydra where the possibility of agelessness exists, but it isn't completely straightforward to pin that down to whether it is in fact the case or just looks a lot like it for a few years. It isn't as though you can wait for an indefinite period of time to check, and few scientists even study this question in the first place. Funding is better than no funding. But this funding comes from an organization that is about to embark on paying theologians to generate more nonsense about angels on the head of a pin, and other, similarly futile undertakings from ethicists that have absolutely nothing to do with advancing actual, concrete, actionable human knowledge. The organization will be trying to paint a picture with all of this, mixing up rigorous science with religious and secular fictions, and that certainly rubs me the wrong way.

Still, money has no provenance, and knowledge gained is knowledge gained. But I am concerned about the long-term effects of this sort of project. I noticed an article on this topic today:

Living Forever, the Right Way

But if mankind can become immortal - and, granted, that's a big "if" - what will it mean? What would a world filled with people who never age look like? Will immortality damage the environment and deepen the class divide? Is the immortal life even a life worth living?

One of the philosophers looking for answers to some of these tough questions is John Martin Fischer, a UC Riverside professor best know for his work on free will and determinism. He is leading the Immortality Project, an ambitious and first-of-its-kind endeavor fueled by a $5 million grant from the John Templeton Foundation. The project will eventually involve dozens of scientists, philosophers, and theologians.

While not yet fully scaled, the project's biological sciences component, which will look to the natural world for clues on how to extend human life, is well underway. Last June, Fischer and a panel of judges announced ten winners of the Immortality Project's $250,000 research grants (the philosophical and theological grants will be awarded this June). One winner was Dr. Daniel Martínez, a world-leading expert on the hydra, a multicellular fresh water organism. Some sub-species of hydra are capable of regenerating themselves - "almost as if they were immortal," Fischer says - while others cannot. Martínez is trying to figure out why. "He's doing this with an eye to figuring possible ways that this could apply to human longevity and possibly human immortality," Fischer says.

There is also plenty of room for innovation regarding the ethics of immortality; experts are looking at everything from examinations of near-death experiences to comparative religious ideas about the afterlife to gain a better understanding of the phenomenon. By the time the project concludes in 2015, Fischer hopes to have set the foundation for a discussion about potential criteria for ethical long-term living. Call it a life-hack for immortality - because it's one thing to live forever, and another to live forever well.

"Innovation" is not a word I'd apply to ethics, the secular theology of our times. It must be a pleasant job to be paid to make up new myths that will be used by believers to justify interference with the process of saving lives through better medicine. That said, it is way too early for anyone to be spending large sums of money agonizing over potential, not yet actual, perhaps nonexistent moral issues relating to greatly enhanced human longevity. We're all still dying here and now, today, on a short timeframe, and where are the establishment foundations spending money to address the moral aspects of that important concern? Meanwhile the medical research projects that might put a halt to aging and age-related disease in the decades ahead are very poorly funded indeed. At this time $5 million would fund a full year of SENS research and advocacy, for example.

But it isn't news that priorities are badly askew in this world of ours.

Intermittent fasting can extend life in laboratory animals and was recently demonstrated to improve immune function under at least some circumstances. There is a fair amount of research that demonstrates the benefits of fasting in conjunction with standard cancer treatments. The changes in metabolism that take place during fasting may make it a useful addition to a range of medical procedures, improving outcomes and survival rates. Here is one example of supporting evidence for this assertion:

Ischemia-reperfusion injury (IRI) is inevitable during kidney transplantation leading to oxidative stress and inflammation. We previously reported that preoperative fasting in young-lean male mice protects against IRI. Since patients are generally of older age with morbidities possibly leading to a different response to fasting, we investigated the effects of preoperative fasting on renal IRI in aged-overweight male and female mice.

Male and female F1-FVB/C57BL6-hybrid mice, average age 73 weeks weighing 47.2 grams, were randomized to preoperative ad libitum feeding or 3 days fasting, followed by renal IRI. Body weight, kidney function and survival of the animals were monitored until day 28 postoperatively. Kidney histopathology was scored for all animals and gene expression profiles after fasting were analyzed in kidneys of young and aged male mice.

Preoperative fasting significantly improved survival after renal IRI in both sexes compared with normal fed mice. Fasted groups had a better kidney function shown by lower serum urea levels after renal IRI. Histopathology showed less acute tubular necrosis and more regeneration in kidneys from fasted mice. Similar to young-lean, healthy male mice, preoperative fasting protects against renal IRI in aged-overweight mice of both genders. These findings suggest a general protective response of fasting against renal IRI regardless of age, gender, body weight and genetic background. Therefore, fasting could be a non-invasive intervention inducing increased oxidative stress resistance in older and overweight patients as well.

Link: http://dx.doi.org/10.1371/journal.pone.0100853

There is a natural range of variation in the pace of aging that is largely determined by lifestyle until later old age, at which point genetic influences become more important. Aging is a global phenomenon throughout the body: if someone ages more rapidly, it tends to be the case that every manifestation of aging is worse at any given chronological age. So when researchers find ways to measure an aspect of aging at one age, it should be expected that this measure correlates statistically with differences in future life span.

Women who are able to have children after the age of 33 have a greater chance of living longer than women who had their last child before the age of 30. "Of course this does not mean women should wait to have children at older ages in order to improve their own chances of living longer. The age at last childbirth can be a rate of aging indicator. The natural ability to have a child at an older age likely indicates that a woman's reproductive system is aging slowly, and therefore so is the rest of her body."

The study was based on analysis of data from the Long Life Family Study (LLFS) - a biopsychosocial and genetic study of 551 families with many members living to exceptionally old ages. The study investigators determined the ages at which 462 women had their last child and how old those women lived to be. The research found that women who had their last child after the age of 33 years had twice the odds of living to 95 years or older compared with women who had their last child by age 29.

The findings also indicate that women may be the driving force behind the evolution of genetic variants that slow aging and decrease risk for age-related genes, which help people live to extreme old age. "If a woman has those variants, she is able to reproduce and bear children for a longer period of time, increasing her chances of passing down those genes to the next generation." The results of this study are consistent with other findings on the relationship between maternal age at birth of last child and exceptional longevity. Previously, the New England Centenarian Study found that women who gave birth to a child after the age of 40 were four times more likely to live to 100 than women who had their last child at a younger age.

Link: http://www.eurekalert.org/pub_releases/2014-06/bumc-rli062414.php

The Methuselah Foundation is publishing a series of interviews in recent weeks related to their activities in support of the research community. The overall purpose of the Foundation is to accelerate progress towards the defeat of aging, but since spinning off the Strategies for Engineered Negligible Senescence (SENS) research initiatives into the SENS Research Foundation, the Methuselah Foundation staff have focused most of their efforts on tissue engineering, with a side-helping of numerous other projects related to aging research and biotechnology. The Foundation was one of the early investors in the bioprinting venture Organovo, for example, and has some influence behind the scenes in the regenerative medicine research community thanks to the New Organ initiative.

Here is an interview with Robert Langer, one of the luminaries of the field of tissue engineering. Some things are always true in the sciences, one being that there is never enough funding for any given research to progress at the best possible pace. There is always work for advocates and fundraisers, and the delivery of more funding can make a real difference. This is just as true in comparatively wealthy fields such as tissue engineering as it is for their poorer cousins such as biogerontology. Researchers who work on aging and longevity would be ecstatic with the level of attention and funding enjoyed by the stem cell research community, and the chance to experience resource issues at that higher level, but in the end every lab does less than its researchers would like to achieve. Most people don't value medical research in the slightest, and that fact is reflected by the vanishingly narrow slice of total economic activity that is devoted to building better treatments and healthier lives.

On Taking Risks and Thinking Big

MF: In your mind, what is the most promising work going on these days in tissue engineering?

Langer: I think there's a lot of it - everything from IPS cells to stem cells to new materials. There's a lot of very good basic and applied work going on. People are trying to understand and design bioreactors, factors that affect cell growth, new kinds of biomaterials, decellularized constructs. There are all kinds of animal and clinical trials going on. And then in each particular area, I think there's been exciting work - skin, lung, eyes, kidneys, pancreas, vocal cords, spinal cords, etc. There's just a tremendous amount of good work being done.

MF: You've founded and been involved with a lot of biotech companies. What have been the biggest challenges to success, especially in the U.S.?

Langer: The key is raising money, because it's just so incredibly expensive. I think they estimate now that it costs well over a billion dollars to create a new drug. So raising money is crucial. You also have to have mitigation strategies for things that don't work out. You don't get that many shots on goal. Doing good science and having good intellectual property are the foundation, but anything in the medical area is a very, very expensive proposition. It's not like the internet.

MF: Are you happy with the amount of funding that tissue engineering is receiving?

Langer: No, I think it needs a lot more. To me that's a huge issue.

MF: How do we change that situation?

Langer: Well, it's very hard. For example, I think what you're doing with New Organ is great, but you're doing it on the back end, and the problem is that we need more funding on the front end. Government grants are really the key, and it's very hard to get them.

MF: The philanthropic sector seems to be underfunding these areas as well, and has been for some time.

Langer: I think that's probably fair. I would agree with that.

MF: Why do you think that is? For example, when I look at the Giving Pledge signers list - 100 plus billionaires committing 50% or more of their net worth toward charity - it's hard to find many of them who are allocating funds toward tissue engineering or regenerative medicine.

Langer: I think people do things on a fairly disease-specific basis. Cancer and heart disease are still the number one killers, and people usually support things they've seen close relatives die from.

It is worth noting that Langer is very much a part of the governmental medical research edifice, and thus this is where his biases lie when thinking about large-scale strategic funding of his field. Even in the US public funds probably make up only a third or so of all research funding in the life sciences, however. Government funds are much more easily measured and thus much more frequently discussed by the media than is the case for private for-profit and philanthropic funding efforts, but they are not the whole story.

From what I've seen over the years if you want to see radical change in research, it will always come from philanthropy. Even those programs viewed as being largely governmental receive a great deal of support from philanthropists, who donate to fill the gaps where more adventurous work must be undertaken. The controlling institutions of public funding for medical research are very, very risk averse and resources are usually only available for the most incremental and certain late stages of the research process. All of the early, more speculative work is funded by other sources.

I suspect that we'll see spreading use of immune cell transfer therapies in the years ahead. The time is right for it: stem cell researchers are continually improving their ability to generate cells to order, knowledge of how the immune system works in detail is growing, and so is the understanding of just how important immune system decline is in aging. Somewhere between today and a future in which an age-damaged immune system can be completely restored to youthful function lies a span of decades in which regular infusions of tailored immune cells are a routine part of older life, a treatment that temporarily enhances immune system function across the board, or which can be used to attack specific targets such as an infection or a cancer.

For this to come to pass the infrastructure for such therapies must improve, becoming more efficient, more reliable, and much less costly than is presently the case. This is happening now, step by step, such the progress cited in this article. It is aimed at use for transplant patients, but should be relevant to a range of similar future applications:

Therapeutic transfer of virus-specific T cells to immunocompromised patients can help battle life-threatening infections, but the process for generating such cells is lengthy and laborious. A [recently published] paper suggests a speedy alternative. Ten days in culture was all it took for researchers to generate multivirus-specific T cells that, when transferred into transplant patients, could wipe out multiple infections at once. "The original manufacturing processes were really convoluted and complicated." They involved using live viruses to infect donor B cells, and then using those cells to stimulate T cells. "With all that, we are talking 10 to 12 weeks of manufacturing." Furthermore, the live viruses in question are considered biohazards. When a procedure is that difficult and hazardous, "it's never going to go beyond specialized academic centers."

[The researchers] streamlined the process, bypassing the live virus and B cell steps, and instead stimulating the T cells directly with peptides. A similar technique has been used previously to generate T cells specific for fighting cytomegalovirus. But the new method extends the concept, using a mix of peptides that together cover the antigenic proteins of five of the most common viruses to infect transplant patients.

When active T cell preparations were transferred into bone marrow transplant patients suffering viral infections the cells led, in almost all cases, to resolution of the infections. In eight patients treated, 15 of 18 total infections among the individuals were resolved, while one was reduced. Three additional patients were given the T cells prophylactically and remained infection-free for more than three months. The varying ability of the T cell preparations to tackle multiple viruses is thought to be due to the donor's prior exposure to the viruses in question. That is, if the donor has not tackled the virus before then, their blood would lack the necessary memory T cells. A future goal would be "generating such antigen-specific T cells from naive cells as opposed to people who have already got a T cell memory to the antigens."

Link: http://www.the-scientist.com/?articles.view/articleNo/40353/title/Speeding-Up-Antiviral-T-Cell-Production/

Studies show that vegetarians tend to have modestly lower mortality rates, but as for all such observations of human populations there is plenty of room to debate why this is the case. All the normal arguments can be deployed: that a vegetarian diet tends to result in a lower calorie intake and thus less excess fat tissue, that it is more often practiced by people who are more health-conscious in the first place, that it is associated with greater wealth and education, that it results in a lower intake of dietary advanced glycation end products, and so forth. But which of those factors are more important? Therein lies the question.

The development of better medical technologies in the future has the goal of making all of this sort of debate over health practices irrelevant. Rejuvenation biotechnology and other forms of new medicine should render it moot as to how you lived your life: the benefits provided to health and longevity will be enormous in comparison to those derived by living well. But we are not there yet, and there are decades yet to get past if we want to benefit from the rejuvenation treatments presently in very early development. These research press materials are an odd mix of environmentalist and health concerns, and I point it out for the latter, not the former:

The mortality rate for non-vegetarians was almost 20 percent higher than that for vegetarians and semi-vegetarians. On top of lower mortality rates, switching from non-vegetarian diets to vegetarian diets or even semi-vegetarian diets also helps reduce greenhouse gas emissions. The vegetarian diets resulted in almost a third less emissions compared to the non-vegetarian diets. Modifying the consumption of animal-based foods can therefore be a feasible and effective tool for climate change mitigation and public health improvements, the study concluded. "The takeaway message is that relatively small reductions in the consumption of animal products result in non-trivial environmental benefits and health benefits."

The study drew data from the Adventist Health Study, which is a large-scale study of the nutritional habits and practices of more than 96,000 Seventh-day Adventists throughout the United States and Canada. The study population is multi-ethnic and geographically diverse. "The study sample is heterogeneous and our data is rich. We analyzed more than 73,000 participants. The level of detail we have on food consumption and health outcomes at the individual level makes these findings unprecedented." The analysis is the first of its kind to use a large, living population, since previous studies relating dietary patterns to greenhouse gas emissions and health effects relied on simulated data or relatively small populations to find similar conclusions. "To our knowledge no studies have yet used a single non-simulated data set to independently assess the climate change mitigation potential and actual health outcomes for the same dietary patterns."

Link: http://www.sciencedaily.com/releases/2014/06/140625145536.htm

Cells are very dynamic entities. They don't sit still, and they and their components are constantly in a state of flux. A cell is a sack of things that can be listed, understood and counted, sure, but at any given moment in time numerous parts are being dismantled and new parts created from raw materials. Levels of proteins ebb and flow as they are formed and destroyed.

All of this dynamism places an interesting spin on attempts to understand and then repair aspects of aging that depend on malfunctioning cellular components. Within cells there exist a range of important structures called organelles, some of which number in the hundreds or thousands, such as mitochondria. These are themselves very dynamic entities, busy with the process of dividing, fusing, and exchanging proteins between one another. Damage in mitochondria is not a static thing, as those damaged proteins can be shared around, and damaged and undamaged mitochondria can fuse to create an organelle that works. The only forms of damage that can last are those that provide some survival advantage to a mitochondrion, such as the ability to evade cellular quality control mechanisms, or wherein the particular form of damage can overwhelm undamaged variants.

Most interesting of all cells can even pass around mitochondria, which is a great way for potentially harmful forms of persistent or replicating damage to spread and thus have a greater detrimental effect than would otherwise be the case. The present view of mitochondria in aging is that there are indeed forms of damage to mitochondrial DNA that cause dysfunction in mitochondrial function that is both harmful and leads to the spread of damaged mitochondria because they evade quality control mechanisms. Thus the damaged forms can divide and multiply to take over a cell - and if exported elsewhere they will take over that cell as well. This doesn't actually appear to happen to more than a small fraction of cells over a human life span, but that small fraction is enough to cause great harm to tissues, blood vessels, and more.

The research linked below is another reminder that mitochondrial biochemistry is complicated, delving further into how mitochondrial pass around between cells. In this case it definitely looks like a vector by which bad mitochondria of the sort we care about could spread more than they otherwise would. Any approach to repairing mitochondria in aged tissue must thus be sufficiently comprehensive to ensure that all these tricks have no effect: it cannot matter how dynamic or widely traveled a mitochondrion is, the treatment must either repair it along with all of its peers or destroy it, leaving none of the damage behind to spread once more.

Getting Rid of Old Mitochondria

It's broadly assumed that cells degrade and recycle their own old or damaged organelles, but [researchers] have discovered that some neurons transfer unwanted mitochondria - the tiny power plants inside cells - to supporting glial cells called astrocytes for disposal. The [findings] suggest some basic biology may need revising, but they also have potential implications for improving the understanding and treatment of many neurodegenerative and metabolic disorders.

"It does call into question the conventional assumption that cells necessarily degrade their own organelles. We don't yet know how generalized this process is throughout the brain, but our work suggests it's probably widespread. The discovery of a standard process for transfer of trash from neuron to glia will most likely be very important to understanding age-related declines in function of the brain and neurodegenerative or metabolic disorders. We expect the impact to be significant in other areas of biomedicine as well."

Transcellular degradation of axonal mitochondria

Mitochondria are organelles that perform many essential functions, including providing the energy to cells. Cells remove damaged mitochondria through a process called mitophagy. Mitophagy is considered a subset of a process called autophagy, by which damaged organelles are enwrapped and delivered to lysosomes for degradation. Implicit in the categorization of mitophagy as a subset of autophagy, which means "self-eating," is the assumption that a cell degrades its own mitochondria. However, we show here that in a location called the optic nerve head, large numbers of mitochondria are shed from neurons to be degraded by the lysosomes of adjoining glial cells. This finding calls into question the assumption that a cell necessarily degrades its own organelles.

There is a wealth of evidence to show that benefits to health and longevity result from increased levels of autophagy in various species. Autophagy refers to processes of cellular housekeeping that remove damaged components, and which have been found to operate with greater enthusiasm as a result of a range of different interventions in laboratory animals that increase life span and slow the progression of aging. Indeed, some researchers believe that increased autophagy is an important contribution to all of these longevity-enhancing approaches.

Given this it is surprising to see so little effort going towards drug discovery with safely increased autophagy as the primary target. As is usually the case, where drug discovery is undertaken, efforts are first focused on repurposing existing drugs that are already approved, even if the effects are marginal. This is because it costs much less to try to obtain regulatory approval for a new use of an existing drug than to push through a completely new medical technology - one of the many ways in which medical regulation distorts the research process in the direction of deliberately aiming for inferior results and slower progress towards new knowledge.

Aging has been defined as a gradually decreasing ability to maintain homeostasis and increasing risk to die. Growing evidence supports malfunctioning with age of quality control system. At an older age, accumulation of altered macromolecules and membranes may impair cell functioning; accumulation of altered mitochondria and peroxisomes may boost the yield of ROS per unit of produced energy and accelerate the aging process.

Evidence was produced that autophagy, an essential part in cell housekeeping during fasting, may help removal of altered membranes, mitochondria and peroxisomes selectively and account for the antiaging effects of caloric restriction. Stimulation of autophagy may improve innate and adaptive immunity; decrease the risk of myopathy, heart disease, liver disease, neurodegeneration and cancer; and retard aging. Functioning of autophagy may decline in well fed adults and is almost negligible at older age. Induction of autophagy may result in "cleaner cells" lower in oxidative status and more resistant to injury and disease.

The administration of antilipolytic drugs to fasted animals was shown to intensify autophagy in a physiologically appropriate manner, to enhance submaximal antiaging effects of low level of caloric restriction, to rapidly rescue older cells from the accumulation of altered mtDNA and older peroxisomes, to increase urinary 8-OHdG levels, and counteract the age-related hypercholesterolemia in rodents. In conclusion, benefits of long-lasting stimulation of autophagy and protein and organelle turnover shows that antilipolytic drugs might find a novel therapeutic application in antiaging medicine.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24958217

Why build a completely new method of removing unwanted proteins or destroying unwanted cells, when a system capable of these tasks already exists in the body? That is the idea behind the many different forms of immune therapy, technology platforms that will come to be commonplace in medicine over the next few decades. Here is an open access review of the recent past and near future approaches to enlisting a patient's immune system to treat Alzheimer's disease:

Vaccination has been an instrument in the tool chest of the clinician since the late 18th century when Edward Jenner first used the related cowpox virus to immunize patients against small pox. The basic concept of active immunization is to prime the immune system to recognize an antigen as a foreign protein in order to mount a response against it. It has only been recently that investigators have attempted to utilize the human immune system to rid the body of potentially harmful or toxic proteins that are endogenously produced.

Alzheimer's disease (AD) is an incurable, progressive, neurodegenerative disorder affecting over 5 million people in the US alone. This neurological disorder is characterized by widespread neurodegeneration throughout the association cortex and limbic system caused by deposition of Aβ resulting in the formation of plaques and tau resulting in the formation of neurofibrillary tangles. Active immunization for Aβ showed promise in animal models of AD; however, the models were unable to predict the off-target immune effects in human patients. A few patients in the initial trial suffered cerebral meningoencephalitis.

Recently, passive immunization has shown promise in the lab with less chance of off-target immune effects. Several trials have attempted using passive immunization for Aβ, but again, positive end points have been elusive. The next generation of immunotherapy for AD may involve the marriage of anti-Aβ antibodies with technology aimed at improving transport across the blood-brain barrier (BBB). Receptor mediated transport of antibodies may increase central nervous system exposure and improve the therapeutic index in the clinic.

Link: http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00114/full

The American Federation for Aging Research (AFAR) has been around for a while, and best represents the gently-gently approach to moving forward towards greater human longevity. They speak to an audience of researchers who are largely disinterested in working to extend healthy life, an attitude typical of the silent majority in the field, with an eye to moving more of them into the so far smaller category of researchers who support and actively engage in efforts to modestly extend life. This sort of work is typified by initiatives aimed at the development of age-slowing drugs, such as calorie restriction mimetics or compounds that influence mTOR.

From my point of view this approach to longevity science is a slow boat to nowhere, highly unlikely to produce any end result of great utility to old people: slowing aging just a little bit is of very limited use when you are already old. Folk such as myself who support progress towards SENS-like rejuvenation treatments based on repair of the underlying causes of aging have to remember that we are still the upstart minority, however. Despite tremendous growth in support for SENS inside and outside the scientific community over the past decade, it is still the case that work on drug development to slightly slow aging through altering the operation of metabolism receives far, far more funding and attention. In turn work on merely studying aging, with no attempt or interest in doing anything to treat aging as a medical condition, receives yet again far greater funding and attention than does drug development aimed at modestly slowing aging. The times are changing, but this is the present picture.

In the charitable viewpoint, organizations such as AFAR are putting a great deal of effort into raising the waters for longevity science. They are helping to create an environment in which it is easier for more ambitious scientific goals - such as the development rejuvenation therapies in the SENS model - to find support. The principals at AFAR certainly do their part to collaborate with more ambitious organizations such as the SENS Research Foundation. A counterpoint to this is that if we all sat around and adopted the gently-gently approach of advocating small, incremental advances, then going for small incremental advances would be the outside, extreme position in the exchange of ideas. Then nothing would happen, as the middle conservative position would be to do just about nothing. Too many decades have been spent doing next to nothing to treat aging, even in the presence of numerous promising biotechnologies that can be brought to bear on the challenge.

In any case, here is a pointer to the latest AFAR annual report, which is available as a PDF. Make your own mind up after taking a look at the pitch. You might also look over a separate publication from late last year on the topic of the Longevity Dividend, which is a flagship initiative of political advocacy that aims to steer much more US government funding into the sorts of research programs mentioned above.

American Federation for Aging Research 2013 Annual Report and Financials

This year, the American Federation for Aging Research strengthened and supported the field of aging research through a range of public programs and publications to engage investigators, industry leaders, and consumers with the latest biomedical research that will enable us all to live healthier, longer. Understanding the biology of aging is key to unlocking the etiology of the chronic diseases of old age. This outcome promises many medical and economic benefits to society and individuals alike.

Yet, for far too long, aging research has been separated from chronic disease research. But a promising shift in the scientific community's approach began taking shape in 2013: amid newfound attention to aging research, the interdisciplinary commitment to understanding the relationship between aging and age-related diseases, known as geroscience, has emerged. In the past 10 years, geroscience has yielded discoveries that once might have sounded unimaginable. Today, this growing scientific approach has profound implications for medicine and healthy aging. One of the most significant is the ability to modify the aging process in laboratory animals through a variety of interventions, including caloric restriction, pharmaceuticals, and genetic manipulation.

Scientists now believe they will soon be able to delay or even prevent the diseases of old age in humans. Indeed, for many years, geroscientific research by AFAR-affiliated investigators nationwide has been providing increasing evidence that studying aging and chronic disease together yields mutually beneficial results.

Calorie restriction extends life and slows progression of near all measurable aspects of aging in near all species tested to date. The underlying mechanisms are inherited from the deep evolutionary past and are therefore very similar even between yeast, nematode worms, mice, and humans. One of the most interesting things about the calorie restriction response is that researchers can study nematodes and then have a fair expectation that much of what is learned will have some relevance to human biochemistry.

There are of course limits to the degree to which one can take findings in lower animals and expect them to hold up in humans. Nematodes for example have a dauer stage in growth that they enter and exit based on environmental circumstances: it is a form of stasis in which they can survive for great lengths of time in comparison to their normal life span. Effects that involve the dauer stage are unlikely to be of any great relevance to higher species that do not have this capability, however. So I think it is very speculative that this research will have any great application to human metabolism, for all that it is well crafted:

Organisms in the wild often face long periods in which food is scarce. This may occur due to seasonal effects, loss of territory, or changes in predator-to-prey ratio. During periods of scarcity, organisms undergo adaptations to conserve resources and prolong survival. When nutrient deprivation occurs during development, physical growth and maturation to adulthood is delayed. These effects are also observed in malnourished individuals, who are smaller and reach puberty at later ages.

Developmental arrest in response to nutrient scarcity requires a means of sensing changing nutrient conditions and coordinating an organism-wide response. How this occurs is not well understood. We assessed the developmental response to nutrient withdrawal in the nematode worm Caenorhabditis elegans. By removing food in the late larval stages, a period of extensive tissue formation, we have uncovered previously unknown checkpoints that occur at precise times in development. Development progresses from one checkpoint to the next. At each checkpoint, nutritional conditions determine whether animals remain arrested or continue development to the next checkpoint.

Diverse tissues and cellular processes arrest at the checkpoints. Insulin-like signaling and steroid hormone signaling regulate tissue arrest following nutrient withdrawal. These pathways are conserved in mammals and are linked to growth processes and diseases. Given that the pathways that respond to nutrition are conserved in animals, it is possible that similar checkpoints may also be important in human development.

Link: http://dx.doi.org/10.1371/journal.pgen.1004426

It is always good to more respectful attention given to the Strategies for Engineered Negligible Senescence (SENS) approach to rejuvenation treatments. Rendering us immune to mitochondrial DNA damage and its consequences is just one of a number of future therapies that will be needed to reverse all of the underlying causes of aging, but in and of itself this is perhaps the most technically interesting of the biotechnologies adopted and advocated by SENS:

In this fast-paced talk by Dr. Aubrey de Grey, we hear about a breathtakingly radical approach to forestalling aging, which (in a nutshell) involves moving all remaining mitochondrial genes into the nuclear DNA, so that mutations in mitochondrial DNA, per se, are rendered irrelevant. This technique of "obviation" of mitochondrial-DNA breakdown isn't a new idea (it's been around for at least 30 years). What's new is that, technologically, we're in a position to make it happen.

Most mitochondrial genes are, of course, already in the nucleus. The majority of scientists accept that mitochondria got their start as bacterial endosymbionts; a long-ago ancestor of today's alphaproteobacteria took up residency in an anaerobe. The anaerobe provided the invading bacterium with a nutrient-rich environment in which to live, while the bacterium provided oxygen-detoxification services (and a lot of adenosine triphosphate) to the host. Most likely, the invading bacterium had around 1,500 genes. Over time, ~500 redundant genes were lost and the remaining 1,000 or so migrated to the host cell's nuclear DNA (a much safer environment for DNA than the mitochondrion), leading to the present-day situation where (human) mitochondria have an extremely small circular chromosome encoding just 13 proteins. But we know mitochondria actually contain around 1,000 different proteins, most of which are encoded in nuclear genes.

The majority of mitochondrial genes (in the nucleus) encode proteins that are made in cytoplasm and imported into the mitochondrion. For import, proteins must be in an unfolded state. Some proteins (the most hydrophobic ones) are actually made on the surface of the mitochondrion and slurped into the interior of the mitochondrion as they're being made. Folding of the proteins then takes place inside the organelle.

Can the remaining 13 mitochondrial protein genes be moved to the nucleus? If we succeed in doing that, will cells live longer? What technical obstacles remain? What progress has been made? These and other questions are addressed in Aubrey de Grey's talk, which is well worth a listen.

Link: http://asserttrue.blogspot.com/2014/06/a-different-approach-to-anti-aging.html

Jason Hope is one of the more generous philanthropists to have funded projects in rejuvenation biotechnology carried by under the auspices of the SENS Research Foundation. His funds went towards making a start on breaking down glucosepane cross-links in old tissues, thereby removing its contribution to loss of skin elasticity, arterial stiffening, and other forms of degeneration caused when sugar compounds link proteins together in ways that hamper tissue function. This buildup of cross-links is an important aspect of numerous age-related medical conditions, but in principal it and its effects are reversible - if the glucosepane can just be safely removed.

The challenge here is twofold: firstly that there are few tools in the biotechnology toolkit for working with glucosepane and similar compounds, and secondly that the people involved in most ventures in medical research are not going to break new ground by building tools when there are a thousand other potentially profitable things they could be doing for which the tools already exist. Unfortunately those other profitable activities don't fix the glucosepane problem. This is where the network of researchers, advocates, and philanthropists connected to the SENS Research Foundation really shines: acting together they can find this sort of blockage in research where a comparatively small effort can push a field over the hump and make it much more attractive for development.

In any case, Jason Hope isn't just interested in glucosepane. In recent months he's published a series of articles that covers more of the SENS portfolio of research projects. Aging is a phenomenon caused by a number of fundamental processes, and all of them will have to be addressed in some meaningful way in order to achieve rejuvenation of the old and indefinite postponement of all age-related disease. If any one of the contributing causes of aging were removed as if by magic tomorrow, then the others would still kill us on roughly the same time frame of a normal present day human life span.

In the article quoted below, Hope looks at one of the areas of SENS that I feel needs less help than the others. Numerous different types of important cells are damaged or lost over the course of aging, such as stem cells and long-lived nerve cells, and these must be replaced or repaired to restore function. Fortunately there is an enormously active medical research and development community focused on the manipulation and use of stem cells so as to do just this. These researchers just need to be steered into focusing a little more on aging in the context of their work, but even this is not a huge challenge: all of the most profitable potential applications of cell-based regenerative medicine involve the treatment of age-related conditions. The stem cell community is thus already forced into the position of needing to figure out how to overcome the effects of aging on stem cells - and eventually on cells in general - in order to reliably treat the majority of their potential patients.

This is of course not to say that everything is rosy, and that there are no lagging areas that need attention, but the situation is far better than is presently the case for most of the rest of the technologies that need to be produced to form a near future comprehensive toolkit of rejuvenation treatments. One area in which the SENS Research Foundation is intervening to accelerate progress is that of thymic regeneration, restoring an old thymus to its youthful structure and function and thus boost immune system activity. This is something that does not attract as much attention as it might from the broader research community perhaps because it is natural for the thymus to atrophy quite early in life, and there is a strong - and frankly rather silly - bias in much of the medical establishment against anything that might be perceived as enhancement.

SENS Research Foundation Investigates Cell Loss

In many tissues, the body tries to replace lost cells quickly with specialized, tissue-specific stem cells. Exercise can stimulate the division of specialized stem cells in muscle tissue, for example. This works well in young bodies but over time, the degenerative process of aging makes older stem cells less effective at repairing damaged cells. Additionally, some tissues are not equipped with such specialized stem cells: in such tissues, the cells a person has in early adulthood are all he or she has to last a lifetime.

This is especially significant when long-lived tissue, like that in the brain, heart and muscles begins to lose cells and the ability to function well. Decreased cell count and poor function in the brain causes neuron loss that contributes to cognitive decline, dementia, and loss of muscle coordination. Diminished cell count causes skeletal muscles to weaken and fail to respond to exercise. Cell loss in heart tissues results in poor cardiovascular function associated with old age and invites a host of cardiac conditions.

Nowhere, perhaps, is cell loss more devastating than in the thymus. The thymus is a pyramid-shaped organ in the chest, located between the breastbone and the heart. Before birth, throughout childhood and into puberty, the thymus is instrumental in the production and maintenance of a specific type of white blood cell that protects the body from viruses and other threats. This white blood cell, known as T-lymphocytes or T cells, is essential to human immunity. It circulates around the body, searching for cellular abnormalities and infections.

The thymus begins to shrink after puberty, and its functional tissue is slowly replaced with fat. The organ slows T-cell production as it shrinks. This leaves the aging person increasingly vulnerable to infectious diseases, including influenza and pneumonia. Engineering a youthful thymus, therefore, would help restore a youth immune system.

SENS Research Foundation funding is helping Dr. John Jackson's lab at the Wake Forest University Institute for Regenerative Medicine investigate the potential to engineer a new thymus gland to restore a youthful and vital immune function. SENS Research Foundation continues to work towards reversing the detrimental effects of aging that cause widespread and unnecessary debilitation and misery among the older population. Their advances in preventing cell loss in vital organs can vastly improve the lives of the aging population that now inhabits planet earth.

Artificial vision devices are presently very crude: grids of electrodes embedded in the retina that can stimulate retinal cells to create the appearance of a pattern of glowing dots based on what a camera sees. This is enough to pick out letters, navigate a room, or distinguish faces with practice, which is a big step up from being absolutely blind. These are still prototypes, however, steps on the way to better things. Researchers are laying the groundwork for more a subtle integration between microelectronic devices and retinal cells:

Just 20 years ago, bionic vision was more a science fiction cliché than a realistic medical goal. But in the past few years, the first artificial vision technology has come on the market in the United States and Western Europe, allowing people who've been blinded by retinitis pigmentosa to regain some of their sight. While remarkable, the technology has its limits. "It's very exciting for someone who may not have seen anything for 20-30 years. It's a big deal. On the other hand, it's a long way from natural vision."

Although much of visual processing occurs within the brain, some processing is accomplished by retinal ganglion cells. There are 1 to 1.5 million retinal ganglion cells inside the retina, in at least 20 varieties. Natural vision - including the ability to see details in shape, color, depth and motion - requires activating the right cells at the right time. The new study shows that patterned electrical stimulation can do just that in isolated retinal tissue. In laboratory tests, researchers [focused] their efforts on a type of retinal ganglion cell called parasol cells. These cells are known to be important for detecting movement, and its direction and speed, within a visual scene. When a moving object passes through visual space, the cells are activated in waves across the retina.

The researchers placed patches of retina on a 61-electrode grid. Then they sent out pulses at each of the electrodes and listened for cells to respond, almost like sonar. This enabled them to identify parasol cells, which have distinct responses from other retinal ganglion cells. It also established the amount of stimulation required to activate each of the cells. Next, the researchers recorded the cells' responses to a simple moving image - a white bar passing over a gray background. Finally, they electrically stimulated the cells in this same pattern, at the required strengths. They were able to reproduce the same waves of parasol cell activity that they observed with the moving image.

"There is a long way to go between these results and making a device that produces meaningful, patterned activity over a large region of the retina in a human patient. But if we can handle the many technical hurdles ahead, we may be able to speak to the nervous system in its own language, and precisely reproduce its normal function."

Link: http://www.nei.nih.gov/news/pressreleases/060514.asp

The immune system is very complex and one of the least understood areas of our biology, which is reflected in the presently poor knowledge of the causes of autoimmune disorders and lack of effective treatment options. There is a lot of work taking place on manipulating the immune system to attack cancer, however, and this and other work on immunity will in the years ahead establish the understanding that is presently lacking. This research is an example of the type, and may ultimately turn out to be more valuable for what it reveals about the immune system rather than its use in cancer treatment:

A class of drug currently being used to treat leukaemia has the unexpected side-effect of boosting immune responses against many different cancers. The drugs, called p110δ inhibitors, have shown such remarkable efficacy against certain leukaemias in recent clinical trials that patients on the placebo were switched to the real drug. Until now, however, they have not been tested in other types of cancer.

The team showed that inhibiting p110δ in mice significantly increased cancer survival rates across a broad range of tumour types, both solid and haematological cancers. For example, mice in which p110δ was blocked survived breast cancer for almost twice as long as mice with active p110δ. Their cancers also spread significantly less, with far fewer and smaller tumours developing.

"When we first introduced tumours in p110δ-deficient mice, we expected them to grow faster because p110δ is important for the immune system. Instead, some tumours started shrinking. When we investigated this unexpected effect, we found that p110δ is especially important in so-called regulatory T cells which are suppressive immune cells that the tumours engage to protect themselves against immune attack. Our work shows that p110δ inhibitors can shift the balance from the cancer becoming immune to our body's defences towards the body becoming immune to the cancer, by disabling regulatory T cells. This provides a rationale for using these drugs against both solid and blood cancers, possibly alongside cancer vaccines, cell therapies and other treatments that further promote tumour-specific immune responses."

Link: http://www.ucl.ac.uk/news/news-articles/0614/12-06-14-Leukaemia-drug-stimulates-cancer-immunity

When it comes to extending the healthy human life span and eliminating the suffering caused by age-related disease - and indeed by aging in general - the overwhelming majority of the world's population lie somewhere in the midst of disinterest, disbelief, and ignorance. To a first approximation no-one really cares about medical science, for all that they owe their health to this field of research and development. Similarly despite living in the midst of an age of radical change, with completely new technologies and medical therapies turning up every few years, people generally assume that the rest of their lives will take roughly the same course as did those of their parents and grandparents. If you bring up the topic of great longevity through medical science, often as not the notion is rejected out of hand: people express no interest in their own longevity, or claim not to want to live any longer than their grandparents managed.

All of this is why there must be advocacy for longevity science. In a world in which more than 100,000 people die horribly every day due to degenerative aging and its consequences, while everyone else ambles heedlessly to the same fate, it is vital that some of us speak out, so as to change minds and raise funds for the research programs that can bring an end to all of this suffering and death. Aging is just a medical condition, and will one day be bought under control in the same way as any medical condition: through hard work, research funding, and new clinical treatments.

Medical biogerontologist Aubrey de Grey is one of the more vocal and energetic advocates involved in the present generation of scientific initiatives to treat aging. He and a sizable network of allies associated with numerous foundations and associations have accomplished a great deal in the past decade, changing the culture of the aging research community, and making inroads into changing broader perceptions of aging and medicine held among the public at large. In addition to this work, de Grey helps to manage ongoing research at the SENS Research Foundation, an organization he co-founded in order to accelerate the development of a planned list of biotechnologies needed to create real, working rejuvenation treatments.

Here is a recent presentation given by de Grey at TEDxOxbridge entitled "Rejuvenation biotechnology: the sweet spot between prevention and treatment of age-related ill-health":

Most infectious diseases have been easily prevented: sanitation; vaccines; antibiotics; carrier control. Age-related diseases have not. If historical rates continue, US healthcare spending will be 34% of GDP by 2040. In 2010, the US spent $1.186 trillion on healthcare for 65+ people.

Aging is: The life-long accumulation of damage to the tissues, cells, and molecules of the body that occurs as an intrinsic side-effect of the body's normal operation. The body can tolerate some damage, but too much of it causes disease and disability.

Age-related diseases are caused by aging! Thus, they are: widespread now that infections are "rare"; staggeringly costly; universal if you live long enough; not medically curable, in the strict sense. But they, and aging itself, are nonetheless medical problems and medically preventable in principle.

I rarely discuss supplements in the context of longevity, as there is little to say: the weight of scientific evidence is overwhelmingly against most of what is sold under claims of providing some benefit to long-term health. Much of what is written out there in the world on this topic is written by people who sell supplements, and who therefore have every incentive to lie to you and lie to themselves in order to keep up a revenue stream. There are just a few exceptions to this state of affairs, where the state of evidence swings in the direction of benefits and few harms for ordinary people who are not vitamin deficient, and one of them is vitamin D.

Even here it isn't that there is an iron-clad case for taking it, just a decent case: there is good evidence for vitamin D levels in blood to correlate statistically with decreased mortality, there is very little sign of any harms from supplementing with vitamin D in animal and human studies, and vitamin D is very cheap. However it is magical thinking to assume that taking vitamin D to raise levels in blood will have the same effect as a natural variation observed in a population - one could imagine scenarios in which an artificially induced increase in vitamin D levels shuts off some useful process, for example, or in which natural variations in vitamin D levels are a side-effect of a beneficial process that is unaffected by supplementation. So there must still exist evidence to show that supplementing over the long term does actually produce benefits.

The rational person should spend all of five minutes thinking this through, make a decision, and then move on to much more important matters. The potential benefit here is not large in comparison to the potential outcomes of improved medical science over the next few decades, such as work on the SENS vision for rejuvenation biotechnology, so if we're going to spend time on thinking about longevity, far better for that time to go to SENS.

To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences [we undertook a] meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US [consisting of] 26,018 men and women aged 50-79 years

25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses.

[We conclude that] despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.

Link: http://dx.doi.org/10.1136/bmj.g3656

Transthyretin (TTR) amyloidosis, also known as senile systemic amyloidosis, occurs as a misfolded form of transthyretin forms solid deposits in tissues. In young people this is only threatening when accompanied by rare genetic mutations that greatly accelerate the process, but ongoing accumulation of this amyloid throughout life happens to everyone. If you live to a very great age and survive all of the other forms of age-related disease, then this amyloid will grow to clog your cardiovascular system and kill you. Safe removal of this transthyretin amyloid must thus be a part of any future rejuvenation treatment, and so the SENS Research Foundation funds some lines of research, such as work on catabodies that can break down amyloid deposits. Unfortunately this is in general a small, poorly funded area of research - few groups are looking into TTR amyloidosis, which is why non-profits like the Foundation are trying to hurry matters along.

In this open access paper researchers suggest that in earlier old age TTR amyloid causes other issues, in particular a painful form of degeneration known as lumber spinal stenosis - though more work than was accomplished here would be needed for proof. Producing treatments for this manifestation of amyloidosis would probably be more of a motivation for developers to work on ways to remove amyloid, as there are more patients and thus greater potential revenue from a therapy. So it goes:

Senile systemic amyloidosis (SSA) derived from wild-type transthyretin is a fairly common condition of old individuals, particularly men. The main presentation is by cardiac involvement, which can lead to severe restrictive cardiomyopathy. SSA is, however, a systemic disease, and amyloid deposits may appear in many other tissues but are thought to be without clinical symptoms outside the heart. Amyloid is a very common finding in cartilage and ligaments of elderly subjects, and transthyretin has been demonstrated in some deposits.

Lumbar spinal stenosis is a clinical syndrome of usually elderly individuals that depends on narrowing of the lumbar spinal canal. It is characterized by compression of sensory and motoric nerves to the lower limbs, leading to an often disabling condition. The pathogenesis is probably heterogeneous but includes disc degeneration with disc height decrease and secondary facet-joint subluxation leading to osteoarthritis. Also a degenerative spondylolisthesis of the affected spinal segment may be involved in most cases. Other central factors are general degenerative processes in cartilage and ligaments, including ligamentum flavum.

We questioned whether lumbar spinal stenosis sometimes could be a manifestation of undiagnosed SSA. In this first report we have studied the presence of amyloid in material obtained at surgery for spinal stenosis in 26 patients. Amyloid was found in 25 subjects. Transthyretin was demonstrated immunohistochemically in 5 out of 15 studied resected tissues. Four of the positive materials were analyzed with Western blot revealing both full-length transthyretin (TTR) and C-terminal TTR fragments, typically seen in SSA. We conclude that lumbar spinal stenosis quite frequently may be a consequence of SSA and that further studies are warranted.

Link: http://dx.doi.org/10.3109/03009734.2014.895786

How is it that salamanders can regenerate major organs and limbs, while mammals cannot? There is some interest in this question in the medical community, for all the obvious reasons, although it remains unknown as to how challenging it will be to pick out specific elements in the biochemistry of another species and port them over to we humans. Any given case might be made to work with near-future biotechnology or might prove to be unfeasible for the foreseeable future, but we won't know until researchers make it 80% of the way to the final goal. Thus there is funding and enthusiasm in a range of laboratories for work on better understanding the essential differences in regeneration between salamanders and mammals, spurred on by incidental, unrelated discoveries such as a breed of mice capable of healing some wounds without scarring, or a better grasp of the rare cases in which human fingertips grow back.

Over the past decade a steady series of research results have increased knowledge of the mechanisms of salamander regeneration, both in terms of how different cell populations are behaving, and at the lower level of changes in protein levels, signaling pathways, and gene expression. Here is another piece of the puzzle, though it is clearly still a long way from here to a level of understanding that enables safe manipulation of mammalian cells via this mechanism to create greater feats of regeneration:

Salamanders give clues to how we might regrow human limbs

Although we do not yet understand the exact mechanisms by which salamanders are able to regrow their limbs, we do know that this animal regeneration takes place by the reprogramming of adult cells. This means that for regeneration to take place, adult cells - such as muscle cells - that form the limb have to lose their muscle identity and proliferate to give rise to new cells that will contribute to form the new structure. This process is rarely found in mammalian cells and this has been suggested as the basis for their poor regenerative abilities.

We recently found a critical component of the reprogramming mechanism. In our [study], we demonstrated that the sustained activation of a molecular pathway (a group of molecules in a cell that work together to control a particular function or functions) - called the ERK pathway - plays a key role during the natural reprogramming of salamander muscle cells. Only when the ERK pathway is constantly switched "on" are the cells able to re-enter the cell cycle, which is key to their regenerative potential.

We also compared salamander and mammalian muscle cells. In contrast to salamander cells, we found that mammalian cells can only activate the ERK pathway transiently, and fail to keep the pathway switched "on". Critically, we found that if we forced these mammalian cells to keep the ERK pathway activated (by giving them a piece of DNA that allows them to produce a protein that activates the pathway), the cells could produce the proteins involved in cell cycle re-entry. This suggests that the manipulation of the pathway could contribute to therapies to enhance the regenerative potential in humans.

Sustained ERK Activation Underlies Reprogramming in Regeneration-Competent Salamander Cells and Distinguishes Them from Their Mammalian Counterparts

In regeneration-competent vertebrates, such as salamanders, regeneration depends on the ability of various differentiated adult cell types to undergo natural reprogramming. This ability is rarely observed in regeneration-incompetent species such as mammals, providing an explanation for their poor regenerative potential. To date, little is known about the molecular mechanisms mediating natural reprogramming during regeneration. Here, we have identified the extent of extracellular signal-regulated kinase (ERK) activation as a key component of such mechanisms. We show that sustained ERK activation following serum induction is required for re-entry into the cell cycle of postmitotic salamander muscle cells, partially by promoting the downregulation of p53 activity.

Remarkably, while long-term ERK activation is found in salamander myotubes, only transient activation is seen in their mammalian counterparts, suggesting that the extent of ERK activation could underlie differences in regenerative competence between species.

This open access review paper looks over some of the better known ways to modestly slow aging and extend healthy life in laboratory animals and their relationship with the progressive degeneration of memory with advancing age:

The aging process has been associated with numerous pathologies at the cellular, tissue, and organ level. Decline or loss of brain functions, including learning and memory, is one of the most devastating and feared aspects of aging. During the past century, age-related memory impairments have emerged as one of the top public health threats. Both psychiatric and neurodegenerative disorders comprising schizophrenia, depression, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are associated with age-related memory impairment. In humans, cognitive decline starts in mid-life and deepens with advancing age suggesting that the greatest risk factor is age itself. Thus, ultimately, prevention of these pathologies necessitates thorough understanding of the molecular mechanisms underlying their links with the aging process.

Learning and memory are fundamental processes by which animals adjust to environmental changes, evaluate various sensory signals based on context and experience, and make decisions to generate adaptive behaviors. Age-related memory impairment is an important phenotype of brain aging. Understanding the molecular mechanisms underlying age-related memory impairment is crucial for the development of therapeutic strategies that may eventually lead to the development of drugs to combat memory loss.

Studies in invertebrate animal models have taught us much about the physiology of aging and its effects on learning and memory. In this review, we survey the molecular mechanisms and genes associated with longevity that have also been implicated in cognitive aging. We further focus on recent work in invertebrate model organisms linking learning and memory impairment with age.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4044971/

One of the more interesting results from the study of health and lifestyle choices in recent years is the finding that time spent sitting correlates with increased mortality and a shorter life expectancy regardless of whether or not individuals also exercised. As for all such statistical investigations, there is a lot of room to speculate as to the web of related associations and which of them are actually contributing meaningfully to differences in health. This metastudy expands on the picture by looking specifically at cancer risk:

Sedentary behavior is emerging as an independent risk factor for chronic disease and mortality. However, the evidence relating television (TV) viewing and other sedentary behaviors to cancer risk has not been quantitatively summarized. We performed a comprehensive electronic literature search for published articles investigating sedentary behavior in relation to cancer incidence. Because randomized controlled trials are difficult to perform on this topic, we focused on observational studies that met uniform inclusion criteria.

Data from 43 observational studies including a total of 68936 cancer cases were analyzed. Comparing the highest vs lowest levels of sedentary time, the relative risks (RRs) for colon cancer were 1.54 for TV viewing time, 1.24 for occupational sitting time, and 1.24 for total sitting time. For endometrial cancer, the relative risks were 1.66 for TV viewing time and 1.32 for total sitting time. A positive association with overall sedentary behavior was also noted for lung cancer. Sedentary behavior was unrelated to cancers of the breast, rectum, ovaries, prostate, stomach, esophagus, testes, renal cell, and non-Hodgkin lymphoma.

[We conclude that] prolonged TV viewing and time spent in other sedentary pursuits is associated with increased risks of certain types of cancer.

Link: http://dx.doi.org/10.1093/jnci/dju098

Atherosclerosis is a fearsome age-related condition, as it is quite possible to suffer the progressive build up of arterial plaque with few or no apparent symptoms all the way up until some of it suddenly ruptures to cause the catastrophic blockage of blood flow known as an infarction, and that either cripples you or kills you over the course of an exceedingly painful few minutes. If this affects your heart or your brain you will be lucky to survive, and luckier to recover.

The various contributing causes of atherosclerosis are numerous, each layer of cause and effect feeding into the one above. An incomplete list might include: the evolved reaction to disturbed blood flow in blood vessel walls; the details of fat metabolism; accumulation of lipofuscin constituents such as 7-KC in macrophages attracted to blood vessel damage; damaged cholesterol molecules created by the toxic output of cells overtaken by damaged mitochondria; and last but far from least the standard issue risk factors for all of the common age-relate diseases: becoming fat, being sedentary, and taking up smoking.

I'll point out the recent article on atherosclerosis quoted below as it caught my eye by virtue being interesting and balanced within its own lack of vision regarding the treatment of the condition. The author discusses diet, which is of little consequence in comparison to the outcome of medical research. Atherosclerosis is not a modern condition, and indeed the progress in health over the past few centuries has rendered us far better off at any given age than our distant ancestors. If we see more of atherosclerosis and its threat of sudden death today, it is because we have engineered longer lives, control of the lion's share of serious infectious disease, and the medical technologies need to pay closer attention to the progression of atherosclerosis as we age. Now more people survive or never even see the mortal threats that thinned the ranks of those who came before us:

Death by Affluence?

Many different societies in human history have mummified their dead, using naturally occurring cold, hot, or dry conditions with or without embalming, and HORUS researchers took these ancient corpses, from different societies and times and continents, and put them through CT scanners. The deposits of atherosclerosis proved common. They were present in a third of the mummies, despite their average age at death being 36 (an age which does not fit neatly with the idea of a "natural" life being blissfully healthy). Atherosclerosis was as easily spotted in the dead gatherer-hunters as in the late pastoralists; as common in those who had lived on fish and seafood as in those who feasted on steak.

The HORUS study cannot tell us anything about the superiority of one diet over another, but it does reveal that when it comes to tackling atherosclerosis by altering diet and lifestyle, there may not be a magic preventive or cure. Far from being the peculiar side effect of modernity, problems with blood vessels narrowing and hardening occur routinely with age in all human societies. The foggy idea that modern life fosters atherogenesis - a notion that for too long was accepted without having been properly examined - evaporates under the sunlight.

Outside of the SENS vision of reversing and preventing age-related disease by fixing root causes, which include the lipofuscin and damaged mitochondria mentioned above, much of medical science operates at a higher level in the chain of consequences. Researchers aim to interfere much further along, in attempts to reduce the severity of the results without reducing the the severity of the underlying causes. This doesn't sound very sensible when put this way, and from a high level perspective it really isn't the best way forward. Medical science works this way because, constrained by regulation, research tends to run backwards from the end state of a defined, named disease, so the first new things discovered are the proximate causes. Thus when it comes time to try to create profitable therapies from these discoveries, the development community has to work on patches that make things somewhat better for late stage disease rather than working on methods of prevention and repair that can stop the disease from ever happening in the first place, and cure it for those who do suffer its effects already. This state of affairs will change, and it has to change if we are to see great improvements in the health of the elderly and the prospects for defeating age-related disease.

Here is an example of the sort of research that results from the working backwards approach, the identification of risk factors in metabolism that might be modified to reduce the accumulation of root causes. This is of course of limited utility to those already damaged, as it does nothing to remove existing damage:

New research can improve heart health

Danish researchers [have] shown that people with variation in a gene that inhibits a specific protein in the blood - the so-called apolipoprotein C3 - have a significantly lower level of normal blood lipids than people without this gene variation [as] as well as a significantly reduced risk of cardiovascular disease. Furthermore, the same individuals also have a 41 per cent lower risk of arteriosclerosis. The research is highly relevant as at least one pharmaceutical company has a drug in the pipeline which inhibits precisely apolipoprotein C3.

The scientific results are based on two of the world's largest population studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, with a total 75,725 participants who were followed for 34 years.

All near alternatives to calorie restriction with optimal nutrition are attracting more scientific attention these days, among them intermittent fasting and methionine restriction. All three of these have been demonstrated to extend life in mice and rats to varying degrees, and the collection of mechanisms involved appears to be somewhat different in each case: overlapping sets of metabolic reactions to low levels of food or reduced amounts of one of a few dietary constitutents such as methionine.

It is interesting to see FGF21 levels mentioned in the methionine restriction study below, as using genetic engineering to increase the levels of FGF21 in mice has been shown to extend life by influencing one of the better known longevity mechanisms in mammals. Everything touches on everything else in metabolism, and the diversity of methods by which aging can be slowed in laboratory species really reflects a smaller number of core mechanisms that can be altered in many different ways:

Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similar to caloric restriction, MR extends lifespan, but is accompanied by increased food intake and energy expenditure. Most studies have examined MR in young animals; therefore, the aim of this study was to investigate the ability of MR to reverse age-induced obesity and insulin resistance in adult animals.

Male C57BL/6J mice aged 2 and 12 months old were fed MR (0.172% methionine) or control diet (0.86% methionine) for 8 weeks or 48 h. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. Methionine restriction in 12-month-old mice completely reversed age-induced alterations in body weight, adiposity, physical activity, and glucose tolerance to the levels measured in healthy 2-month-old control-fed mice. This was despite a significant increase in food intake in 12-month-old MR-fed mice.

Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight.

Our findings suggest that MR feeding can reverse the negative effects of aging on body mass, adiposity, and insulin resistance through an FGF21 mechanism. These findings implicate MR dietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12238/full

Nuclear DNA is essentially a big complicated molecule, and stuck in the middle of the dynamic environment of the cell it accumulates damage due to reactions with other molecules. Near all of this damage is repaired quickly, but only near all. So we accumulate somewhat random mutations scattered across our cells as we age. There is some debate over whether this is actually a cause of general age-related degeneration over the present human life span versus only a cause of cancer.

This paper looks at human mutation rates in the exome, a classification that includes only small fraction of our DNA, but which is thought to encompass most of the important known mutations associated with various diseases. There is thus an energetic community that studies this small part of the genome:

The inability of genomic variants to fully explain known or suspected inherited and spontaneous components of a wide variety of diseases may indicate that there may be additional undiscovered factors that complicate analysis. These factors include the number and rapidity with which one accumulates genomic variants, which if known could be compensated for, like ethnicity and sex. Genetic characterization of aging, therefore, may hold a key to questions regarding the importance of acquired somatic variants, variation in aging within a population, and their role in human diseases. Adding time and the accompanying mosaic changes as variables may enhance the accuracy and utility of population-scale analysis of human traits and disease.

In an attempt to begin to address this gap, we hypothesized that the inherited genome is not static but rather dynamic with time with individual experiences punctuating genomes differently. To test this hypothesis we used exome sequencing of normal epithelial samples from three healthy individuals serially collected at different ages in their life. We found the human genome to be dynamic, acquiring a varying number of mutations with age (5,000 to 50,000 in 9 to 16 years). These mutations span across 3,000 to 13,000 genes, which commonly showed association with Wnt signaling and Gonadotropin releasing hormone receptor pathways, and indicated for individuals a specific and significant enrichment for increased risk for diabetes, kidney failure, cancer, Rheumatoid arthritis, and Alzheimer's disease - conditions usually associated with aging.

[This demonstrates] that the exome of an individual is dynamic and constantly experiences environmental and evolutionary pressures and over time enriches for deleterious variants. This finding indicates that the accumulation of somatic variants and possibly the rate of accumulation will contribute to how an individual ages, and prompting age-related diseases. It challenges our existing approach in population-scale sequencing studies and establishes "age" as an important variable that must be accounted for in the analysis and interpretation of any given human genome. These observations are supportive of new paradigm, "Multiple genomes per individual".

Link: http://www.impactaging.com/papers/v6/n6/full/100674.html

The AMA, Ask Me Anything, events at Reddit have evolved over a few years into a sort of semi-formalized crowdsourced interview via bulletin board. Their success somewhat parallels the rise of crowdfunding projects and the steady demise of personal expectations of privacy, and I don't think that this is a coincidence in either case: it all factors in to the motivations, economic and otherwise, that encourage people to engage with an audience in this way. It is interesting to note that the online bulletin board as used in practice is only a little younger than the internet, four decades old or so now, and new yet new modes of use and cultural establishments built atop it still come and go with regularity.

The r/Futureology community at Reddit is an open forum for following and discussing technological advances relevant to the modern futurist viewpoint - which is essentially the transhumanist viewpoint, as the transhuman visions for technological development outlined in 1980s zines and the online forums of the 1990s are now either presently already in their infancy, or are otherwise quite widely accepted as being sensible mainstream ideas. Molecular nanotechnology, strong AI, and - most importantly - work on radical life extension and working rejuvenation therapies: these were all too recently derided and yet are now taken as common sense futurism. It is hopefully a short step from there to more people deciding to donate to speed up rejuvenation research rather than just waiting and hoping on the sidelines.

The moderators at /r/Futureology today hosted an AMA with Aubrey de Grey of the SENS Research Foundation, a prominent figure in the longevity science community who should need no introductions to the audience here. It is very pleasing to see de Grey in front of an appreciative, intelligent online audience who have some knowledge of the work of the Foundation and its great importance to our lives. I'll cut right to the most interesting point, but you should certainly scan the whole thing, as there are some other tidbits in there:

Aubrey de Grey AMA

Q: Mr. De Grey, has Google tried to hire you? Being a leader in your field of investigation I thought they'd bend over backwards to have you on board for Calico.

A: We're talking to them, but it's still very preliminary - they are taking their time to decide their direction.

The SENS Research Foundation's lab is of course just down the road from Google's HQ, and there probably half a hundred people in that town who are on first name terms with all three of de Grey, Sergey Brin, and Larry Page. Noteworthy support for the SENS vision of repair-based approaches to reverse age-related damage and disease has existed in the Bay Area technology and venture community for years, especially in those circles associated with Clarion Capital.

My prediction for the median expected outcome of the next few years of Google's California Life Company (Calico) initiative is that they will focus on what is currently mainstream, which is to say the genetics of longevity and efforts to slow aging via metabolic alteration. They will throw tens of millions of dollars at this, spawn several businesses, produce an enormous volume of new information, and fail to produce any way to meaningfully extend human life.

The hires made so far and most of the discussion to date has supported this view; I think that the network of SENS researchers and supporters, despite being very close at hand both in the network of relationships and physically, will have to grow larger yet before it can acquire large patron organizations such as Calico. I hope to be proven wrong and pleasantly surprised, but I expect to see the few entities in the sphere of aging research with a lot of funding and the will to use it to both try and fail with every path other than SENS before finally coming around to focus on rejuvenation biotechnologies based on repair of the known forms of damage that cause aging.

But who knows? The future is what we make of it. The SENS Research Foundation are not the only group putting forward largely repair based approaches to treating aging. There is a proposal from Spanish aging researchers put forth a year ago that differs in the details from SENS, but is otherwise very similar in intent, to pick one example. It is possible that the next wave of interest in treating aging and funding prospective therapies, once people have got the fixation on development and use of genetic technologies out of their system, will see varied groups arguing over what to repair and how. That would be a large step up from the present situation, in which the only research plans likely to produce functional treatments that reverse the harms of aging in the old are still on the margins of the scientific community, moving along slowly with little funding.

The most important thing to take away from this? The following, I think:

Q: Dr. De Grey, No questions, I just wanted to thank you for your passion and dedication to such an important cause.

A: Thanks back! So, what are you doing to help?

Researchers are step by step establishing a better understanding of kidney regeneration that should improve efforts to spur regrowth and repair through stem cell treatments and other forms of regenerative medicine:

Doctors and scientists have for years been astonished to observe patients with kidney disease experiencing renal regeneration. The kidney, unlike its neighbor the liver, was universally understood to be a static organ once it had fully developed. "We wanted to change the way people thought about kidneys - about internal organs altogether. Very little is known even now about the way our internal organs function at the single cell level. This study flips the paradigm that kidney cells are static - in fact, kidney cells are continuously growing, all the time."

[Researchers] conducted a study using a "rainbow mouse" model, a mouse genetically altered to express one of four alternative fluorescent markers called "reporters" in each cell. "We were amazed to find that renal growth does not depend on a single stem cell, but is rather compartmentalized. Each part of the nephron is responsible for its own growth, each segment responsible for its own development, like a tree trunk and branches - each branch grows at a different pace and in a different direction."

Using the rainbow mouse, the researchers were able to pinpoint a specific molecule responsible for renal cellular growth called the "WNT signal." Once activated in specific precursor cells in each kidney segment, the WNT signal results in robust renal cellular growth and generation of long branches of cells. "Our aim was to use a new technique to analyze an old problem. No one had ever used a rainbow mouse model to monitor development of kidney cells. It was exciting to use these genetic tricks to discover that cellular growth was occurring all the time in the kidney - that, in fact, the kidney was constantly remodelling itself in a very specific mode."

"This study teaches us that in order to regenerate the entire kidney segments different precursor cells grown outside of our bodies will have to be employed. In addition, If we were able to further activate the WNT pathway, then in cases of disease or trauma we could activate the phenomena for growth and really boost kidney regeneration to help patients. This is a platform for the development of new therapeutics, allowing us to follow the growth and expansion of cells following treatment."

Link: http://www.aftau.org/newsroom?8d683461-b0e3-4a61-9898-f85fb3bb934f

A comparatively small number of misfolded proteins form solid aggregates in tissue due to the change in chemical properties caused by this misfolding, and the result is called an amyloid, and a consequent medical condition is called an amyloidosis. The best known type of amyloid is that associated with Alzheimer's disease, but for many of the others it isn't as clear as how these aggregates cause damage. Nonetheless amyloids all accumulate with age, and thus should be removed by any comprehensive suite of rejuvenation treatments.

One of the other amyloids clearly linked to harm is misfolded transthyretin (TTR), which is implicated as the cause of death in most people who make it to very advanced ages. In the very elderly this form of amyloid clogs the cardiovascular system. There is also an inherited variant of TTR amyloidosis that occurs rarely in younger people due to an unfortunate genetic mutation, and as is often the case in these matters most past research has focused there.

Here is a pointer to a recent paper that results from SENS Research Foundation funded work on one possible way to safely break down transthyretin amyloid, removing its contribution to age-related mortality through the use of catalytic antibodies, thought to be a type of functional component in the innate immune system. If selective antibodies effective at breaking down this form of amyloid are established by searching through the many different types present in humans, then these few proteins can be manufactured in bulk and used as the basis for a treatment:

Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the [correctly folded] TTR (phyTTR).

IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins.

The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function. Catalytic IgMs may clear misfolded TTR and delay amyloidosis [and] the innate antibody repertoire is a source of selective catabodies to toxic proteins.

Link: http://dx.doi.org/10.1074/jbc.M114.557231

To what degree does it help to understand the mechanisms by which various species of long-lived mammals are in fact long-lived? That is an open question. There is a great deal of ongoing study of some of these species, such as naked mole rats, and efforts to at least sequence the DNA of others, such as some whales and longer-lived bats.

If we look to the more distant future, it seems fairly straightforward to argue that at the point at which it becomes possible to design new functional human genomes to support people with different metabolisms that nonetheless operate safely over the course of an extended lifetime, then yes, there might be a lot of beneficial alternative or additional modes of operation that can be pulled from the metabolic biochemistry of other species. Perhaps a significant fraction of the more beneficial aspects presently known to exist in other mammals can be made to work quite well in future variants of Homo sapiens machinatum. That isn't an unreasonable projection: it is all just a matter of knowledge and technology, and most of the fundamental technology needed to actually create alternative human genomes already exists or is near realization.

The research community is far behind on the knowledge front, however, and is thus a long, long way from being able to create any sort of stable alternative working metabolism in humans, let alone doing so safely. At the present time just trying to recreate the well-studied and easily achieved alternative metabolic mode of operation produced through the practice of calorie restriction is proving to be a challenge, with all too little to show other than an increase in knowledge after ten years and a few billion dollars - and this is really the first baby step on the road towards engineering entirely new human metabolisms that introduce other improvements.

So how much success should we expect from mining other species for their unusual and beneficial metabolic quirks in the near term? Researchers will certainly make good progress in understanding why naked mole rats are long-lived and immune to cancer in the next few years. There is momentum there. But that doesn't necessarily mean that scientists can then do anything with that knowledge immediately: knowing the signaling pathways or precise differences between rats and naked mole rats doesn't automatically result in ways to alter rats that will work. The operation of metabolism is fantastically complex, a linked web of protein machines all reacting to one another's presence. You can't alter anything in isolation, and it is always an expensive challenge to even prove safety for the comparative crude manipulations achieved today. So as I said above, it is an open question as to whether the outcome of the study of long-lived mammals is simply more knowledge or something more useful than that.

Here is a good popular science article that gives an overview of work on naked mole rat metabolism, details of some of the latest results, and the hopes of the researchers involved:

The end of aging: do naked mole rats have the secret to long, healthy lives?

When he first saw a naked mole rat in 1842, German naturalist and explorer Eduard Rüppell thought he might have found a diseased specimen because it lacked fur. But there's something special about naked mole rats that Rüppell couldn't have seen. Similarly-sized rodents, under ideal conditions, can live for five years or less. The life span of a naked mole rat is about six times as long. Even into their twenties, they barely seem to age, retaining strong heartbeats, dense bones, and remaining fertile. Scientists have dosed them with all sorts of carcinogenic chemicals and radiation, but unlike every other mammal, a naked mole rat has never once been observed to develop cancer.

Until recently, what let the naked mole rats conquer cancer and live so long was a total mystery. But over the past few years, a handful of researchers around the world have uncovered strange mechanisms inside their cells that seem to be the basis for the animals' uncommon longevity. The scientists' ambition is lofty, but not surprising: they want to harness these discoveries to one day vanquish cancer and battle aging in humans too.

Upon hearing about these discoveries, most people ask the same reasonable question: can they be applied to cure cancer and slow aging in humans? The answer, like many in science, is complicated. It's one thing to discover a rodent has marvelous adaptations that allow it to live a really long time. It's another entirely to put them in another species.

Where where I stand, work on understanding longevity in other species looks like just another path to slowing aging through altering metabolism. It is fascinating, but highly unlikely to produce therapies that will greatly extend life or restore health to the old. Slowing aging just slows down the accumulation of damage, which is of limited benefit to those already very damaged by aging. The only types of treatment that will be of great benefit to the elderly are those based on repair of the causes of aging, restoring the metabolism we already have rather than building a new one, as these are in theory capable of actual rejuvenation when realized. Since we might expect at least another two decades to pass before any useful and widespread medical technologies emerge from any lines of present research into treating aging, then we should firmly reject the goal of slowing aging in favor of the goal of repairing and reversing aging. Why work so hard on a course of action that will produce end results that are of no benefit to your older self?

The prevailing focus in Alzheimer's disease (AD) research is on removal of amyloid, solid aggregates of misfolded proteins, considered the main agent of harm. More sophisticated researchers consider why there is more amyloid in the brains of Alzheimer's patients, and the elderly in general, and how that comes about and how it might be prevented. For example the SENS research program includes periodic removal of all amyloids as a goal because the presence of amyloid is a fundamental difference between old and young tissue, and therefore should be eliminated as a part of any repair-based rejuvenation treatment.

No consensus goes unchallenged in medical science, however, and there are a range of alternative views and proposed mechanisms for the harm caused by Alzheimer's disease, some of which add to the amyloid viewpoint as this one does. That there is further damage caused by amyloid that is not restored by simply removing the amyloid deposits is an incentive to develop periodic amyloid clearance treatments. These should be applied to healthy people throughout life, so as to prevent amyloid ever rising to the level at which it causes these further harms. All too much of the research community remains entirely committed to the model of waiting until the late stages of disease and then trying to repair everything that goes wrong at that time, however.

[This] research was motivated by the recent failure in clinical trials of once-promising Alzheimer's drugs being developed by large pharmaceutical companies. "Billions of dollars were invested in years of research leading up to the clinical trials of those Alzheimer's drugs, but they failed the test after they unexpectedly worsened the patients' symptoms." The research behind those drugs had targeted the long-recognized feature of Alzheimer's patients' brains: the sticky buildup of the amyloid protein known as plaques, which can cause neurons in the brain to die. "The research of our lab and others now has focused on finding new drug targets and on developing new approaches for diagnosing and treating Alzheimer's disease."

[The] research team found the neurotransmitter, called GABA (gamma-aminobutyric acid), in deformed cells called "reactive astrocytes" in a structure in the core of the brain called the dentate gyrus. This structure is the gateway to the hippocampus, an area of the brain that is critical for learning and memory. "Our studies of AD mice showed that the high concentration of the GABA neurotransmitter in the reactive astrocytes of the dentate gyrus correlates with the animals' poor performance on tests of learning and memory."

The high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter, a novel drug target found in this study, to enhance GABA inhibition in the dentate gyrus. With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus are not fired up like they normally would be when a healthy person is learning something new or remembering something already learned.

"After we inhibited the astrocytic GABA transporter to reduce GABA inhibition in the brains of the AD mice, we found that they showed better memory capability than the control AD mice. We are very excited and encouraged by this result because it might explain why previous clinical trials failed by targeting amyloid plaques alone. One possible explanation is that while amyloid plaques may be reduced by targeting amyloid proteins, the other downstream alterations triggered by amyloid deposits, such as the excessive GABA inhibition discovered in our study, cannot be corrected by targeting amyloid proteins alone."

Link: http://news.psu.edu/story/318364/2014/06/13/research/discovery-may-lead-improvements-diagnosing-treating-alzheimers

Researchers have discovered an unexpected effect of oxytocin on muscle regeneration. One has to wonder just how much the fact that use of oxytocin is already approved by regulators factors into this work: there is a strong incentive for researchers to look for new marginal effects in the existing set of approved drugs and compounds rather than work on radically new and better medical technologies. This is because regulators impose vast costs on novel technologies, but only very large costs on reuse of existing treatments in new ways, and this structure percolates all the way back up the research chain due to its effects on funding. This is just one of many detrimental distorting effects of regulation on the course, speed, and effectiveness of medical research.

A few other biochemical factors in blood have been connected to aging and disease in recent years, but oxytocin is the first anti-aging molecule identified that is approved by the Food and Drug Administration for clinical use in humans. "Unfortunately, most of the molecules discovered so far to boost tissue regeneration are also associated with cancer, limiting their potential as treatments for humans. Our quest is to find a molecule that not only rejuvenates old muscle and other tissue, but that can do so sustainably long-term without increasing the risk of cancer."

The new study determined that in mice, blood levels of oxytocin declined with age. They also showed that there are fewer receptors for oxytocin in muscle stem cells in old versus young mice. To tease out oxytocin's role in muscle repair, the researchers injected the hormone under the skin of old mice for four days, and then for five days more after the muscles were injured. After the nine-day treatment, they found that the muscles of the mice that had received oxytocin injections healed far better than those of a control group of mice without oxytocin. "The action of oxytocin was fast. The repair of muscle in the old mice was at about 80 percent of what we saw in the young mice."

Interestingly, giving young mice an extra boost of oxytocin did not seem to cause a significant change in muscle regeneration. "This is good because it demonstrates that extra oxytocin boosts aged tissue stem cells without making muscle stem cells divide uncontrollably." The researchers also found that blocking the effects of oxytocin in young mice rapidly compromised their ability to repair muscle, which resembled old tissue after an injury.

Link: http://newscenter.berkeley.edu/2014/06/10/oxytocin-helps-muscle-regeneration/

The latest SENS Research Foundation newsletter arrived in my in-box today, with an update on what is new in the Foundation's programs of research into the foundations of future rejuvenation treatments. There is a conference coming up later this year, a new crop of young scientists interning at various research centers to help advance the state of the art, and recently published research directed at the removal of a form of amyloid implicated in the death of those who live the longest and survive everything else that aging throws at us.

The Foundation staff have set themselves an aggressive mid-year fundraising goal of $250,000 before the end of August. Your home town will burn that much on their next game night, but here this is enough to fund numerous sophisticated projects that advance the state of knowledge in areas of medical science most relevant to treating and reversing the underlying processes that cause aging. There is always a balance between saving for the future and spending now to build better options in the future, but no society in history has ever come close to funding enough work on building better medicine. More is always better. Now we have a golden chance to eliminate the suffering and death caused by age-related disease in just a few short decades of work, and the price to achieve this goal is falling dramatically as biotechnologies improve.

As I mentioned yesterday, we might not be millionaires, but we are the ones with vision enough to band together and help to fund the early work on rejuvenation treatments, the necessary foundations for the proof of concept in mice that will exist in years to come. The big donors always turn up late to the party to pick up the sure thing and carry proven, demonstrated work the last few yard into the clinics. Without us, there would be no party.

At the end of last year the grassroots community raised $100,000 for SENS research, and I'm pleased to have played a modest role in helping that to happen. That was an investment in ensuring that later in our lives we will not be left helpless in the face of age-related disease. I would like to think that we can do just as well this year: more than just money, it is a matter of showing that there are thousands of people who support this work and the goal of an end to the suffering that comes with advancing age. That support attracts attention, and makes it ever more possible for the Foundation to open doors to traditional and more conservative funding sources.

Help Us Meet Our Mid-Year Fundraising Goal

SENS Research Foundation would like to thank all of you for your ongoing support. hanks to your generous donations of time, money, and encouragement, we have been able to continue advancing our work to cure - not just treat, but cure - the diseases of aging. We are accomplishing this goal in 2014 by:

1) Funding promising new research: SRF currently has 3 internal and 15 extramural research projects taking place at universities and research institutes around the world. In March 2014, SENS Research Foundation secured its highest-profile academic publication to date, with the publication by J. Biological Chemistry of a report of SRF-funded work at the University of Texas at Houston. In this study, Dr. Sudhir Paul and colleagues report the isolation of catabodies selective for the type of amyloid that underpins the number one cause of death in the oldest of the old - those who reach the age of 110. A catabody is an unusual type of antibody, on which Dr. Paul is the world leader; rather than just attaching to their target, they actually cut it up. By this means, we can destroy this amyloid and eliminate a major component of aging.

2) Building a strong, collaborative community: We are bringing together leading scientists, regulators, venture capitalists and the general public together at our upcoming Rejuvenation Biotechnology Conference, August 21-23, 2014, in Santa Clara CA.

3) Training the next generation of bright, young scientists: Currently, 17 interns are hard at work contributing to our funded research projects. These students will be presenting in the Poster Session at the Rejuvenation Biotechnology Conference.

However, in order to continue advancing the field of regenerative medicine, we need your help. Simply put, your funding will help us continue our research, support our interns and bring the community together. We've set a funding challenge to raise at least $250,000 between today and August 31, 2014. If you would like to help these programs continue to grow, please show your support by making your tax deductible donation today.

SRF Education: 2014 Summer Scholars Program Is In Session

SENS Research Foundation is pleased to announce the start of the 2014 Summer Scholars Program. Fifteen students were selected to participate this year at the Buck Institute for Research on Aging, the Harvard Stem Cell Institute / Harvard Medical School, University College London, the University of Oxford, the Wake Forest Institute for Regenerative Medicine, and our very own SRF Research Center. Over the next month, SRF will be posting profiles on the SRF Education blog for each of our summer scholars to give you the opportunity to learn more about each scholar and the research he or she will be conducting.

SRF's Thomas Hunt Awarded 2014 Thiel Foundation Fellowship

SENS Research Foundation would like to congratulate Thomas Hunt, who has been awarded one of the 20 Thiel Fellowships granted in 2014. Thomas, 17, began volunteering in our Research Center three years ago and now works alongside our intramural team studying Alternative Lengthening of Telomeres (ALT), a mechanism that may play a key role in the development of cancer. He has a particular interest in automated high-throughput drug screening to find compounds that reduce ALT activity.

As is usually the case, the best part of the newsletter is the question of the month section, in which Michael Rae answers queries from supporters. This month's topic is something I recall discussing once or twice with folk myself, and certainly in past Fight Aging! posts on unusual lower animals such as possibly ageless hydra and rejuvenating microbes. Why can't researchers just investigate the details of the indefatigable regeneration of the hydra and port the underlying mechanisms into our biology? As it turns out there are very good reasons as why we can't do this, much of which stems from the fact that we are more structurally complex. Our lives and our very selves depend on the fine structural details of our tissues, especially the brain and nervous system, remaining intact without being recycled, rebuilt, or otherwise majorly altered.

Question Of The Month #4: Can Medicine Take a Cue from 'Natural' Negligible Senescence?

Q: Amongst the "Strategies for Engineered Negligible Senescence" (SENS), have you considered the original negligibly-senescing organisms as sources for strategies? Organisms like bristlecone pine, lobsters, and the "immortal jellyfish" Turritopsis dohrnii seem to live indefinitely without suffering age-related ill-health or loss of function, so maybe we could learn their tricks and incorporate them into the human genome.

A: As beautifully illustrated in Rachel Sussman's recent book, The Oldest Living Things in the World, the example of these organisms is inspiring and imaginatively appealing. Among other things, they put the lie to the idea that degenerative aging is simply an ineluctable part of being alive, against which nothing can be done. Still, trying to adapt their specific metabolic and structural mechanisms to human use is not likely to help us achieve our goal of preventing and arresting age-related ill health.

While we don't yet know all the metabolic and molecular details, we do have a pretty good idea of why these organisms don't meaningfully age, and unfortunately those reasons aren't compatible with human biology. For instance, bristlecone pines can be said to "live" for thousands of years, but only the outermost layers of the tree are actually still alive: the wood in the middle of a tree is composed of dead 'husks' of cells. The tree is "alive" because the outer layers surrounding the "dead" inner core continues to carry out the business of life, performing photosynthesis and dividing, allowing the composite structure of the tree to keep growing. There is no plausible way to adapt this as a bulwark against the problems of human aging.

The situation is less extreme in the case of most negligibly-senescing animals - but still, it's difficult to see how their tricks could be applied to us without harm. Most such organisms never stop growing, allowing their continuously-dividing cells to literally dilute aging damage away. Rockfish and lobster, for instance, will continue to grow and grow as long as they are fed and not killed by causes unrelated to aging. Aside from the alarming or ridiculous vision of humans that continued to grow and grow year in and year out for centuries, a major problem with adopting this trick is that some of our most of our most important organs are composed of nondividing cells: heart, brain, and skeletal muscle. (That's why major mitochondrial mutations, for instance, build up in these organs and not (for instance) in the skin or liver). We're rather attached to having these cells stay in place and intact, especially when it comes to the way that our neurons arrange themselves; we wouldn't want to tamper with them by triggering them to begin dividing again.

The jellyfish example is even less compatible with the human life cycle (and with our aims biomedically): their "immortality" comes from the fact that they aren't really even single organisms, but colonies of cooperating unicellular organisms that transiently adopt particular functions within the "meta-organism" of the polyp. The individual cells that comprise the polyp potentially divide indefinitely, and can differentiate and re-differentiate to adopt different functions. When a given polyp is irreversibly damaged, this flexibility allows its constituent cells to disperse, regroup, and create a new polyp, with each constituent of the old polyp transforming itself into a different kind of cell to perform a function that is needed by the newly-formed "daughter" polyp. It is not that these abilities allow T. dohrnii cells to indefinitely preserve the healthy function of a single, identifiable organism over time, in other words, but that it allows them to form new polyps when a given polyp-form can no longer be sustained.

These incompatibilities probably mean that the only way to take advantage of these tricks would be to engineer a completely new human-like organism, starting from the embryo and growing it out. Whether or not the life of such an organism is feasible or desirable, it isn't something that we can do to help humans that are alive today to avert a future of age-related disease and disability.

Instead of starting over from scratch and fundamentally reshaping our bodies and brains and way of being alive in the world, the strategy under pursuit by SENS Research Foundation is to repair and renew the bodies that we already have at the cellular and molecular level over time. Organisms that are naturally negligibly-senescent are able to dilute away the cellular and molecular damage that drives degenerative aging. By developing rejuvenation biotechnologies that remove, repair, replace, and render harmless this damage as it accumulates in our own cells and tissues, we can return our bodies to their youthful structural integrity. Through regular applications of this "cellular surgery," we cam restore the structural and functional youth of our bodies to a state of health, vigor, and vitality, keeping the degenerative aging process and its many diseases and disabilities at bay.

The vast, overwhelming majority of people should undertake regular moderate exercise - just as their physicians no doubt advise, supported by a mountain of evidence for the benefits of exercise. The relationship between physical activity and some specific measures of health is complex, however, because our biology is complex. All sorts of different internal and environmental factors interact and influence one another to arrive at any one specific outcome, though this paper is quite clear that if you want to better retain brain volume as you age, then you should be exercising:

Physical activity influences inflammation, and both affect brain structure and Alzheimer's disease (AD) risk. We hypothesized that older adults with greater reported physical activity intensity and lower serum levels of the inflammatory marker tumor necrosis factor α (TNFα) would have larger regional brain volumes on subsequent magnetic resonance imaging (MRI) scans.

In 43 cognitively intact older adults (79.3 ± 4.8 years) and 39 patients with AD (81.9 ± 5.1 years at the time of MRI) participating in the Cardiovascular Health Study, we examined year-1 reported physical activity intensity, year-5 blood serum TNFα measures, and year-9 volumetric brain MRI scans. We examined how prior physical activity intensity and TNFα related to subsequent total and regional brain volumes. Physical activity intensity was measured using the modified Minnesota Leisure Time Physical Activities questionnaire at year 1 of the study, when all subjects included here were cognitively intact.

Stability of measures was established for exercise intensity over 9 years and TNFα over 3 years in a subset of subjects who had these measurements at multiple time points. When considered together, more intense physical activity intensity and lower serum TNFα were both associated with greater total brain volume on follow-up MRI scans. TNFα, but not physical activity, was associated with regional volumes of the inferior parietal lobule, a region previously associated with inflammation in AD patients. Physical activity and TNFα may independently influence brain structure in older adults.

Link: http://dx.doi.org/10.1016/j.neuroscience.2014.05.005

Advanced glycation endproducts, AGEs, build up in tissues over time as a natural consequence of the operation of metabolism. The detrimental effects that AGEs have on tissue integrity and cellular behavior contribute to degenerative aging - their presence is a form of damage. Some attempts have been made in past years to develop drugs to safely break down AGEs, but little progress has been made. The types of AGE important in humans are quite different from those that matter in rodents, and so promising animal studies went nowhere. At the present time the research community lacks the tools to work with the most common AGE in humans, glucosepane, and the SENS Research Foundation is one of the very few groups trying to do something about this.

This research group shows some of the harm caused by AGEs in brain tissue, and notes that it depends on the presence of the receptor for AGEs, RAGE, which is much as expected. They then take the expected route for mainstream science, proposing an alteration to the operation of cells to block or remove RAGE so as to reduce the impact of AGEs, rather than proposing removal of the AGEs. This sort of inefficient focus on consequences and proximate causes rather than root causes is very common in modern medical research, and it needs to change.

Synaptic dysfunction and degeneration is an early pathological feature of aging and age-related diseases, including Alzheimer's disease (AD). Aging is associated with increased generation and deposition of advanced glycation endproducts (AGEs), resulting from nonenzymatic glycation (or oxidation) of proteins and lipids. AGE formation is accelerated in diabetes and AD-affected brain, contributing to cellular perturbation.

In addition to its ability to directly alter the structure and function of targeted proteins within cells that causes cell or tissue damage, emerging evidence has also demonstrated AGEs as a signaling ligand, interacting with RAGE; AGEs elicit signal transduction changes that adversely affect numerous peripheral organs. Although AGE accumulation is increased in cortical neurons, hippocampal pyramidal neurons, astrocytes, and other glial cells in aging and AD brain, the direct effect of AGEs-RAGE interaction on brain function, in particular on changes in synaptic structure and function, remains largely unknown.

Using our novel transgenic mouse model with neuronal expression of RAGE signaling and lacking neuronal RAGE in the forebrain for evaluation of synaptic transmission and plasticity (almost every brain function relays on synaptic transmission), we provide convincing evidence to support a pivotal role of neuronal AGEs-RAGE interaction on MAPK P38 activation, hippocampal plasticity deficit, and synaptic injury. Addition of AGEs to brain slices impaired hippocampal long-term potentiation (LTP). Similarly, treatment of hippocampal neurons with AGEs significantly decreases synaptic density. Such detrimental effects are largely reversed by genetic RAGE depletion. Notably, brain slices from mice with neuronal RAGE deficiency or DN-RAGE are resistant to AGE-induced LTP deficit.

Taken together, these data show that neuronal RAGE functions as a signal transducer for AGE-induced synaptic dysfunction, thereby providing new insights into a mechanism by which the AGEs-RAGE-dependent signaling cascade contributes to synaptic injury via the p38 MAP kinase signal transduction pathway. Thus, RAGE blockade may be a target for development of interventions aimed at preventing the progression of cognitive decline in aging and age-related neurodegenerative diseases.

Link: http://dx.doi.org/10.1038/cddis.2014.248

The email quoted below recently arrived in my in-box from the Methuselah Foundation. The Foundation is now more than ten years old, an organization whose staff, volunteers, and supporters have had a hand in most of the best changes to occur in the aging and longevity science community over that time. The Methuselah Foundation was the original home of SENS research into the repair of aging, prior to spinning off the dedicated SENS Research Foundation, but is now primarily focused on advancing the state of the art in tissue engineering, so as to accelerate progress towards the creation of organs to order. Beyond that all of the networking and advocacy behind the scenes in the research community continues just as it has for a decade. It isn't enough to just suggest things to researchers every now and again or educate the public, though both of these activities are certainly helpful. The world turns on the basis of networking: alliances must be formed, and connections made between funding sources and promising research groups who had no idea the other side existed. In this matter the Foundation has made great strides over the years.

Dear Friends,

We hope you've been having a productive and satisfying 2014.

If you haven't seen it yet, definitely visit our new Methuselah Foundation blog and let us know what you think. We've been publishing weekly posts, including a primer on the science of organ regeneration and a regenerative medicine news roundup from around the web during April and May.

We've also posted several recent interviews there, with Dr. Alan Russell of Carnegie Mellon, Dr. Takanori Takebe of Yokohama City University, Brock Reeve of the Harvard Stem Cell Institute. In the weeks ahead, look out for part 2 of the Brock Reeve piece, a new interview with MIT's Dr. Robert Langer, and more.

Congratulations to Dr. Huber Warner

On May 30th, at the 43rd Annual Meeting of the American Aging Association in San Antonio, Texas, we awarded a $10,000 Methuselah Prize to Dr. Huber Warner for founding the National Institute on Aging's Intervention Testing Program (ITP), a "multi-institutional study investigating treatments with the potential to extend lifespan and delay disease and dysfunction in mice." Dr. Warner is a former program director for the NIA Biology of Aging Program and former Associate Dean of Research for the College of Biological Sciences at the University of Minnesota.

According to Kevin Perrott, Executive Director of the Methuselah Prize, "The vision Dr. Warner showed, and his persistence over years of resistance to establish the ITP, is truly worthy of recognition. This program is going to provide not only potential near-term interventions in the aging process, but hard data to support claims of health benefits in a statistically significant manner. Science needs solid foundations on which to base further investigations, and the ITP provides the highest level of confidence yet established."

"I saw lots of papers from grantees of the NIA about slowing down aging and extending lifespan," said Dr. Warner, "but they were rarely backed up and given credibility through testing. Research over the last 25 years has been characterized by great success in identifying genes that play some role in extending the late-life health and longevity of several useful animal models of aging, such as yeast, fruit flies, and mice. The next challenging step is to demonstrate how this information might be used to increase the health of older members of our human populations around the world as they age."

Other News

With New Organ, we've been busy growing our partner alliance, garnering endorsements (for example, from the Founding Fellows of the Tissue Engineering and Regenerative Medicine International Society), defining criteria for our upcoming heart prize, and working toward an official announcement of our first group of teams participating in the liver prize. We've had good initial interest, with five teams committed so far, and we're currently in dialogue with many more.

The pre-release construction phase of our beautiful marble and granite monument installation in the U.S. Virgin Islands, to honor all of the major donors who are part of the Methuselah 300, will be completed by August. We've got some cool surprises in store, and our goal is to formally dedicate the monument in the first quarter of 2015, during the peak tourist season - with as many of you in attendance as are able!

Finally, don't miss the SENS Research Foundation's upcoming Rejuvenation Biotechnology Conference, taking place on August 21-23 in Santa Clara, CA.

Warm regards,

Dave Gobel

It is good to hear that the New Organ prize initiative continues to gather support and interest. Like many initiatives in the research community it is often hard to see what is actually going on, as much of the important action happens behind the scenes.

For me this email is a reminder that we're halfway through the year already, and so the next time I look up from a keyboard it will likely be nearly a year since the last SENS Research Foundation grassroots fundraising initiative. That was a very spur of the moment affair for me, but nonetheless the community rallied round and raised $100,000 in the last two months of 2013 and January 2014. I would like to do better this year, on matters of organization at least, given that no-one I know has unexpected become stupendously wealthy since January. We may not be millionaires, or at least most of us are not, but our support is nonetheless important and our donations fund real, meaningful projects at the cutting edge of medical biotechnology.

So all things considered it is probably time to start thinking about plans for a round of rejuvenation biotechnology research fundraising starting just a few short months from now.

This open access review outlines an interesting basis for the development of targeted cancer treatments in which stem cells are used as the vector to deliver modified genes. This is apparently well underway, progressing at least as well as other targeted cell killing approaches to treating cancer that are currently in laboratory studies and clinical trials. The breadth of different technology platforms forming the next generation of cancer treatments is one of the reasons why I am optimistic about progress towards robust, highly effective therapies for near all forms of cancer.

For practicing clinicians, who treat patients suffering from advanced cancers with contemporary systemic therapies, the challenge is to attain therapeutic efficacy, while minimizing side effects. Unfortunately, all systemic therapies, including chemotherapy, radiation therapy, and radio-immunotherapy, affect to some extent also healthy cells; thus cause side effects. Therefore, there is an urgent need for the patients' personalized and the cancers' targeted therapies.

Stem cells have the unique potential for self renewal and differentiation. This potential is the primary reason for introducing them into medicine to regenerate injured or degenerated organs, as well as to rejuvenate aging tissues. Recent advances in genetic engineering and stem cell research have created the foundations for genetic engineering of stem cells as the vectors for delivery of therapeutic transgenes. One of the most advanced approaches is based on introduction into tumor cells of genes capable for converting a non-toxic pro-drug into a cytotoxic agent. Specifically in oncology, the stem cells are genetically engineered to deliver the cell suicide inducing genes selectively to the cancer cells only. Expression of the transgenes kills the cancer cells, while leaving healthy cells unaffected.

Herein, we present various strategies to bioengineer suicide inducing genes and stem cell vectors. Moreover, we review results of the main preclinical studies and clinical trials. However, the main risk for therapeutic use of stem cells is their cancerous transformation. Therefore, we discuss various strategies to safeguard stem cell guided gene therapy against [this outcome].

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031908/

Tissue engineered replacement retinal tissue lies somewhere in the future, and researchers are making progress towards that goal. Retinal degeneration spurred by the accumulation of metabolic waste products in long-lived retinal cells causes a number of common forms of age-relative blindness, and replacing retinal tissue is one potential approach to repairing these conditions. Here induced pluripotent stem cells are used to generate tissue that somewhat resembles that of a real retina:

Previous studies showed that an early-stage retina, including photoreceptors with primary cilia and parts of the inner segment structure, can be generated in culture from induced human pluripotent stem cells (iPSCs). Now [researchers] demonstrate the ability to grow the most mature retinal tissue from iPSCs yet: the in vitro product was able to develop functional photoreceptor cells. "The major advance here is the ability to make retinal cells that can respond to light and that form into what appears to be remarkably proper orientation."

The miniature human retinal tissue was able to form the outer-segment discs that are essential for light-sensing and contained all seven retinal cell types, including the four types of photoreceptor cells that express opsins, the transmembrane proteins that transfer captured photons into a physiological sensory response to light. While others have also developed systems to study the human retina in the lab, the current study extends these capabilities.

"Outer segments, which are the business end of photoreceptors, have not been previously shown to form from scratch in culture. This study is important as it demonstrated the extent to which we can study the retina in a culture dish. The stem cells could build up the retinal structure almost autonomously. Somehow the cells knew what to do and we just needed to give them time to do it. This was really surprising. The major lessons that [such] stem cell studies are leading us towards is that there are intrinsic instructions within the stem cells themselves to build tissue. We really don't know about these yet, but they are revealing themselves - if we are careful enough to observe them. It makes our jobs as tissue engineers much more doable, if we are working with cells that have these intrinsic emergent properties to build tissues."

Link: http://www.the-scientist.com/?articles.view/articleNo/40169/title/Light-Sensing-Retina-in-a-Dish/

Heterochronic parabiosis is a process of linking the circulatory systems of an old and a young laboratory animal, such as mice. It is an investigative technique used by researchers in efforts to identify the differences in circulating proteins between old and young tissue environments, and which of these changes are important or can be altered to produce benefits in old animals. The entry point for much of this research is stem cell biology, the study of regeneration, tissue maintenance, and especially why stem cell activity declines with age, and the precise mechanisms behind this decline.

Stem cell treatments show great potential as therapies for many age-related conditions, but in order for these therapies to be as effective as they might be for the old, the problem of stem cell decline has to be solved, or at the very least worked around while a solution is created. The true solution for this, as for all aspects of aging, is to implement methods of repair that can remove the low-level cellular and molecular damage that causes aging. But in the meanwhile, it might be possible to gain some benefits and improve the outcome of stem cell treatments by overriding the protein signals in aged tissue to make native and transplanted stem cells behave as though in young tissue - at least for a while, long enough to make a difference.

Cancer is a real concern in these matters, however. The consensus position on declining stem cell activity with aging is that it is an evolved response to aging that has the effect of suppressing cancer incidence. Fewer active stem cells means less of a chance that any one of those cells gains just the wrong set of mutations to run amok as the seed of a new cancer. The cost to this is that we all suffer progressive failure of tissue maintenance and a slow, drawn out decline leading to death by organ failure. New biotechnologies mean that researchers can start to alter this balance of risk, however: perhaps it will be acceptable to put old stem cells back to work for a few months at a time in order to somewhat repair some forms of damage in portions of the aged body. Worn joints, for example, or weakened muscles. That would not be true rejuvenation, as all too much of the damage of aging has nothing to do with stem cells per se. It would be better than nothing, however, and it appears to be increasingly plausible as an option in the next decade or so.

As researchers continue in their investigations of parabiosis, they are cataloging the various systems and cell populations that benefit from the youthful blood of the younger partner in the pairing. Here is an interesting example:

In Revival of Parabiosis, Young Blood Rejuvenates Aging Microglia, Cognition

Aging brings with it not only a decline in cognition but also a smoldering inflammation within the innate immune system. In the brain, this manifests as an abnormal state of that organ's main resident immune cell, the microglia. To see whether this is an internal affair of the aging brain or influenced by the periphery, [researchers]returned to a blood-sharing experiment called parabiosis. [They had] previously used it to show that a young systemic environment can essentially rejuvenate neurogenesis and other aspects of the aging brain.

[Researchers] said that pairing an 18-month-old with a 3-month-old mouse, and letting them live together for five weeks, reversed microglial aging. Microglial activation as measured by CD68 expression was down in the brains of old mice exposed to young blood. In the electron microscope, the old mice's microglia looked like those of young mice. [The team compared] the microglial transcriptome from old mice paired with other old mice to that from old mice paired with young mice. They saw that blood supplied by a young mouse did indeed largely reverse the gene expression phenotype of microglial aging.

Whether these changes at the molecular and cellular level amount to better function is difficult to assess in parabiotic mice. The pairs run the rotarod together, but rigorous behavior assays are not possible. Instead, the [scientists] decided to model parabiosis by transferring young plasma into an old mouse once every three days for three weeks. In this study, old mice injected with plasma from young mice outperformed untreated old mice in the radial arm water maze and a fear-conditioning test. The treated mice also recapitulate other previously shown parabiosis phenotypes, including more neurogenesis, synaptic plasticity, spine density, and less neuroinflammation.

The advent of efficient techniques for gene editing such as CRISPR is moving us into an era in which all sorts of beneficial enhancements to human biology become possible. The regulatory establishment is exceedingly conservative with regard to genetic alterations and will vigorously resist all such treatments, of course, but gene therapies with good evidence of beneficial effects will become available via medical tourism in the same way as stem cell treatments did more than a decade ago. Myostatin knockout is a good example of a possible target of benefit to basically healthy people as well as those suffering age-related frailty, as it induces greater muscle mass and growth. But there are many other possible targets for gene therapies, such as the example here:

Individuals with naturally occurring loss-of-function PCSK9 mutations experience reduced blood low-density lipoprotein cholesterol (LDL-C) levels and protection against cardiovascular disease. The goal of this study was to assess whether genome editing using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system can efficiently introduce loss-of-function mutations into the endogenous PCSK9 gene in vivo.

We used adenovirus to express Cas9 and a CRISPR guide RNA targeting Pcsk9 in mouse liver, where the gene is specifically expressed. We found that within three to four days of administration of the virus, the mutagenesis rate of Pcsk9 in the liver was as high as 50% or more. This resulted in decreased plasma PCSK9 levels, increased hepatic LDL receptor levels, and decreased plasma cholesterol levels (by 35%-40%) in the blood. No off-target mutagenesis was detected in 10 selected sites.

Genome editing with the CRISPR-Cas9 system disrupts the Pcsk9 gene in vivo with high efficiency and reduces blood cholesterol levels in mice. This approach may have therapeutic potential for the prevention of cardiovascular disease in humans.

Link: http://circres.ahajournals.org/content/early/2014/06/10/CIRCRESAHA.115.304351.abstract

This paper is one example of numerous varied critiques of the mainstream consensus view that accumulating amyloid in the brain is the proximate cause of Alzheimer's disease pathology. No current consensus in science ever goes unchallenged, especially when working therapies are slow to emerge as a result of that consensus:

The "amyloid hypothesis" has dominated Alzheimer research for more than 20 years, and proposes that amyloid is the toxic cause of neural/synaptic damage and dementia. If correct, decreasing the formation or removing amyloid should be therapeutic. Despite discrepancies in the proposed mechanism, and failed clinical trials, amyloid continues to be considered the cause of a degenerative cascade.

Alternative hypotheses must explain three features: (i) why amyloid toxicity is not the etiology of Alzheimer's disease (AD), (ii) what alternative mechanisms cause the degeneration and dementia of AD, and (iii) why increased amyloid accumulates in the brain in AD. We propose that AD, which occurs in elderly, already vulnerable brains, with multiple age-related changes, is precipitated by impaired microvascular function, resulting primarily from decreased Notch-related angiogenesis. With impaired microvasculature, a lack of vascular endothelial-derived trophic factors and decreased cerebral blood flow cause the atrophy of neural structures. Therapeutic strategies should focus on supporting normal angiogenesis.

Link: http://dx.doi.org/10.1016/j.jalz.2013.11.003

Disease is a much abused word, and the boundaries of its varied meanings to different groups shift over time. Most of the well-known failures that occur in organs and other biological systems over the later stages of aging are referred to as diseases, but are in fact better designated as medical conditions. Medical condition is much broader term that clearly covers unpleasant things that happen to everyone, and are thus not abnormal in a given age group.

Why should anyone care about these fine lines in nomenclature? Why is there a perennial debate as to whether or not aging itself is a disease? The answer, as is the case in so many similar matters, involves the intersection of large amounts of money and government regulation of medical development and clinical practice. The FDA, to pick one of the worst and most intrusive of the world's regulatory bodies, only permits development and clinical use of treatments for specific named diseases. FDA bureaucrats have a list in which diseases are enumerated and painstakingly defined. If a medical condition isn't on the list, then the only way to bring potential treatment to customers within the US is to first engage in year after year of political lobbying and funding studies with no certainty of useful application. This certainly has a deadening effect on the ability to raise funds all the back up the chain, and steers allocation of resources for even fundamental research.

Nonetheless, this process grinds on for aspects of aging such as sarcopenia, the progressive loss of muscle mass and strength. Since aging isn't a disease per the FDA, the development community slowly chips away at converting small manifestations of aging into officially named diseases. People who have more of that manifestation than the average are declared diseased, and thus it becomes possible within the regulatory regime to officially start work on ways to treat them. This whole process, something that has been going on for the better part of a lifetime, is an enormous dead weight atop the natural tendency for innovation and competition. Funds are efforts are diverted from the straightest path to producing new treatments into much less effective sidelines, wherein the entire structure of research and its end goals are first and foremost shaped by regulation rather than the needs of patients.

All this being the case, the regulation of commercial clinical services will nonetheless be bypassed relatively quickly and effectively as soon as viable treatments for aging emerge. Look at what happened for stem cell therapies: they were offered everywhere in the world except the most highly regulated regions, and the regulators eventually blinked because the risk to their careers became ever greater they longer they acted as roadblocks. But this is only the case when treatments are available elsewhere, and when the public is very aware of this fact. There are any number of potential treatments that we don't see at all because of the slowing effect that regulation has on research in the wealthiest and most active scientific communities. The public is none the wiser there, and so the harmful effects of regulation continue unabated. How many lines of research languish without progress or move at a snail's pace because of this? Too many to easily count.

All of this goes some way to explain why people care as to why aging or any specific aspect of aging is a disease. It is keyed to money, pace of progress, and efforts to work within the ridiculous systems of medical regulation in wealthier countries.

Here is an open access opinion piece on this topic where I agree and disagree with varied different aspects of the author's viewpoint. The approach to aging and age-related conditions is presently terrible and inefficient, and it must change to focus more on underlying causes and less on patching over the late stage consequences. The nature of this dominant and futile approach to age-related conditions is very driven by regulation, being an extension of the incentives and regulatory barriers discussed above. Yet where this author advises abandoning work on reversing aging, I say double down on research into ways to repair the causes, to reverse the outcomes, and to create real working rejuvenation therapies.

Aging Is Not a Disease: Implications for Intervention

Aging of biological systems occurs in spite of numerous complex pathways of maintenance, repair and defense. There are no gerontogenes which have the specific evolutionary function to cause aging. Although aging is the common cause of all age-related diseases, aging in itself cannot be considered a disease. This understanding of aging as a process should transform our approach towards interventions from developing illusory anti-aging treatments to developing realistic and practical methods for maintaining health throughout the lifespan. Age-induced health problems, for which there are no other clear-cut causative agents, may be better tackled by focusing on health mechanisms and their maintenance, rather than only disease management and treatment. Continuing the disease-oriented research and treatment approaches, as opposed to health-oriented and preventive strategies, are economically, socially and psychologically unsustainable.

One's understanding of biological aging, either as a disease or as a process that increases the chances of the onset of diseases, has serious implications with respect to interventional strategies. If aging is considered as a disease, then, in an ideal condition and in principle, this could be fully treatable, and a disease-free state could be achieved. However, if aging is understood as an emergent phenomenon occurring progressively in each and every individual surviving beyond certain duration of life within the evolutionary framework, then aging cannot be considered as a disease. This latter viewpoint then transforms our approach towards aging interventions from the so-called anti-aging treatments to achieving healthy aging. This also means abandoning enemy-oriented rhetoric, such as the "war against aging", "defeating aging", and "conquering aging" etc. Instead, interventions in aging require a health-oriented approach and the use of a positive language such as maintaining health, achieving healthy aging, and having active aging. Of course, optimal treatment and management of every disease, irrespective of age, is a social and moral imperative. But considering aging as a disease that happens to everybody is an oxymoron.

Naked mole rats live up to nine times longer than other similarly sized rodent species, and display little in the way of evident signs of aging across much of this span. Researchers, being thorough, are working their way through specific organs and systems of the body to see whether this holds generally for all of them - a part of the process of determining exactly why naked mole rats are so long-lived. Here the focus is the cardiovascular system:

The naked mole-rat (NMR) is the longest-lived rodent known, with a maximum lifespan potential (MLSP) of more than 31 years. Despite such extreme longevity, these animals display attenuation of many age-associated diseases and functional changes until the last quartile of their MLSP.

We questioned if such abilities would extend to cardiovascular function and structure in this species. To test this, we assessed cardiac functional reserve, ventricular morphology, and arterial stiffening in NMRs ranging from 2 to 24 years of age. Dobutamine echocardiography revealed no age-associated changes in left ventricular (LV) function either at baseline or with exercise-like stress. Baseline and dobutamine-induced LV pressure parameters also did not change. Thus the NMR, unlike other mammals, maintains cardiac reserve with age.

NMRs showed no cardiac hypertrophy, evidenced by no increase in cardiomyocyte cross-sectional area or LV dimensions with age. Age-associated arterial stiffening did not occur as there were no changes in aortic blood pressures or pulse-wave velocity. Only LV interstitial collagen deposition increased 2.5-fold from young to old NMRs. However, its effect on LV diastolic function is likely minor since NMRs experience attenuated age-related changes in diastolic dysfunction in comparison to other species.

Overall, these findings conform to the negligible senescence phenotype, as NMRs largely stave off cardiovascular changes for at least 75% of their MLSP. This suggests that using a comparative strategy to find factors that change with age in other mammals but not NMRs could provide novel targets to slow or prevent cardiovascular aging in humans.

Link: http://dx.doi.org/10.1152/ajpheart.00305.2014

The thymus is the gateway for immune cell creation, but it is only highly active in the first two decades of life. After that it atrophies. This effectively places a cap on the number of immune cells supported by the body, which is a limit we'd like to work around in order to better maintain immune function in the old. One approach is to rebuild the thymus, such as via tissue engineering or some form of treatment that alters cell signaling to convince existing cells in the body that they are young and thus should be recreating a large and active thymus.

It is as big as an apple in children, but shrinks to peanut size in later life. A quirk of evolution had transformed a "raging torrent", which pumps out [a large number of] T-cells a day in the young, into a "dripping tap" in adults. "The human body was programmed to live for two quick generations in the jungle. Nowadays we all live much longer. We're dealing with an ageing population sitting there without a thymus."

Now [scientists] say they have created the "seeds" to regrow the organ which produces the immune system's soldier cells. [The researchers] have found a way of fashioning stem cells that can develop into the thymus, a pyramid-shaped organ near the heart. The breakthrough [is] the first step in rewiring humans' immune systems to keep pace with their longer life expectancy. The study, which took three years, converted human embryonic stem cells into "thymic" stem cells capable of sprouting a full-sized thymus. The cells could be injected into adult thymuses, triggering renewed growth, or used to grow another thymus from scratch elsewhere in the body.

The next step is to convert the cells into a three-dimensional structure, by cultivating a cluster of the cells around a framework of microscopic fibres in a test tube, and transplanting it under a fold of skin or a membrane around the kidney. The budding thymus is then "logged on" to blood vessels so that it can attract the blood stem cells it converts into T-cells. Last year [scientists] succeeded in doing this in mice. While clinical trials on humans are about five years away, [the] approach could be a major boost for AIDS sufferers or people with depleted immunity. They include cancer patients on chemotherapy or radiation therapy, transplant recipients on anti-immunity drugs, and elderly people who have become so run down that ordinary viruses pose a significant threat.

Link: http://www.theaustralian.com.au/news/seed-cells-will-rewire-immunity/story-e6frg6n6-1226946142735

The Interventions Testing Program has been underway at the National Institute on Aging for something like a decade now. The aim is to rigorously test all the supplements and drug-like compounds thought to modestly extend life in mice on the basis of older studies, and the results to date have largely been a demonstration that very few such items do in fact extend life in mice. Sufficient rigor was lacking in many old exploratory studies, some of which were conducted in advance of the present widespread understanding that any inadvertent reduction in calorie intake in studied mice is going to extend life. Introducing novel compounds into the diet or which might cause nausea turns out to be an excellent way to make that happen.

So it goes. A lot of these past results were simply wrong, just as a majority of results in the sciences are wrong. Research is hard and has a high failure rate, which is why we need the scientific method in order to sift the gold from the dross. It has taken until now for there to be enough of an interest in treating aging, as well as a critical mass of researchers willing to stand up and say it is possible and plausible to treat aging, for more expensive assessment programs like this to emerge. The ITP is by no means the only such effort to obtain greater rigor in data on ways to extend life in mice. I should also point out this initiative:

Historic BAIT Project Underway at the Buck Institute

With BAIT, [researchers] are building a resource for tracking how mice age, both in response to drug treatment and under normal physiological conditions. It's a "big data" project that is yielding terabytes of information on physiological markers of health including cardiac function, metabolism, bone density, body composition, activity and blood pressure, among others. "We are creating the gold standard for looking at variability in aging in mice."

"For a long time, we as an aging research community really have been focused on the survival curve. The goal had been to find treatments or genetic mutations that increase lifespan in mice, pushing the survival curve to the right. However, there have been precious few examples of understanding what the functional consequences of pushing the survival curve are. It's not necessarily a given that if you increase lifespan you will increase healthspan. Data from BAIT will provide us with numerous jumping-off points to push the research forward. We want to move therapies into the clinic; knowing how treatments impact specific functional parameters in the mice could give us a way to guide clinical trials in humans. This is the vital information that's been lacking."

The initial BAIT project involves 770 genetically identical mice that entered the study at 20 months of age (roughly equivalent to a 60-year-old human). One subset is aging normally; other subsets are being individually treated with four drugs that have already been shown to increase lifespan in simple animals such as worms and flies. BAIT is already the largest study in the world looking at functional aging in mice, and now that the pipeline is established, there is no reason not to scale up even further. [Researchers] think that, given the resources, BAIT could handle up to 50 or 60 compounds, providing a next-generation resource for drug development.

This is exciting stuff for those who feel that there is promise in working on ways to marginally slow aging through drug development, such as varied initiatives focused on calorie restriction mimetics. But a more sober assessment of what is possible and plausible suggests that this will gather a great deal of new knowledge but fail to produce ways to greatly extend life. The goals for the metabolic manipulation approach to slow aging, such as those put forward by the Longevity Dividend advocates, are to add five to ten years to healthy life by the mid-2030s. The cost of a serious attempt to achieve this goal will be stupendous: the entire research and pharmaceutical industry focused on turning a fraction of the present drug development pipeline to these efforts. We already know how much this costs and the sort of results (or lack of same) to expect, as we can just look at the past decade of sirtuin research to see in the vicinity of a billion dollars spent and very little to show for it yet.

The end result of drug development to slow aging is a treatment that is of limited use to old people even if it works, and most of us will be old by the time any such thing arrives. Aging is a process of damage accumulation, and slowing aging merely means a slower pace of that damage accumulation. Not much good if you are already so damaged that your mortality risk is high and quality of life low. The only way to make radical breakthroughs in the decades ahead, to produce methods of rejuvenation that can add decades of renewed, improved health for people already old, is to focus on - and fund - something other than the drugs and dietary compounds that so many people fixate on. Regular readers know by now that "something other" is best represented by the SENS research program, but any group working on ways to repair and reverse the underlying damage that causes aging rather than just slow it down has potentially far more promise than the mainstream approach of drugs to slow aging.

We don't have all the time in the world. If funding institutions and researchers continue to focus on scientific programs that are both inordinately expensive and very unlikely to produce therapies with meaningful effects for people who are already old, then we will miss our chance at a radical extension of healthy life far beyond present limits.

Most older people undertake far less exercise than they might, and there is a cost in health and life expectancy associated with the choice to live a sedentary life. Studies like this one help to quantify the difference between exercise and no exercise, and therefore the health benefits that are either obtained or lost:

Our previous studies have shown that 70-year-old men with lifelong participation in football possess a postural balance and rapid muscle force that is comparable to that of 30-year-old untrained men. This time we have gone one step further by evaluating the intensity of football training as well as the health and fitness effects of football for untrained elderly men with little experience of football.

The study revealed that inactive elderly men improved their maximum oxygen uptake by 15% and their performance during interval exercise by as much as 50% by playing football for 1 hour two times per week over 4 months. Moreover, muscle function was improved by 30% and bone mineralization in the femoral neck increased by 2%.

The results provide strong evidence that football is an intense, versatile and effective form of training, including for untrained elderly men. It is definitely never too late to start playing football. Football boosts physical capacity and heart health, and minimizes the risk of falls and fractures in elderly, men who have never played football before or have not played for decades.

Our study shows that intense training such as football can change the lives of elderly men. The remarkable improvements in aerobic fitness and muscle strength make it easier for the players to live an active life and overcome the physical challenges of everyday life such as climbing stairs, shopping, cycling and gardening.

Link: http://www.holdspil.ku.dk/english/news/2014/granddad-football/

The overwhelming balance of scientific evidence shows that damage to nuclear DNA increases with age. This is one of the reasons why cancer is an age-related condition: as time goes by there is an ever greater chance of some cell somewhere in the body suffering just the right combination of mutations to become cancerous. The mainstream position is that this damage also provides a meaningful contribution to the broader aging process by causing disarray in the processes of cells where it occurs, although this point is debated. It may be that beyond cancer incidence the level of nuclear DNA damage suffered over the present human life span is not large enough to provide a significant contribution to age-related disease, frailty, and death.

Here is a review of the literature that confirms the correlation between nuclear DNA damage and age. It is necessary in the scientific process to continually anchor every concept with ever more evidence, especially when the matter at hand is a complex system only partially understood:

Although DNA is not the only target changed with aging, taking account of the major role of this macromolecule in the regulation of all cellular structures and its own cell cycle, DNA damage has been studied with particular attention. The alterations could have several consequences for genome stability with repercussions on cellular component synthesis, cell cycle machinery and signaling pathways that control cell cycle arrest, and programmed cell death or apoptosis. The consequences of DNA damage will depend on the type of damage, genes affected and type of cell and tissue damaged.

The prevailing view is that there is a tendency for an age-related DNA damage accumulation. However, on examination, results of studies show inconsistency; it is possible that confounding factors influence this relation and explain some of the inconsistency. Factors such as diet, lifestyle, exposure to radiation and genotoxic chemicals seem to have a significant influence on the relationship between cumulative DNA damage and age. Methodological factors might have also influenced the observed results. Indeed, different assays may be used to measure DNA damage. Furthermore, the measured DNA damage could reflect changes in the causative factors, and/or changes in DNA protection and/or changes in DNA repair capacity. It must also be noted that the type of cell and tissue used could reflect different aging rates within the organism.

Although there are several excellent narrative reviews on age-related nuclear DNA damage, they usually refer to individual animal and humans studies and, as far as we know, no meta-analytic technique has been used to estimate the extent of effect of potential moderators on age-related DNA damage in humans. Thus, the overall goal of this paper is to address this important gap in the literature.

Electronic databases and bibliographies for studies published since 2004 were searched. A total of 76 correlations from 36 studies with 4676 participants were included. Based on our analysis, a correlation between age and DNA damage was found. The test for heterogeneity of variance indicates that the study's results are significantly high. Moderator variables such as smoking habits, technique used, and the tissue/sample analyzed, are shown to influence age-related DNA damage. Nevertheless, sex did not show any influence on this relation.

In conclusion, this meta-analysis showed an association between age and DNA damage in humans. It was also found that smoking habits, the technique used, and tissue/sample analyzed, are important moderator variables in age-related DNA damage.

Link: http://www.impactaging.com/papers/v6/n6/full/100667.html

The mammalian liver is an odd organ, all things told. It has the greatest natural capacity for regeneration among our internal organs, which makes it a prime target for research into regenerative medicine. On the one hand we want to know exactly why the liver has this ability to regrow large sections of lost tissue in mammals, something that none of our other organs can manage, while on the other hand the fact that it can do this suggests that achieving greater results with either stem cell treatments or growing an entire new liver from a patient's own cells should be easier than is the case for other organs. However, the more time that researchers spend digging into the mechanisms of liver regrowth, the more they find that the biological details are quite different from those of other organs. Thus in fact the liver might not be the best place to look for ways to create a general platform for enhanced regeneration throughout the body. It is entirely possible that ways to manipulate liver biochemistry to enhance regeneration may have only limited application elsewhere.

This news of recent research well illustrates these points. In comparison to other organs, the liver may be far more reliant on a widespread as-needed transformation of normal cells, rather than a small population of empowered stem cells, when it comes to regrowth and regeneration. This has echoes in it of what is known of the way in which lower animals such as salamanders regenerate organs and limbs, which makes sense in this context:

A new model of liver regeneration: Switch causes mature liver cells to revert back to stem cell-like state

Switching off the Hippo-signaling pathway in mature liver cells generates very high rates of dedifferentiation. This means the cells turn back the clock to become stem-cell like again, thus allowing them to give rise to functional progenitor cells that can regenerate a diseased liver. The liver has been a model of regeneration for decades, and it's well known that mature liver cells can duplicate in response to injury. Even if three-quarters of a liver is surgically removed, duplication alone could return the organ to its normal functioning mass. This new research indicates that there is a second mode of regeneration that may be repairing less radical, but more constant liver damage, and chips away at a long-held theory that there's a pool of stem cells in the liver waiting to be activated.

"I think this study highlights the tremendous plasticity of mature liver cells. It's not that you have a very small population of cells that can be recruited to an injury; almost 80 percent of hepatocytes [liver cells] can undergo this cell fate change. "I think that maybe it is something that people have overlooked because the field has been so stem cell centric. But I think the bottom line is that the cells that we have in our body are plastic, and understanding pathways that underlie that plasticity could be another way of potentially manipulating regeneration or expanding some kind of cell type for regenerative medicine."

Hippo Pathway Activity Influences Liver Cell Fate

The Hippo-signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. [We] demonstrate that Hippo pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level.

As the researchers note, this is a promising set of results from the point of view of generating supplies of liver cells for research and regenerative therapies - which is no small thing. It is probably of little application for anything other than liver tissue, however.

Just as scientists are attempting to build calorie restriction mimetics to recapture the well-studied benefits of eating fewer calories, so too some research groups are in search of ways to replicate the benefits of exercise. These efforts are nowhere near as far along as calorie restriction mimetic studies, but I expect that the field will grow in the years ahead. Here is an example of present work, which is still very much at the stage of discovering important mechanisms that might later be manipulated:

In the last few years, the benefits of short, intense workouts have been extolled by both researchers and exercise fans as something of a metabolic panacea. In a new study, [scientists] confirm that there is something molecularly unique about intense exercise: the activation of a single protein. The study revealed the effects of a protein known as CRTC2. The scientists were able to show that following high-intensity exercise, which enlists the sympathetic nervous system's "fight or flight" response, CRTC2 integrates signals from two different pathways - the adrenaline pathway and the calcium pathway, to direct muscle adaptation and growth only in the contracting muscle.

Using mice genetically modified to conditionally express CRTC2, the scientists showed that molecular changes occurred that emulated exercised muscles in the absence of exercise. "The sympathetic nervous system gets turned on during intense exercise, but many had believed it wasn't specific enough to drive specific adaptations in exercised muscle. Our findings show that not only does it target those specific muscles, but it improves them - the long-term benefits correlate with the intensity of the workout."

In the genetically altered animal models, this resulted in a muscle size increase of approximately 15 percent. Metabolic parameters, indicating the amount of fuel available to the muscles, also increased substantially - triglycerides went up 48 percent, while glycogen supplies rose by a startling 121 percent. In an exercise stress test, the genetically altered animals improved 103 percent after the gene was activated, compared to an 8.5-percent improvement in normal animals.

Link: http://www.scripps.edu/news/press/2014/20140605conkright.html

The evidence for metformin to modestly slow aging and extend life in mammals is very mixed, with study results falling all over the map. This is worth bearing in mind when reading any new paper claiming metformin to extend life in other species, as this is just one more item in a distribution of results that does not show clear, compelling, easily replicated evidence of life extension. So that said, here researchers are suggesting that metformin extends life via hormetic effects. Since they are proposing a mechanism, this should lead to ways to better test and replicate the claim without involving metformin itself:

Recently it has been suggested that metformin, the most commonly used antidiabetic drug, might also possess general health-promoting properties. Elucidating metformin's mode of action will vastly increase its application range and will contribute to healthy aging.

Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance.

We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling.

Link: http://dx.doi.org/10.1073/pnas.1321776111

Regular intermittent fasting practices such as alternate day fasting are not as well studied as calorie restriction, but do seem to have similar effects with regard to improved health and extended healthy life spans. In some studies this is absolutely because intermittent fasting is reducing overall calorie intake. But even in studies where the calorie intake is controlled, so that fasting individuals consume the same amount as non-fasting controls, lesser benefits to health and longevity in rodents are still observed. So as is usually the case in the life sciences the underlying biology must be a complex mess of overlapping mechanisms.

We're probably going to be hearing a lot more about these overlapping mechanisms of intermittent fasting in the next few years as at least one group is working towards clinical trials based on human studies, and the folk involved have in mind starting up a company to market some sort of related products based on their data.

The latest work from the group looks at the details of the relationship between fasting and immune function, which turns out to be of interest to the cancer research community, among others. Ways to better recover from treatments like chemotherapy that greatly impact the immune system by thinning the ranks of white blood cells are high on the priority list. Since there is already a fair amount of work underway on generating better outcomes for cancer patients by combining calorie restriction with chemotherapy, it shouldn't be surprising to find that there is funding for work on intermittent fasting as well.

Fasting triggers stem cell regeneration of damaged, old immune system

Cycles of prolonged fasting not only protect against immune system damage - a major side effect of chemotherapy - but also induce immune system regeneration, shifting stem cells from a dormant state to a state of self-renewal. In both mice and a Phase 1 human clinical trial, long periods of not eating significantly lowered white blood cell counts. In mice, fasting cycles then "flipped a regenerative switch": changing the signaling pathways for hematopoietic stem cells, which are responsible for the generation of blood and immune systems, the research showed.

The study has major implications for healthier aging, in which immune system decline contributes to increased susceptibility to disease as we age. By outlining how prolonged fasting cycles - periods of no food for two to four days at a time over the course of six months - kill older and damaged immune cells and generate new ones, the research also has implications for chemotherapy tolerance and for those with a wide range of immune system deficiencies, including autoimmunity disorders.

Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression

Because during prolonged fasting (PF) mammalian organisms minimize energy expenditure in part by rapidly reducing the size of a wide range of tissues, organs, and cellular populations including blood cells, the reversal of this effect during refeeding represents one of the most potent strategies to regenerate the hematopoietic and possibly other systems and organs in a coordinated manner.

Here, we show that PF causes a major reduction in white blood cell (WBC) number, followed, during refeeding, by a coordinated process able to regenerate this immune system deficiency by changes beginning during the fasting period, which include a major increase in [stem cell activity and lineage balancing]. In fact, we show that PF alone causes a 28% decrease WBC number, which is fully reversed after refeeding. Even after WBCs are severely suppressed or damaged as a consequence of chemotherapy or aging, cycles of PF are able to restore the normal WBC number and lineage balance, suggesting that the organism may be able to exploit its ability to regenerate the hematopoietic system after periods of starvation, independently of the cause of the deficiency.

To begin to determine whether PF cycles can potentially promote a similar effect in humans, we also analyzed the hematological profiles of cancer patients from a phase I clinical trial for the feasibility and safety of a 24 - 72 hr PF period in combination with chemotherapy. Although three different platinum-based drug combinations were used, the results from a phase I clinical trial indicate that 72 but not 24 hr of PF in combination with chemotherapy were associated with normal lymphocyte counts and maintenance of a normal lineage balance in WBCs. These encouraging preliminary results will need to be expanded and confirmed in the ongoing phase II randomized phase of the clinical trial.

As modern research results go, this ranks highly if scored in terms of cost and difficulty to implement for any given individual (near zero) versus benefits derived (greater than zero). That is true of anything relating to calorie restriction or fasting, however. Anyone can do it, though in this case the cautious late adopter would wait a few years for more human data that uses relatively healthy old people rather than cancer patients undergoing chemotherapy as a baseline. It may well be that this doesn't in fact do much for the aged immune system in people, while still being a helpful enough approach to use in conjunction with cancer treatments. Trying this in old people would be a comparatively low cost study to set up, so I imagine we won't have to wait too long for that data to emerge.

The phenomenon of contact inhibition is of importance in resisting cancer, and also appears to influence cellular senescence. Both of these topics are of considerable interest to researchers working on in aging and longevity, and the more so since it seems that naked mole rat cancer immunity appears to be based on more effective contact inhibition. One has to wonder whether this also contributes to their considerable longevity as well, perhaps via suppression of cellular senescence.

During cell cycle arrest caused by contact inhibition (CI), cells do not undergo senescence, thus resuming proliferation after replating. The mechanism of senescence avoidance during CI is unknown. Recently, it was demonstrated that the senescence program, namely conversion from cell cycle arrest to senescence (i.e., geroconversion), requires mammalian target of rapamycin (mTOR). Geroconversion can be suppressed by serum starvation, rapamycin, and hypoxia, which all inhibit mTOR.

Here we demonstrate that CI, as evidenced by p27 induction in normal cells, was associated with inhibition of the mTOR pathway. Furthermore, CI antagonized senescence caused by CDK inhibitors. Stimulation of mTOR in contact-inhibited cells favored senescence. In cancer cells lacking p27 induction and CI, mTOR was still inhibited in confluent culture as a result of conditioning of the medium. This inhibition of mTOR suppressed p21-induced senescence. Also, trapping of malignant cells among contact-inhibited normal cells antagonized p21-induced senescence.

Thus, we identified two nonmutually exclusive mechanisms of mTOR inhibition in high cell density: (i) CI associated with p27 induction in normal cells and (ii) conditioning of the medium, especially in cancer cells. Both mechanisms can coincide in various proportions in various cells. Our work explains why CI is reversible and, most importantly, why cells avoid senescence in vivo, given that cells are contact-inhibited in the organism.

Link: http://dx.doi.org/10.1073/pnas.1405723111

There are many good reasons to better manage your general health in earlier life. As researchers produce more data on the workings of our biology over the course of aging they uncover specific causal links between the earlier consequences of poor lifestyle choices and later damage to vital organs. Here the link is between high blood pressure, one of the many expected results of living a sedentary, overweight lifestyle, and the integrity of the brain and its blood vessels:

For the study, 4,057 older participants free of dementia had their blood pressure measured in middle-age, (average age of 50). In late life (an average age of 76) their blood pressure was remeasured and participants underwent MRIs that looked at structure and damage to the small vessels in the brain. They also took tests that measured their memory and thinking ability.

The study found that the association of blood pressure in old age to brain measures depended on a history of blood pressure in middle age. Higher systolic (the top number on the measure of blood pressure) and diastolic (the bottom number on the measure of blood pressure) blood pressure were associated with increased risk of brain lesions and tiny brain bleeds. This was most noticeable in people without a history of high blood pressure in middle age. For example, people with no history of high blood pressure in middle age who had high diastolic blood pressure in old age were 50 percent more likely to have severe brain lesions than people with low diastolic blood pressure in old age.

However, in people with a history of high blood pressure in middle age, lower diastolic blood pressure in older age was associated with smaller total brain and gray matter volumes. This finding was reflected in memory and thinking performance measures as well. In people with high blood pressure in middle age, lower diastolic blood pressure was associated with 10 percent lower memory scores.

"Older people without a history of high blood pressure but who currently have high blood pressure are at an increased risk for brain lesions, suggesting that lowering of blood pressure in these participants might be beneficial. On the other hand, older people with a history of high blood pressure but who currently have lower blood pressure might have more extensive organ damage and are at risk of brain shrinkage and memory and thinking problems."

Link: https://www.aan.com/PressRoom/Home/PressRelease/1288

A few days ago I pointed out an example of the viewpoint on aging research that focuses on drugs, lifestyle, and metabolic manipulation and sees present work in that area to be a matter of significant and ongoing process. I disagree, for reasons that were explained in that post. Today, I'll take a glance at a different view of the science of aging and longevity, one that is far more popular in the mainstream research community, and with which I also vehemently disagree.

Researchers in this field might be loosely divided into three camps, which are as follows ordered from largest to smallest: (a) those who study aging as a phenomenon without seeking to produce treatments, (b) those who see to slow aging through development of means to alter the operation of metabolism, such as calorie restriction mimetic drugs, and (c) those who aim to produce rejuvenation biotechnology capable of reversing aging. The vast majority of the aging research community at present consider that too little is known of the details of the progression of aging to make significant inroads in the design of treatments, and that the way forward is fundamental research with little hope of meaningful application for the foreseeable future. This attitude is captured here:

Let me ask you this: 'Why can't we cure death yet?'

We can't 'cure death' because biology is extremely complicated. Without a fundamental understanding of how biological organisms work on a molecular level, we're left to educated guesses on how to fix things that are breaking in the human body. Trying to cure disease without a full understanding of the underlying principles is like trying to travel to the moon without using Newton's laws of motion.

The reason we haven't cured death is because we don't really understand life.

This is only half true, however. It is true if your goal is to slow down aging by engineering metabolism into a new state of safe operation in which the damage of aging accumulates more slowly. This is an enormous project. It is harder than anything that has been accomplished by humanity to date, measured on any reasonable scale of complexity. The community has only a few footholds in the vast sea of interactions that make up the progression of metabolism and damage through the course of aging, and this is despite the fact that there exists an easily obtained, very well studied altered state of metabolism that does in fact slow aging and extend life. Calorie restriction can be investigated in almost all laboratory species, and has been the subject of intense scrutiny for more than a decade now. Yet that barely constitutes a start on the long road of figuring out how to replicate the effects of calorie restriction on metabolism, let alone how to set off into the unknown to build an even better metabolic state of operation.

Listing these concerns is not even to start in on the fact that even if clinicians could perfectly replicate the benefits of calorie restriction, these effects are still modest in the grand scheme of things. It probably won't add more than ten years to your life, and it won't rejuvenate the old, nor restore any of their lost functionality. It is a way of slowing down remaining harm, not repairing the harm that has happened. All in all it seems like a poor use of resources.

People who argue that we don't understand enough of aging to treat it are conveniently omitting the fact that the research community does in fact have a proven, time-tested consensus list of the causes of aging. These are the fundamental differences between old tissue and young tissue, the list of changes that are not in and of themselves caused by any other process of aging. This is the damage that is the root of aging. There are certainly fierce arguments over which of these are more important and how in detail they actually interact with one another and metabolism to cause frailty, disease, and death. I've already said as much: researchers are still in the early days of producing the complete map of how aging progresses at the detail level. The actual list of damage and change is not much debated, however: that is settled science.

Thus if all you want to do is produce good treatments that reverse the effects of aging, you don't need to know every detail of the progression of aging. You just need to remove the root causes. It doesn't matter which of them are more or less important, just remove them all, and you'll find out which were more or less important in the course of doing so - and probably faster than those who are taking the slow and stead scholarly route of investigation. If results are what we want to see then instead of studying ever more esoteric little corners of our biology, researchers might change focus on ways to repair the known forms of damage that cause aging. In this way treatments can be produced that actually rejuvenate patients, and unlike methods of slowing aging will benefit the old by reversing and preventing age-related disease.

This is exactly analogous to the long history of building good bridges prior to the modern age of computer simulation and materials science. With the advent of these tools engineers can now build superb bridges, of a quality and size that would once have been impossible. But the engineers of ancient Rome built good bridges: bridges that allowed people to cross rivers and chasms and some of which still stand today. Victorian engineers built better bridges to facilitate commerce that have stood the test of time, and they worked with little more than did the Romans in comparison to today's technologies. So the aging research community could begin to build their bridges now, we don't have to wait for better science. Given that we are talking about aging, and the cost of aging is measured in tens of millions of lives lost and hundreds of millions more left suffering each and every year, it is amazing to me that there are not more initiatives focused on taking what is already known and settled about the causes of aging and using that knowledge to build rejuvenation treatments.

What we see instead is a field largely focused on doing nothing but gathering data, and where there are researchers interesting in producing treatments, they are almost all focused on metabolic engineering to slow aging. The long, hard road to nowhere helpful. Yet repairing the known damage of aging is so very obviously the better course for research and development when compared to the prospect of an endless exploration and cataloging of metabolism. If we want the chance of significant progress towards means of treating aging in our lifetime, only SENS and other repair-based approaches have a shot at delivering. Attempts to slow aging are only a distraction: they will provide a growing flow of new knowledge of our biochemistry and the details of aging, but that knowledge isn't needed in order to work towards effective treatments for aging today.

When you look at official statistics on the causes of death in old age and how they have changed over time, it is worth remembering that the underlying records are of terrible quality for more advanced ages, even in wealthier regions of the world. A great deal of work must take place to make anything of them, and all sorts of varying assumptions are baked into that work. In some cases the data simply isn't there, obscured by the tradition of marking the cause of death as 'old age' rather than any more specific item if known.

The researchers extracted information about the place and cause of death of centenarians in England between 2001 and 2010 from the ONS death registration database, linked these data with area level information on deprivation and care-home bed capacity, and analyzed the data statistically. Over the 10-year study period, 35,867 centenarians (mainly women, average age 101 years) died in England. The annual number of centenarian deaths increased from 2,823 in 2001 to 4,393 in 2010.

[The] findings suggest that many centenarians have outlived death from the chronic diseases that are the common causes of death among younger groups of elderly people and that dying in the hospital is often associated with pneumonia. Overall, these findings suggest that centenarians are a group of people living with a risk of death from increasing frailty that is exacerbated by acute lung infection. The accuracy of these findings is likely to be affected by the quality of UK death certification data. Although this is generally high, the strength of some of the reported associations may be affected, for example, by the tendency of clinicians to record the cause of death in the very elderly as "old age" to provide some comfort to surviving relatives.

'Old age' was the most common cause of certifying death (28%), followed by pneumonia (18%) and other respiratory diseases (6%); stroke (10%); heart disease (9%) and other circulatory diseases (10%); dementia and Alzheimer's disease (6%); and cancer (4%). Pneumonia accounted for the largest group of hospital deaths, while across non-hospital settings 'old age' formed the largest category followed by pneumonia. Overall, three-quarters of centenarian death certificates stated 'old age' as either an underlying cause (28%) or contributing cause (47%). The main causes of death changed with increasing age. In the group aged 80-85 years, heart disease was stated on 19% of death certificates, with 'old age' on only one per cent of certificates.

Link: http://dx.doi.org/10.1371/journal.pmed.1001653

These days, the term "vaccine" covers a very broad range of immune system manipulations, especially when it comes to prospective treatments for cancer. The high level plan is to guide the immune system to aggressively destroy cancer cells without causing it to attack ordinary cells, but there are many different approaches that can achieve this goal. Here is one example:

Alpha-fetoprotein, or AFP - normally expressed during development and by liver cancer cells as well - has escaped attack in previous vaccine iterations because the body recognizes it as "self." AFP is expressed by about 80 percent of most common liver cancer cells but not typically by healthy adults. For cancer to flourish, cells must revert to an immature state, called dedifferentiation, which is why liver cancer cells express a protein during development and why the immune system can recognize AFP as "self."

In a process called antigen engineering, [researchers] tweaked AFP just enough to get the immune system to recognize it but still keep the AFP expressed by liver cancer cells in the bull's eye. [The] modified AFP was delivered in a vehicle with a proven record for getting into cells. The lentivector is the backbone of the human immunodeficiency virus, or HIV, minus most of its genes. It is particularly good at targeting dendritic cells, whose job is to show the immune system antigens then activate T cells to attack.

In a proven model where mice are exposed to chemicals known to induce liver cancer, the vaccine blocked cancer about 90 percent of the time. Mice receiving the vaccine had more T cells generally and more that targeted AFP, which could keep an eye out for re-emerging liver cancer. Recurring tumor cells is an unfortunately realistic scenario for liver cancer patients, who have a 70 percent recurrence rate in five years. Patients typically have surgery to remove the diseased portion of the liver, but there are currently no effective adjuvant therapies, such as chemotherapy, to reduce recurrence. Ideally, some version of [this] vaccine will one day provide that key missing piece and dramatically improve patient survival.

Link: http://www.sciencedaily.com/releases/2014/06/140603092535.htm

Regrowth and replacement of age-damaged cartilage is one of the obvious candidates for early applications of tissue engineering. It tends to be most in need of treatment in non-vital parts of the body, such as joints, and is not as evidently complicated to work with from a surgical point of as, say, a major organ such as the heart or liver. Which is all a way of saying that it should cost less to get underway, while failures should be nowhere near as likely to cause enormous harm to patients in trials or undergoing eventual treatments. It is not a terrible approach to start at the shallow end of the difficulty pool and work into deeper waters once that is going well.

Unfortunately cartilage is tremendously complicated at the small-scale level of proteins and tissue structure. If you throw a bunch of cartilage cells into even a sophisticated bioreactor and grow them, then the result is a pseudo-tissue that bears little resemblance to real cartilage. The most important aspects of cartilage are its mechanical properties, such as the ability to bear load, for example. These arise from the fine structure of cartilage extracellular matrix (ECM), arrangements of cells, and relationships between proteins, and getting that right has proven to be a challenge. It is only recently that some researchers claim to have produced cartilage tissue that does begin to measure up.

This open access review paper covers attempts in past years to build nanoscale-featured scaffold materials to guide cartilage regrowth. Such a scaffold is a partial replacement for the extracellular matrix in living tissue, and in an ideal situation would be digested and replaced with real extracellular matrix by the cells that colonize it. This approach has shown considerable promise for the engineering of other tissues, such as bone, skin, and muscle. Efforts to make it work for cartilage have so far met with limited success, however, and for the reasons noted above.

Nanotechnology Biomimetic Cartilage Regenerative Scaffolds

There are three different forms of cartilage in the body: hyaline, elastic and fibrous cartilage. Each can be found in specific sites and with different properties and functions. Hyaline cartilage can be found in the joints, nose, trachea and ribs. To date, detailed cartilage regeneration studies of human hyaline cartilage have been predominantly focused on articular cartilage. This has been driven by the volume of demand related to degenerative osteoarthritis. Articular cartilage samples have been more widely available to science due to the prevalence of joint replacement surgery. Nonetheless, the fundamental principles and advances of cartilage regeneration derived from articular cartilage studies provide a template for the engineering of head and neck cartilage.

Tissue engineering has advanced over the past two decades and continues to evolve in search of optimal tissue replacements alongside nanotechnology. The concept and results of mimicking the structure and function of the natural ECM form the current direction of travel for the fabrication of an optimal tissue regenerative scaffold.

Although the results of current studies have been encouraging, further refinements need to be made. As active growth factors used in current studies are inevitably subjected to contact with organic solvents or time-consuming procedures during processing and scaffold fabrication, it is likely that the majority of the growth factors are denatured. Uncompromised delivery of any growth factor at an optimal concentration with precise release kinetics is ideally required to translate growth factor delivery from an in vitro to in vivo level for tissue regeneration. A system of cell-mediated activation of available bioactive molecules may provide a breakthrough. This might be achieved by incorporating the latent form of the desired protein into the scaffold design. The incorporation of nanotechnology and bioactive cues into tissue scaffold design should prove increasingly promising in cartilage engineering.

Many research studies in cartilage tissue engineering often focus on specific areas of interest with encouraging results, but these studies often lack the holistic requirements to produce a successful tissue replacement. Thus, a multidisciplinary collaborative approach which includes specialised stem cell culture, nanotechnology and bioactive cues, materials science, environmental and mechanical stimulation, and bioreactor culture as well as vascular tissue engineering may offer a breakthrough in functional cartilage regeneration.

Moderate regular exercise correlates with better health and life expectancy in human epidemiological studies, and is shown in animal studies to be the cause of better health and life expectancy. Here is one of many studies to show that the benefits of exercise continue all the way into old age:

The majority of adults aged 65 and older remains inactive and fails to meet recommended physical activity guidelines, previous research has shown. However, these studies have not represented elders living in retirement communities who may have more access to recreational activities and exercise equipment. Now, [researchers] found that older adults in retirement communities who reported more exercise experienced less physical decline than their peers who reported less exercise, although many adults - even those who exercised - did not complete muscle-strengthening exercises, which are another defense against physical decline.

"Physical decline is natural in this age group, but we found that people who exercised more declined less. The most popular physical activities the residents of the retirement community reported doing were light housework and walking, both of which are easily integrated into individuals' daily lives, but these exercises are not the best choices for maintaining muscle strength."

[Researchers] studied the physical activity of 38 residents at TigerPlace, an independent-living community in Columbia, four times in one year. The researchers tested the residents' walking speed, balance and their ability to stand up after sitting in a chair. Then, researchers compared the results of the tests to the residents' self-reported participation in exercise. [Residents] who reported doing more exercise had more success maintaining their physical abilities over time.

Link: http://munews.missouri.edu/news-releases/2014/0602-seniors-who-exercise-regularly-experience-less-physical-decline-as-they-age-mu-study-finds/

Mitochondrial DNA (mtDNA) damage is an important cause of degenerative aging. Via a complicated chain of events it leads to a small population of malfunctioning cells overtaken by malfunctioning mitochondria that export harmful reactive compounds into surrounding tissue.

There are a number of possible approaches to fix this issue, reversing its contribution to aging and age-related disease. One of them is to deliver undamaged, replacement mitochondrial DNA to all cells in the body, such as via protofection. The issue with this approach is that mitochondria are essentially like bacteria in the way they reproduce. Certain types of damage to their DNA produce mitochondria that evade cellular quality control mechanisms and outcompete their undamaged peers despite the fact that they are dysfunctional. Delivering fresh undamaged mitochondrial DNA into that cell doesn't get rid of the damaged copies, and the damaged copies have already demonstrated an ability to thrive. The suspicion is that the benefits of such a treatment would be temporary at best.

But what if this delivery of new mitochondrial DNA could be paired up with a means to selectively remove the damaged mitochondrial DNA? Given such a technology it might even be possible to skip the delivery entirely and just remove damaged DNA. This would sacrifice a small number of cells, those in a state of dysfunction that lack any remaining undamaged mitochondrial DNA to recreate a population of working mitochondria. Here is an example of such research; like most work on mitochondrial repair it is focused on inherited mitochondrial disease rather than aging, but could produce a technology platform applicable to aging:

Delivery and selection of mtDNA in mitochondria in a heritable manner is yet to be achieved, so alternative approaches to genetic therapy of primary mitochondrial diseases are being sought. One of these approaches is based on pathogenic mtDNA mutations being generally heteroplasmic, with observable pathology only present when the ratio of mutated mtDNA exceeds a certain threshold. The selective elimination of mutated mtDNA allows a cell to repopulate with wild-type mtDNA molecules by a yet uncharacterized mechanism of mtDNA copy number maintenance, alleviating the defective mitochondrial function that underlies mtDNA disease.

We designed and engineered mitochondrially targeted obligate heterodimeric zinc finger nucleases (mtZFNs) for site-specific elimination of pathogenic human mitochondrial DNA (mtDNA). Expression of mtZFNs led to a reduction in mutant mtDNA haplotype load, and subsequent repopulation of wild-type mtDNA restored mitochondrial respiratory function in a [cell model of mtDNA damage]. This study constitutes proof-of-principle that, through heteroplasmy manipulation, delivery of site-specific nuclease activity to mitochondria can alleviate a severe biochemical phenotype in primary mitochondrial disease arising from deleted mtDNA species.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992073/

There are many, many people who think of fighting aging only in terms of exercise, diet, and supplements. As hobbies go, there are certainly innumerable far worse ways to spend your time and energy, but bear in mind that the expected outcome of being fanatically conscious of your health and aging is only a marginally longer life expectancy of perhaps 5 to 10 years, all of which emerges from either exercise or calorie restriction, and all of which can be captured by very laid back arrangements of regular aerobic exercise and a sane calorie restricted diet. All that fuss over advanced and ornate supplement plans and lifestyle engineering produces essentially nothing: the best scientific evidence suggests that effects are negative if they exist at all.

The modern health and supplements view on aging has evolved with the times, reaching out to encompass and follow research that aims to produce drugs and other interventions that marginally slow aging. This is a very understandable, logical progression. If you are interested in supplement research in the context of health and aging, then it is a short step from there to be interested in sirtuins, rapamycin, and other attempts to extend life by artificially altering metabolism that are presently underway. A person can be rigorous and sensible in following this research, throwing out all that is speculative, and decrying the hype, confusion, and outright lies that make up the "anti-aging" industry.

Today I'll point out a good example of this sort of viewpoint to contrast with my own views on science and aging. A recent post from the site Aging Sciences - Anti-Aging Firewalls provides an excellent insight into the mindset of those who are far more enthusiastic about the development of drugs to slow aging than I am, and who see the present as a time of palpable progress towards near term goals in this arena:

Five-Year Progress Report on Major Trends Impacting on Longevity

This is a progress report on the changing state of human longevity during the five-year lifespan of this blog. From the broadest perspective, a combination of better scientific knowledge, social trends and initiatives, industry and engineering developments are already propelling the general populations in our country and in other advanced societies towards greater health and enhanced longevity. It is not just that science will do this in the future; it is already happening by the interaction of science, social and commercial developments and engineering developments. Extending human lifespans is not just something that is going to be in the future. It is something very much with us in the fabric of what is happening right now.

From a personal perspective, I believe that the swelling stream of scientific knowledge about health and longevity is increasingly enabling earlier adapters to live lives that are longer, healthier, and more productive than the lives experienced in the general population. Enhanced life extension is increasingly available for those willing to learn about how to pursue it and who are willing to modify their lifestyles and habits to bring it about.

Starting now, every seven years will see the emergence of practical age-extension interventions (ones that have a potential of leading to extraordinary longevity) that double the power of the interventions available at the start of the 7 year period. That is, on an average basis, the practical anti-aging interventions available at the end of a seven-year period will enable twice the number of years of life extension than did the interventions available at the start of the period. Life extension is measured in years of life expectancy beyond those actuarially predicted for a given population starting in a certain base year.

I've cut out the references in favor of the summary in the quote above, so you should scan the whole thing; a lot of work went into it. Fundamentally the view is that progress is taking place now, and this progress is the most interesting aspect of aging research: we should be watching excitedly for studies that show new ways to use pharmaceuticals or the like to slow aging in mice, and consider how rapidly they could be brought into human trials. The expectation is that for the bigger picture of all potential treatments considered as a whole there is a sliding scale of improvement, and that improvement has been happening, is still happening, and will continue to happen on quite a short time frame.

This is all far removed from my view of aging research and present progress. With no great offense intended to those who spend so much time and effort on this aspect of research, I have to say that it is very clearly a road to nowhere, one that is not in any way producing steady gains at this time. Yes, there is an increasing portfolio of methods to increase life span in mice by 10-30% via metabolic alteration, usually the low end of that range, but little to show that these methods stack. At base most are turning out to be simply different ways of manipulating the same few core mechanisms. The outer limit of mouse life extension has not been rising to approach the record of over 60% set more than decade ago by the discovery of growth hormone receptor knockout mutants.

Further, consider that those methods of life extension with dramatic effects in mice that have existing, measurable analogs in humans, such as calorie restriction and growth hormone receptor knockout mutants, do not extend life by anywhere near the same degree in our species. We'd have certainly noticed by now if human life span could be extended 40% by eating less, for example. There is no reason to expect this current portfolio of ways to slow aging in mice to have wondrous results in people, and for most there is no evidence whatsoever to support anything other than ethereal hope. There is still no such thing as a solid, proven method of measuring biomarkers of aging in humans over short periods of time and using that to make confident predictions on the effects of a treatment on mortality and aging. It doesn't exist yet, and until it does you can't talk about effects on life span due to methods of metabolic manipulation emerging from the labs now in anything but a very speculative way.

What do I see when I look at aging research today? Where the quoted folk above see a gradual upward slope, I see a low, flat swamp of muddy humps that leads to a soaring cliff in the distance. Near all of present day aging and longevity research is a matter of people slogging to the top of one of these muddy humps, and is of very little benefit other than to better map the swamp. But if the research community works instead on making it to the cliffs, through programs such as the development of SENS repair biotechnologies, then at some point in the decades ahead there will be a sudden take-off as means of reversing aging emerge. Not just slowing, but reversing: making the old physically younger, preventing the occurrence of age-related disease, and extending healthy life by decades initially and indefinitely later.

To my eyes the evidence for the foundation technologies of SENS to produce large benefits to health and longevity, based on the identification of the causes of degenerative aging, is far better than that supporting any branch of metabolic manipulation, most of which is still a matter of exploration rather than tackling clear and known line items.

The chief problem today is that most people who might support meaningful work on treatments for degenerative aging are focused on the swamp, which in this analogy is work on slowing aging through drugs and genetic engineering of metabolism. They don't see the cliffs ahead as a viable goal, or don't understand that the clifftops exist as a possibility. But the only way we are going to obtain significant extension of life in our lifetimes is by reaching for the greater goal: the development of rejuvenation treatments that repair the known root causes of aging. Tinkering with metabolism can do no more than slow down the damage: it can't prevent it or remove it. It is useless to the old, and of only marginal benefit to the young. It won't greatly extend our lives, and focusing on it is thus a waste and a lost opportunity.

For at least the earlier stages of some forms of dementia it has been shown that lost memories are still there, just inaccessible. The storage is not destroyed, but rather the process of retrieval is impacted. Here researchers demonstrate that they can block and restore interaction with memory in rats, but it isn't yet clear that the restoration portion of their work can be applied to age-related loss of memory. The underlying cellular mechanisms look similar, but may or may not turn out to be similar enough, and there is also the case that the actual demonstration is quite specific to one portion of the nervous system. So a confirmation of utility for human medicine is something to look for in the years ahead:

Scientists optically stimulated a group of nerves in a rat's brain that had been genetically modified to make them sensitive to light, and simultaneously delivered an electrical shock to the animal's foot. The rats soon learned to associate the optical nerve stimulation with pain and displayed fear behaviors when these nerves were stimulated. Analyses showed chemical changes within the optically stimulated nerve synapses, indicative of synaptic strengthening.

In the next stage of the experiment, the research team demonstrated the ability to weaken this circuitry by stimulating the same nerves with a memory-erasing, low-frequency train of optical pulses. These rats subsequently no longer responded to the original nerve stimulation with fear, suggesting the pain-association memory had been erased. In what may be the study's most startlingly discovery, scientists found they could re-activate the lost memory by re-stimulating the same nerves with a memory-forming, high-frequency train of optical pulses. These re-conditioned rats once again responded to the original stimulation with fear, even though they had not had their feet re-shocked.

In terms of potential clinical applications [researchers] noted that the beta amyloid peptide that accumulates in the brains of people with Alzheimer's disease weakens synaptic connections in much the same way that low-frequency stimulation erased memories in the rats. "Since our work shows we can reverse the processes that weaken synapses, we could potentially counteract some of the beta amyloid's effects in Alzheimer's patients."

Link: http://www.newswise.com/articles/how-to-erase-a-memory-and-restore-it

The Methuselah Foundation occasionally makes awards to researchers who are doing more than others to advance aging research. In this case it is the Interventions Testing Program that is being rewarded, a rigorous effort that is serving to remove the uncertainty over which of the existing ways thought to slow aging in mice actually work. Many past studies were flawed, or didn't use enough mice for statistical certainty, or were compromised by inadvertent calorie restriction.

This is all quite important for gaining a better understanding of the details as to how aging progresses, and for researchers who are trying to build treatments that alter metabolism to slow aging, but it is probably of less scientific relevance to rejuvenation research based on repair of cellular and molecular damage. The whole point of the latter field is that it doesn't require a full understanding of the progression of aging or alteration of the operation of metabolism in order to achieve significant reversal of aging and age-related disease. But beyond the science there is the ever illogical world of politics and funding, where success in carrying out an initiative like the ITP can translate into more attention and a better fundraising environment for all efforts relating to enhancing human longevity.

Methuselah Foundation, a medical charity focused on advancing the field of regenerative medicine to extend healthy life, is pleased to announce the Award of the Methuselah Prize to Dr. Huber Warner at the 43rd Annual Meeting of the American Aging Association. This $10,000 award is being given to recognize Dr. Warner's founding of the National Institute on Aging's Intervention Testing Program (ITP), a "multi-institutional study investigating treatments with the potential to extend lifespan and delay disease and dysfunction in mice."

According to Kevin Perrott, Executive Director of the Methuselah Prize, "The vision Dr. Warner showed, and his persistence over years of resistance to establish the ITP, is truly worthy of recognition. This program is going to provide not only potential near-term interventions in the aging process, but hard data to support claims of health benefits in a statistically significant manner. Science needs solid foundations on which to base further investigations, and the ITP provides the highest level of confidence yet established."

"I saw lots of papers from grantees of the NIA about slowing down aging and extending lifespan, but they were rarely backed up and given credibility through testing," said Dr. Warner. "Research over the last 25 years has been characterized by great success in identifying genes that play some role in extending the late-life health and longevity of several useful animal models of aging, such as yeast, fruit flies, and mice. The next challenging step is to demonstrate how this information might be used to increase the health of older members of our human populations around the world as they age."

The Intervention Testing Program also seeks to demonstrate the legitimacy of utilizing scarce government funding for life extension research. The program has already achieved an early success in proving that the immunosuppressant drug, Rapamycin, extends maximum lifespan in mice.

Link: http://www.prweb.com/releases/2014/06/prweb11899590.htm