Fight Aging!

Today I noticed an open access paper in which the authors examine mortality data for Polish Olympic athletes over the past 90 years or so, and compare it with established historical data for the general population. This blends two topics that are occasionally covered here at Fight Aging!: firstly, the growth in human life expectancy in recent history and its causes, and secondly the topic of how regular exercise and life expectancy interact. It is the present consensus that elite athletes, those at the top of their profession, live longer than the rest of us, but it remains open to debate as to whether this is because more exercise is better, or because very robust people who would have lived longer anyway are more likely to enter the world of professional athletics. Researchers want to map the dose-response curve for exercise, in other words. Even though there is very good, very solid evidence for the benefits of regular moderate exercise versus being sedentary, going beyond that to a more nuanced view of what more or less exercise does for health is a challenging goal given the starting point of statistical snapshots of data from various study populations.

Studying the history of life expectancy isn't much easier, though there the challenges tend to revolve around the ever-decreasing quality of data as you look further back in time. The 20th century marked transitions from hopeful aspiration to solid accomplishment in all fields of medicine, too many profound advances in the capabilities of medical science and practice to list here. As the decades passed, this important progress focused ever more on treatments for age-related conditions. An individual born in the US in 1900 suffered through the end of the era of poor control of infectious disease, prior to modern antibiotics and antiviral drugs, and likely benefited little from later progress towards better control of heart disease and other common age-related diseases. An individual born in the US in 1950, on the other hand, enjoyed a youth with comparatively little fear of disease, and is probably still alive today, with access to far more capable therapies than existed even a couple of decades ago.

Given all of this, one of the interesting things to note in the analysis of the Polish data is that the elite athletes born in the early 20th century appear to have a lower rate of aging than the general population, as determined by a slower rise in mortality over time, but that this difference between athletes and the average individual is greatly diminished for people born in the latter half of the 20th century. This suggests, roughly, that advances in medicine from 1900 to 1950 had a leveling effect, bringing up the average, preventing early deaths, but doing little to address age-related disease. That said, there is a large variation in results across the range of similar studies, both those that look at the history of longevity, and those that look at populations of athletes at a given time. It is wise to consider epidemiological studies in groups rather than one by one, and look for common themes. Still, this one is a fascinating data set for the way in which it combines historical trends and exercise in the study of aging.

Examining mortality risk and rate of ageing among Polish Olympic athletes: a survival follow-up from 1924 to 2012

A sedentary lifestyle is associated with the onset of chronic diseases including ischaemic heart disease, type-II diabetes and neurodegenerative diseases. Frequent exercise is perceived as a major behavioural determinant for improved life expectancy and a slower rate of ageing. There is little doubt that frequent exercise is beneficial for individuals' well-being, and an active lifestyle reduces the risk for chronic diseases. However, it is still uncertain whether the rate of ageing decelerates in response to frequent and intense physical exercise. Our attempt is the first empirical study to show the application of a parametric frailty survival model to gain insights into the rate of ageing and mortality risk for Olympic athletes.

Our participants for this parametric frailty survival analysis were Polish athletes who had participated in the Olympic Games from 1924 to 2010. We assumed that these athletes were elite in their preferred sports expertise, and that they were engaged in frequent, if not intense, physical exercise. The earliest recorded year of birth was 1875, and the latest was in 1982; total N=2305; male=1828, female=477. For reliable estimates, mortality improvements by calendar events and birth cohort had to be taken into consideration to account for the advancements made in medicine and technology. After the consideration of mortality improvements and the statistical power for parametric survival analysis, we restricted our analysis to male athletes born from 1890 to 1959 (M=1273). For reliable estimates, we preassigned recruited athletes into two categorical cohorts: 1890-1919 (Cohort I); 1920-1959 (Cohort II).

Our findings suggest that Polish elite athletes in Cohort I born from 1890-1919 experienced a slower rate of ageing, and had a lower risk for mortality and a longer life-expectancy than the general population from the same birth cohort. It is very unlikely that these survival benefits were gained within a short observational time. Therefore, we argue that participation in frequent sports from young adulthood reduces mortality risk, increases life-expectancy and slows the rate of ageing. The age-specific mortality trajectories of Cohort I elite athletes also suggest frequent exercise can decelerate the rate of ageing by 1% with an achievement of threefold risk reduction in mortality. In comparison with those of the general population, the differences in energy expenditure, behavioural habits, body mass and sports expertise were likely to be the contributing factors to the higher variance in lifespan among elite athletes.

In Cohort II, the estimated rate of ageing is highly similar between elite athletes and the general population, which contradicts our estimates for Cohort I. This may be attributed to mortality improvements from year 1920 onwards in Poland. These mortality improvements have changed individuals' susceptibilities for different causes of death, which has resulted in an increased variation in lifespan both in the general population and for elite athletes. Interestingly, the comparison of the rate of ageing of elite athletes in Cohort I and II shows a similar rate of ageing. Among the elite athletes, the estimates suggest that Cohort II individuals benefited from a 50% mortality risk reduction as compared with individuals born in Cohort I. The estimated overall mortality risk of the Polish general population is 29% lower in Cohort II than in I.

A gene therapy study carried out in pigs has demonstrated promising results for the treatment of pulmonary arterial hypertension, the form of pulmonary hypertension that involves narrowing of the blood vessels in the lungs. The therapy overexpresses SERCA2a, an approach already under development for the treatment of heart failure. When targeted to blood vessels it can produce remodeling, compensating in part for the narrowing that is the proximate cause of pulmonary arterial hypertension - though without addressing any of the root causes, as is unfortunately still the case in the majority of medical research.

Scientists have used a novel gene therapy to halt the progression of pulmonary hypertension, a form of high blood pressure in the lung blood vessels that is linked to heart failure. Pulmonary arterial hypertension (PAH) is a rare, rapidly progressing disease that occurs when blood pressure is too high in vessels leading from the heart to the lungs. There is currently no cure for PAH, and about 50 percent of people who are diagnosed will die from the disease within five years. The high pressure is caused by abnormal remodeling of the lung blood vessels that sometimes leads to failure of the right ventricle and premature death. Thickening and narrowing of pulmonary vessels is seen with all types of pulmonary hypertension and is triggered by abnormal calcium levels within the vascular cells. The sarcoplasmic reticulum calcium ATPase pump (SERCA2a) regulates intracellular calcium in vascular cells and prevents them from proliferating in the vessel wall.

There were two primary objectives for this study. First, scientists wanted to learn if it is feasible to deliver a therapeutic gene called SERCA2a in aerosol form to damaged blood vessels of the lung using an engineered adeno-associated virus as a "vector." Second, they wanted to see if there was a sustained beneficial impact, and if the transferred genes effectively slowed or stopped the vascular changes in the airways that are the hallmark of PAH and other forms of pulmonary hypertension. The current study is the first to explore this approach in a large animal - specifically, a Yorkshire swine model that closely resembles PAH in humans.

In the study, 20 pigs were divided into two groups, half of which received the aerosolized viral vector carrying the SERCA2a gene and half a saline spray. Two months after the gene delivery, scientists performed tests to see if the new therapeutic genes were present and functioning in the vessels of the animals' lungs, and whether the transfer was producing the desired effects. When they examined the animals, they found that that heart and lung function had improved and abnormal cellular changes causing PH were reduced. Additional animal studies focusing on long-term efficacy and safety are warranted before advancing this approach, known as airway gene delivery, to human clinical trials. That's because the current study involved a small number of animals, and they were assessed just eight weeks after gene delivery. Nevertheless, airway gene delivery appears to modify fundamental pathophysiology, and therefore might offer therapeutic benefit to humans with a variety of pulmonary vascular diseases.

Link: http://www.eurekalert.org/pub_releases/2016-04/tmsh-gth042816.php

Here I'll point out a recent study on nicotinamide riboside supplementation in mice. This is a way to increase levels of nicotinamide adenine dinucleotide (NAD), an important player in many aspects of cellular metabolism, particularly mitochondrial function and everything associated with it. Mitochondria are known to be important in aging, either through a decline in their primary function of producing energy stores to power cellular activities, or in the damage they suffer that leads to malfunctioning forms of this cellular component.

Thus far, based on work from the past few years, inducing raised levels of the charged form of NAD, NAD+, in mice appears to be a way to trigger some of the same housekeeping and repair mechanisms as are affected by hormesis and heat shock factors in response to various forms of cellular stress, which is to say that it can modestly slow aging and improve health. Everything is interconnected in cellular biochemistry, so it isn't all at unusual for there to be a dozen or more ways to manipulate any one set of mechanisms. Here the focus is on improved stem cell activity, which is becoming a very common theme in research on aging.

As mice age, the regenerative capacity of certain organs (such as the liver and kidneys) and muscles (including the heart) diminishes. Their ability to repair them following an injury is also affected. This leads to many of the disorders typical of aging. Through the use of several markers, researchers were able to identify the molecular chain that regulates how mitochondria - the "powerhouse" of the cell - function and how they change with age. The role that mitochondria play in metabolism has already been amply demonstrated, "but we were able to show for the first time that their ability to function properly was important for stem cells." Under normal conditions, these stem cells, reacting to signals sent by the body, regenerate damaged organs by producing new specific cells. At least in young bodies. "We demonstrated that fatigue in stem cells was one of the main causes of poor regeneration or even degeneration in certain tissues or organs."

This is why the researchers wanted to "revitalize" stem cells in the muscles of elderly mice. And they did so by precisely targeting the molecules that help the mitochondria to function properly. "We gave nicotinamide riboside to 2-year-old mice, which is an advanced age for them," said the researcher. "This substance, which is close to vitamin B3, is a precursor of NAD+, a molecule that plays a key role in mitochondrial activity. And our results are extremely promising: muscular regeneration is much better in mice that received NR, and they lived longer than the mice that didn't get it." Parallel studies have revealed a comparable effect on stem cells of the brain and skin. So far, no negative side effects have been observed following the use of NR, even at high doses. But caution remains the byword when it comes to this elixir of youth: it appears to boost the functioning of all cells, which could include pathological ones. Further in-depth studies are required.

I'll note that the publicity department that formed up this release should be ashamed of themselves for the title, which is a enormous exaggeration. It is bad enough that the popular press consistently misstates the results of research into aging, when so much of that research produces only small effects, without the allegedly more responsible parties also doing so. Not all longevity science is equal, but when everyone claims to have stopped aspects of aging - when no such thing actually happened - it becomes that much harder for laypeople to gain an appreciation for what is more or less useful in the field.

Link: http://www.eurekalert.org/pub_releases/2016-04/epfd-avt042716.php

I can only speculate as to why a set of better than usual articles on the non-profit cryonics industry have appeared in various popular press publications recently. I pointed out one of them yesterday, and here I'll offer links to another two. While attention from the press tends to come and go in cycles, the past decade, and especially the last few years, has seen a considerable improvement in the quality and tenor of coverage: popular science articles on cryonics providers and human interest pieces on the community of supporters and advocates. This is probably due to a number of factors, among which are the slow burn of low-key publicity efforts on the part of the longer-standing providers such as Alcor and the Cryonics Institute, and the layering of credibility in the journalism community that comes with repeated exposure. I would say, however, that the most important contribution comes from progress in the sciences, firstly the accumulation of better evidence to demonstrate preservation of the fine neural structure thought to encode the data of the mind, and secondly from growing interest in the use of reversible vitrification to improve the industry of tissue engineering and organ transplantation.

Cryonics as an industry offers indefinite low-temperature storage of at least your brain immediately following clinical death. For so long as the data of the mind is preserved, the possibility exists for restoration in a future with more capable technology. Some form of fairly mature molecular nanotechnology and near complete control of cellular biochemistry will be needed, and at the present pace of progress it might take a lifetime to get from here to the point at which revival is a realistic but very expensive process, and another few decades to make it cheap enough that revival is likely. The odds of success for this venture are unknown, depending on many factors that are entirely out of of the control of any one individual, but the odds offered by all of the other presently available end of life choices are zero. Like every effort to extend healthy life, it is all about moving the odds in the right direction, not about certainties.

Vitrification in low-temperature storage, the preservation method presently used by cryonics providers, is attained through the use of cryoprotectant compounds. Cryoprotectants are infused into tissues during cooling, and the ice crystal formation that characterizes straight freezing is minimized in the glass-like vitrified result. The difference is enormous. At this point, researchers have shown that vitrified and restored nematode worms appear to retain memory, and have produced forms of vitrification that result in excellent preservation of fine structure. Reversible vitrification has been carried out in a rabbit kidney, with following transplantation and function for a period of time. A number of research groups are investigating reversible vitrification as a way to greatly improve the logistics of tissue engineered or donated organs: if an organ can be stored indefinitely, then many of the costs and complications associated with these fields vanish. Given all of this, it becomes harder for journalists to reject the cryonics industry out of hand. That doesn't stop them engaging in the traditional practice of finding ridiculous and speculative objections in other places, of course:

If cryonics suddenly worked, we'd need to face the fallout

Right now, in three facilities in the US and Russia, there are around 300 people teetering on the cusp of oblivion. They exist in a state of deep cooling called cryopreservation, and entered their chilly slumber after their hearts had stopped beating. Before undergoing true cell death, the tissues of their brains were suspended using an ice-free process called vitrification. All are legally deceased, but if they could they speak, they would likely argue that their remains do not constitute dead bodies at all. Instead, in a sense, they are just unconscious. No-one knows if it's possible to revive these people, but more and more of the living seem to believe that uncertainty is better than the alternative. Around 1,250 people who are still legally alive are on cryonics waiting lists, and new facilities are opening in Oregon, Australia and Europe soon. "We have a saying in cryonics: being frozen is the second worst thing that can happen to you. There's no guarantee you'll be able to be brought back, but there is a guarantee that if you get buried or cremated, you'll never find out."

To the uninitiated, cryonics might seem the stuff of are slowly chipping away at the possibility of revival. Most recently, a team succeeded at thawing a previously vitrified rabbit brain. Even after several weeks of storage, the synapses that are thought to be crucial for brain function were intact. While a thawed out rabbit brain does not a fully revitalised person make, some believe that cryogenic revival might someday be as commonplace as treating a case of the flu or mending a broken arm. "This is really not so earth-shattering or philosophically weird as you might think. It's just medicine - another form of healthcare that helps people who are seriously sick. Once you get your head around that, it's much less scary."

But assuming cryonics does wind up working, for the newly reborn citizens of the past there would be more to their stories than simply opening their eyes and declaring a happy ending. Instead, they would immediately face the challenge of rebuilding their lives as strangers in a strange land. But even if a cryogenically preserved person was on his or her own, that would necessarily be a deal breaker for eventually attaining happiness. "If you were on an airplane today with all your family and friends and it crashed and you're the only survivor, would you commit suicide? Or would you go out and put your life back together, and make new family and friends? Besides, it doesn't make sense that they'd take the time to revive people into some dystopian, backward future. You can't have the technology to wake people up and not have the technology to do a bunch of other great things, like provide abundance to the population."

What Exactly Is Life After Death if You're a Cryonicist?

While there's plenty to debate about life after death, what about life after a deep-freeze at minus 196 Celsius? For many people in the cryonics community, this is a very serious and expensive question, one that begins with the definition of death itself. The preservation process begins as soon as possible after "legal death" - the point when a person can no longer be resuscitated by current technology - is announced, and a person can pick to have only his or her brain frozen or the entire body. Many cryonicists, according to the Alcor Life Extension Foundation, believe that a person's memory, identity, and personality remain stored inside the brain even after a human being is legally declared dead. They equate the brain to a hard drive in a computer - simply because you turn off a computer doesn't mean the hard drive is wiped out. They hope in the future the medical community can figure out a way to turn back on whatever caused the body to die so that the mind can once again live.

For a decade, Murray Ballard spent time in the United States, the United Kingdom, and around Europe and Russia meeting with individuals and institutions in the cryonics community. Ballard said he initially became hung up on the technical aspects of cryonics and photographed it accordingly, but the more people he met, the more he realized the story was really about the individuals who are part of the community and their interest in perhaps one day being brought back to life. Most of the people he met thought of cryonics as an adventure. He said they tend to shy away from the word faith, possibly because of religious undertones, and they're aware that the odds of this working are quite slim. However, they say, it still beats the alternative. "You can't argue with the fact that you're better off being cryogenically preserved than buried or cremated. In that case you'll never be brought back to life. It's a stopgap, a way of just doing the best that we can at the moment. They can't wait for cryonics to be an outdated thing."

Researchers have provided initial and somewhat speculative data to suggest that the decrease in body temperature that occurs in old age may speed the progression of mechanisms implicated in Alzheimer's disease:

"We know that the incidence of Alzheimer's is low before age 65, but doubles every 5 to 6 years afterward. We also know that metabolism and body temperature decrease as people get older. We therefore tested the hypothesis that the changes in the body's thermoregulation that occur with age amplify the main manifestations of Alzheimer's and that a vicious circle can even set in because the disease expresses itself in certain areas of the brain involved in temperature regulation." The researchers used a type of transgenic mice that express the main manifestations of Alzheimer's disease as they age: They produce beta-amyloid, which leads to the formation of senile plaque in the brain; they are affected by a pathology that renders neurons non-functional; and they lose synaptic proteins. In these mice, memory problems begin to arise at the age of 6 months.

By comparing these transgenic mice with normal ones, researchers first established that the transgenic mice were less able to effectively maintain their body temperature as they aged. The difference reached almost 1° Celsius by the age of 12 months. The researchers also observed that the abnormal tau proteins responsible for neuron deterioration increase more in transgenic mice than normal mice, and the loss of synaptic proteins is more pronounced. Conversely, researchers observed that exposure to a high ambient temperature mitigated some manifestations of Alzheimer's disease. After one week in a 28°C environment, the transgenic mice's body temperature had increased by 1°C, beta-amyloid production had dropped substantially, and memory test results were comparable to those of normal mice. "Our findings suggest that it is worth exploring the treatment of thermoregulation among seniors suffering from Alzheimer's."

Link: http://www.eurekalert.org/pub_releases/2016-04/ul-dib040716.php

Immunotherapies will clearly make up a large fraction of the coming generation of targeted cancer therapies, but the state of progress is very uneven at this stage, and therapies will still be specific to types and subtypes of cancer - the primary reason why cancer research is so expensive and slow. The use of chimeric antigen receptors is one of the more promising approaches within this class of therapy, not only because it is demonstrating considerable success in initial trials, but also because it can in principle be applied to numerous types of cancer with comparatively little additional work. Here, researchers present initial results from a recent trial:

Twenty-seven of 29 patients with an advanced type of leukemia that had proved resistant to multiple other forms of therapy went into remission after their T cells were genetically engineered to fight their cancers. The immune system is well-known for its remarkable ability to locate, recognize and attack invaders like the common cold. However, the immune system is not always able to eliminate cancer cells when they form. And once malignant tumors develop, they can use a variety of evasion tactics to outwit the immune system. This experimental therapy is designed to overcome some of these challenges, harnessing the power of the immune system to fight cancers by genetically engineering patients' T cells with a synthetic receptor molecule called a CAR (for chimeric antigen receptor) that empowers the T cells to recognize and kill cancer cells that bear a specific marker, called CD19.

This trial was designed to evaluate the safety of administering the engineered cells and to lay the groundwork for future improvements. It enrolled only adult patients with advanced disease that had relapsed or would not respond to other therapies. This paper includes data from 30 participants with B-cell acute lymphoblastic leukemia who received the cells. After patients' T cells were extracted from their bodies, a specialized virus delivered the DNA instructions for making the CAR into the cells. Then, the cells were multiplied to the billions in the lab. After chemotherapy, the now-reengineered cells were infused back into the patients they came from about two weeks after they were first extracted. This study is the first CAR T-cell trial to infuse patients with an even mixture of two types of T cells (helper and killer cells, which work together to kill cancer). With the assurance that each patient gets the same mixture of cells, the researchers were able to come to conclusions about the effects of administering different doses of cells.

In 27 of 29 participants whose responses were evaluated a few weeks after the infusion, a high-sensitivity test could detect no trace of their cancer in their bone marrow. The CAR T cells eliminated cancers anywhere in the body they appeared. Of the two participants who did not go into complete remission, one eventually reenrolled in the trial and went into complete remission after receiving a higher dose of cells. Not all patients stayed in complete remission: some relapsed and were treated again with CAR T cells, and two relapsed with leukemias that were immune to the CAR T cells. It is too early to know what the long-term outcomes of the cell therapy are. "It sounds fantastic to say that we get over 90 percent remissions, but there's so much more work to do make sure they're durable remissions, to work out who's going to benefit the most, and extend this work to other diseases."

Link: http://www.eurekalert.org/pub_releases/2016-04/fhcr-s9p042716.php

If you survey people on the topic of developing new medical technologies to enable longer lives, you'll find what looks like widespread opposition to the idea. We are a very conformist species, and in an environment in which everyone else ages to death by 80 or 90, that life span is the goal that many people declare themselves set for - but with a few years added on top to signal personal superiority without veering into a claim that would cause loss of status for other reasons. There is little to no thought given to the realities of the situation, the suffering and pain and loss; this is plain vanilla conformism. Similarly, we live in an age in which anti-technology, pro-death environmentalist philosophy has become so mainstream that the average person in the street feels the need to declare themselves in favor of fewer people, shorter lives, less growth, and less technological progress in order to conform. The Malthusian delusion of impending or actual overpopulation is used as a justification to do nothing to prevent the deaths of billions, and at the small scale as another reason not to publicly declare the urge to live longer than your parents.

People who don the hair shirt to decry their wealth, the technology that sustains them, and their life spans, as well as attempts to improve these metrics, are invariably far from poor when their position in life is considered in the context of the bigger picture. There is a level of attainment in society as a whole at which people become sufficiently insulated from the realities of poverty, or the realities of a lack of technology, or the realities of old age, to forget how things used to be or how life is lived by those who are actually poor or frail. This is pervasive in wealthier nations. Too many people fail to critically consider what it would actually mean to be aged, to have your friends dying around you, and to be diminished, weak, in pain, and dependent. They don't give serious thought as to how exactly it is they will die in this model for the future they put forward, in which their span of health and years follows that of their parents. Then there are the hypocrites, those who have given it thought, but take the shallow path of conformity, helping to weave the web of quiet lies, distortions, and omissions that pervade so much of our society.

The point is made here that perhaps we advocates should do more to persuade people to think meaningfully about what exactly it is that they plan for their own fate. There are personal consequences that accompany the goals declared in opposition to progress in medicine to treat aging, or even when simply following the herd to say that you don't want to live any longer than your parents or grandparents. Many people have a profound misunderstanding of the relationship between medicine, aging, and age-related disease, and of what that will mean for their own lives. Yet they are all doing their part to make it incrementally more difficult for improvements in medicine to be funded, to gain support, and to come into being. On the large scale and over the long-term, the progress that happens is the progress that has broad support across the population as a whole.

How will you die? Cancer, Alzheimer's, Stroke?

I have stated that it is basically a matter of time before we get the diseases of old age (cancer, stroke, dementia...) under control. It is impossible to tell when it will happen. Could be a couple of decades, could be 45 years, could be a century or a bit more. As a precaution, you should never trust anyone who says he can predict the future more than a couple of years in advance. However, progress that is not impossible in principle tends to reliably happen, on its own schedule. Whenever we will get the diseases of aging under control, we will end up with drastically extended healthspan. Simply put, most of us end up sick or dead because of the diseases of old age. Without these diseases, we would end up healthy for much longer. Stating that the diseases of aging will come under control at some point in our future should not be controversial. And you would hope that people would see this as a positive outcome.

Not so.

The prospect that we may finally defeat aging is either rejected as being too improbable, or, more commonly, is rejected as being undesirable. Recently, one of my readers had this very typical reaction: "As for extending human life, I'm not for it." If you tend to agree with my reader, please think it through. Aging does not, by itself, kills us. What kills us are the diseases that it brings, such a stroke, dementia, cancer. So if you are opposed to people living healthier, longer lives, then you are favorable to some of these diseases. I, for one, would rather that we get rid of stroke, cancers and dementia. I do not want to see these diseases in my family.

If you are in favor of short human lifespans through aging, then you must be opposed to medical research on the diseases of aging such as dementia, stroke, and cancer. You should, in fact, oppose anything but palliative care since curing dementia or cancer is akin to extending lifespan. You should also welcome news that members of your family suffer from cancer, Parkinson's and Alzheimer's. They will soon leave their place and stop selfishly using our resources. Their diseases should be cause for celebration. Of course, few people celebrate when they learn that they suffer from Alzheimer's. Yet this disease is all too natural. Death is natural. So are infectious diseases. We could reject antibiotics because dying of an infection is "natural". Of course, we do not.

I am sure that, initially, some people expressed concerns regarding the use of antibiotics. Now that we are starting to think about eliminating the diseases of aging, people object to that as well. But let me assure you that when it comes down to it, if there are cures against the diseases of aging, and you are old and sick, you will almost certainly accept the cure no matter what you are saying now. And the world will be better for it. Please, let us just say no to dementia, stroke and cancer. They are monsters.

Hematopoietic stem cells reside in bone marrow and are responsible for producing blood cells, including immune cells. Recent research illustrates one way in which chronic inflammation, important in the progression of degenerative aging, can harm this stem cell population. Since chronic inflammation rises due to immune system dysfunction in aging, mechanisms of this nature may be an important component of negative feedback loops that arise in later stages of aging, in which damaged systems interact to further degrade one another.

IL-1 is a cytokine long understood to be an essential signal the immune system uses to recruit and activate inflammatory cells needed to protect from and repair acute occurrences of infection or injury. However, elevated levels of IL-1 are a feature of chronic inflammation, as is commonly seen in aging, and with a number of disease conditions including obesity and type 2 diabetes, which are associated with Western diet and lifestyle. "Inflammation evolved to function for very short periods of time, marshaling resources to fight infections and repair damaged tissue. However, over long periods of time, these conditions become very toxic. If you're working under a constant state of emergency, you become stressed and less effective. I think of blood stem cells in the same way."

While blood-forming stem cells, also termed hematopoietic stem cells (or HSCs), are usually dormant in the bone marrow, "waking" occasionally to maintain proper blood levels in healthy individuals. HSCs are sensitive to the amount of IL-1 they encounter, and go to work creating "first responder" myeloid cells needed to fight what they recognize as a crisis of infection or injury. If the IL-1 signal doesn't end, HSCs continue making these cells but at the expense of their ability to regenerate themselves and correctly build the rest of the blood system. "They're receiving a signal telling them they need to keep building myeloid cells and as a result they don't make the other blood cells you need. You can end up with too few red blood cells, reducing the body's ability to deliver oxygen to cells. Or we see decreased production of new lymphoid cells, leaving the system potentially immunodeficient. These are all common features of chronically inflamed and even aged blood systems."

Another major question was whether these effects are reversible, in other words, once an HSC has "learned" to overproduce myeloid cells, can it just as readily unlearn this function? To test the durability of the IL-1 insult to HSCs following chronic inflammation, researchers treated mice for 20 days with IL-1 and then took it away for several weeks to see if the HSCs recovered. "Our data suggest that it is possible to turn back the clock and reverse the effects of chronic inflammation on blood stem cells, perhaps using therapies already available in the clinic to block inflammatory signals such as IL-1. Of course, we don't yet know on a human scale how long it takes a stem cell to 'remember' these insults. It may be that after a longer period of exposure to IL-1, these changes become more fixed." Overall, the study demonstrates for the first time that blood stem cells adapt to meet what they recognize as the body's needs, and that chronic inflammation can act like a thumb on the scale, implying a need that does not really exist.

Link: http://www.eurekalert.org/pub_releases/2016-04/uoca-cil042216.php

Here is a recent example of the more respectful treatment the cryonics industry receives in the popular press these days, though, as ever, the very important differences between freezing and vitrification in terms of their effects on tissues are skipped over. Cryonics providers don't freeze people, they vitrify them, as this offers a greatly improved preservation of fine structures, such as those in the brain that store the data of the mind. Improved methods of vitrification of tissue, with the aim of making it reversible, are in fact under active development by a range of research groups. The goal is use in the tissue engineering and organ transplant communities, to greatly improve the logistics of tissue storage, and I think that growth in that field of research is doing a great deal to change opinions about cryonics.

In the desert climate of Scottsdale, Arizona, rest 147 brains and bodies, all frozen in liquid nitrogen at the Alcor Life Extension Foundation with the goal of being revived one day. It's not science fiction - to some it might not even be science - yet thousands of people around the world have put their trust, lives and fortunes into the promise of cryonics, the practice of preserving a body with antifreeze shortly after death in hopes future medicine might be able to bring the deceased back. "If you think back half a century or so, if somebody stopped breathing and their heart stopped beating we would've checked them and said they're dead. Our view is that when we call someone dead it's a bit of an arbitrary line. In fact they are in need of a rescue." That "rescue" begins the moment a doctor declares a patient dead. Alcor's team then prepares an ice bath and begins administering 16 medications and variations of antifreeze until the patient's temperature drops to near freezing.

"The critical thing is how fast we get to someone and how quickly we start the cooling process," More said. In order to ensure that can happen, Alcor stations equipped teams in the U.K., Canada and Germany and offers members a $10,000 incentive to legally die in Scottsdale, where the record for getting a patient cooled down and prepped for an operation is 35 minutes. Next, a contracted surgeon removes a patient's head if the member selected Alcor's "Neuro" option, as it's euphemistically called, in hopes that a new body can be grown with a member's DNA once it comes time to be thawed out. It's also the much cheaper route. At a price tag of $80,000, it's less than half the cost of preserving your whole body. "That requires a minimum of $200,000, which isn't as much as it sounds, because most people pay with life insurance."

In fact, such a business model is pretty consistent in the nonprofit cryonics community. Michigan-based Cryonics Institute offers a similar payment structure, albeit at the more affordable cost of just $28,000 for whole-body preservation. Which begs the question: Why the price discrepancy? "We've been very conservative in the way we plan the financing. Of that $200,000, about $115,000 of it goes into the patient care trust fund," which is meant to cover eventual costs and is controlled by a board of trustees (a certain number of which is required to have loved ones currently in cryopreservation). The trust currently boasts a total of over $10 million, detailed by Alcor's most recent nonprofit 990 filings.

Link: http://www.cnbc.com/2016/04/26/meet-the-company-offering-a-chance-at-immortality-for-200000.html

UNITY Biotechnology and Oisin Biotechnologies are both early stage startups working on commercial development of therapies capable of clearance of senescent cells. Since accumulation of senescent cells is one of the root causes of aging and age-related disease, periodic removal of these cells is a narrowly focused form of rejuvenation. There are a number of other forms of damage and disarray that contribute to degenerative aging, and all will have to be fixed if aging is to be controlled by medicine, but an individual with fewer senescent cells is absolutely better off than one with more senescent cells regardless of the state of other forms of damage. Earlier this year researchers associated with UNITY Biotechnology published the results of the first life span study in normal mice engineered to destroy their own senescent cells, showing a 25% extension of median life span.

While the Oisin Biotechnologies principals have been pretty open on the topic of how their approach to senescent cell clearance works - it is a form of sophisticated gene therapy - the path chosen by UNITY Biotechnology remains less clear. In part this is because the public research based on gene therapy in mice that led to the life span study noted above is not something that could easily be adapted for use in human trials: it could be done, but almost every other option on the table would be both substantially easier to accomplish and more palatable to regulators. There is a trail of patents for other research leading in to the merger of groups that formed the company, but they cover a fairly wide selection of possible methodologies, including the use of immunotherapies and engineered viruses.

Gene therapies, immunotherapies, and more esoteric modern medical technologies are not the only possible approach to senescent cell clearance, however. In the past couple of years research groups have produced classes of drug - now called senolytic compounds - that can selectively drive senescent cells to self-destruct via the process of apoptosis. The combination of dasatinib and quercetin, for example, removes enough senescent cells in enough different tissues to produce meaningful benefits in mice. It isn't unreasonable to think that this type of result can be improved upon to the point at which it is a competitive option. Judging from recent news, it seems that UNITY Biotechnology will take the apoptosis-inducing drug development path, and, interestingly, is also setting up from the outset to deploy therapies outside the US in less heavily regulated regions:

Ascentage Pharma and UNITY Biotechnology Announce Collaboration for the Development of Senolytic Healthspan Therapies

China-based Ascentage - which is currently working on apoptosis-targeted cancer treatments - will work with UNITY Biotechnology to develop senolytic treatments for age-related diseases in an attempt to roll the back years for seniors. UNITY said it has also demonstrated in animal models that clearing senescent cells reverses or prevents many age-related pathologies, including: osteoarthritis, atherosclerosis, glaucoma, and kidney disease. "At UNITY, we have demonstrated that senescence is a key mechanism in aging and age-related disease. We have evaluated a wide panel of drug candidates that clear senescent cells, and Ascentage's compounds are some of the best we've seen. Access to their compound library through this collaboration will significantly accelerate our efforts to develop drugs to improve healthspan by halting or reversing several age-related diseases."

The biotech chose Ascentage as its partner in this anti-aging field "not only because of its cutting-edge technology, but also because this partnership will allow us to reach a global market." As part of the deal, the companies will also form a joint venture for the development and commercialization of senolytic drugs in China. Though specific terms are undisclosed, Ascentage has said it will acquire an equity interest in UNITY, and in return, the company will make an investment in Ascentage. Robert Nelsen, the co-founder and managing director of ARCH Venture Partners and a UNITY board member, will join the Ascentage board as an observer.

Ascentage Chairman and CEO Dr. Dajun Yang added, "We are one of the leading biopharmaceutical companies with clinical stage compounds targeting key proteins that control programmed cell death pathways. We will continue our efforts to advance clinical stage compounds for targeted anti-cancer therapy and are very pleased to work with UNITY for several unmet medical indications outside of the oncology space, with each aging-related disease potentially representing a multi-billion-dollar market."

Researchers here predict future incidence of sarcopenia, the loss of muscle mass and strength that occurs with aging and that is one of the main components of age-related frailty. As the average age of a population rises, incidence, costs, and burden on health will increase, and the costs at least have been something of a concern in political circles in recent years. There is some value in projecting present trends in epidemiology to create dire warnings on future prevalence of age-related disease, even though these trends are already out of date given what is going on in the labs and in early trials. It is a way to increase support for ongoing research to treat and prevent age-related disease, or ideally to intervene in the underlying processes that cause aging, and research funding always needs all the help it can get. In the case of sarcopenia, potential treatments include myostatin inhibition through gene therapy - or other less permanent methods - to spur more muscle growth than would otherwise occur, something that has already shown considerable potential in early human trials, and for which a large body of animal study data exists.

Sarcopenia is a disease associated with the ageing process. Hallmark signs of the disorder are loss of muscle mass and strength, which in turn affects balance, gait and overall ability to perform tasks of daily living. Due to its complexity, there is as yet no global consensus on the definition of the disease for diagnostic purposes. The European Working Group on Sarcopenia in Older People (EWGSOP) has defined sarcopenia as low muscle mass with low muscle strength OR with low gait speed. With two cutoff points available for each of the three components of this definition, eight different methods of diagnosis of sarcopenia can be used.

Using the Eurostat online database, the researchers retrieved age and gender-specific population projections from 2016-2045 for 28 European countries. The age and gender-specific prevalence of sarcopenia was assessed from a study that precisely compared prevalence estimates according to the different diagnostic cutoffs of the EWGSOP proposed definition. The prevalence estimates were interpolated for adults above 65 years of age. The estimates of sarcopenia prevalence were then applied to population projections until 2045. The results showed that using the definition providing the lowest prevalence estimates, the number of individuals with sarcopenia in Europe in 2016 is 10,869,527. This will rise to 18,735,173 in 2045 (a 72.4% increase). The overall prevalence of sarcopenia in the elderly will rise from 11.1% in 2016 to 12.9% in 2045. Women currently account for 44.2% of prevalent cases. Using the definition providing the highest prevalence estimates, the number of individuals with sarcopenia in Europe is 19,740,527 in 2016, rising to 32,338,990 in 2045 (a 63.8% increase). The overall prevalence of sarcopenia in the elderly will rise from 20.2% in 2016 to 22.3% in 2045. Women currently account for 66.4% of prevalent cases.

"Regardless of which diagnostic cutoff is used to define sarcopenia, the prevalence of sarcopenia is expected to rise substantially in Europe. It is therefore essential that we implement effective prevention and disease management strategies. Health authorities must take action in order to limit the impact on increasingly strained healthcare systems and to help Europeans enjoy healthy, active ageing."

Link: http://www.iofbonehealth.org/news/sarcopenia-which-affects-20-european-seniors-may-increase-63-2045

Researchers here provide a little evidence to suggest that increasing stiffness in muscle extracellular matrix, caused in part by growth in the level of persistent cross-links, explains some of the age-related decline in stem cell activity in that tissue. Removal of cross-links, with the primary target being those involving the advanced glycation endproduct glucosepane, is one of the rejuvenation treatments presently under development within the SENS Research Foundation network of scientists. I expect researchers to ultimately find that the age-related decline in stem cell activity - and all of the signaling involved in that decline - has evolved as a response to levels of molecular damage, rather than as an independent genetic program. Broadly repairing that damage should therefore do a lot to restore stem cell activity, though the stem cells' inherent damage will still have to be addressed as well.

Skeletal muscle aging is associated with a decreased regenerative potential due to the loss of function of endogenous stem cells or myogenic progenitor cells (MPCs). Aged skeletal muscle is characterized by the deposition of extracellular matrix (ECM), which in turn influences the biomechanical properties of myofibers by increasing their stiffness. Since the stiffness of the MPC microenvironment directly impacts MPC function, we hypothesized that the increase in muscle stiffness that occurs with aging impairs the behavior of MPCs, ultimately leading to a decrease in regenerative potential.

We showed that freshly isolated aged myofibers contain fewer MPCs, especially quiescent satellite cells, than adult myofibers. These results were comparable to those of other studies showing that the relative number of satellite cells decreases with age, pointing to a lower rate of self-renewal or to asymmetrical division. We recapitulated the MPC behavior observed on myofibers from adult and aged muscles using stiffness-tunable hydrogels and observed that there was a higher proportion of differentiating MPCs in aged damaged myofibers (18 kPa) than in adult damaged myofibers (2 kPa). This is consistent with the results obtained with MPCs grown on the 2 and 18 kPa hydrogels and indicated that there is a more committed MPC phenotype in aged myofibers. It is possible that an increase in the stiffness to 2 kPa of adult damaged myofibers is beneficial for the activation/proliferation of MPCs. On the other hand, an increase in the stiffness to 18 kPa, as observed in damaged aged myofibers, would be deleterious for the proliferation of MPCs but would favor differentiation. This may be one explanation for the decline in the regenerative capacity of aged skeletal muscle.

A growing body of evidence suggests that the stem cell niche serves as an environment in which stem cells respond to extrinsic stimuli associated with muscle growth and repair and that the mechanisms involved are negatively regulated by aging. As we showed, when MPCs are dissociated from their niche, the proliferation and differentiation potentials of MPCs from aged mice are similar to those of MPCs from adult mice, which lends support to the importance of the MPC niche. The composition of the ECM affects the mechanical properties of the tissue microenvironment, which in turn influences the activity of stem cells. Given that the ECM plays a major role in the increase in stiffness that occurs with age, some authors have suggested that there is a correlation between the increase in collagen deposition and the increase in muscle stiffness, with advanced glycation end-products (AGEs) playing a major role in glycation and collagen reticulation. Changes in the composition of the ECM during aging would thus provide regulatory cues to stem cells, modulating their quiescence, activation, differentiation, and/or self-renewal. In the present study, we confirmed that the increase in collagen deposition in the muscles of aged mice is correlated with an increase in hydroxyproline and AGE levels. These results reinforce the notion that the ECM undergoes qualitative and quantitative modifications with aging that would alter the myofiber repair process.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546553/

The Scientist has published a measured piece on the first results from BioViva's initial test of human gene therapy, telomerase and follistatin overexpression, and the broader context in which this single person test took place. The results indicate that the telomerase gene therapy most likely worked in the sense of delivering telomerase to a significant number of cells, including the immune cells used to measure average telomere length. That is an important thing to validate up front, before thinking about any sort of other outcomes, or expanding to a trial of some sort. Historically, gene therapies have proven to be highly varied in their effectiveness when it comes to uptake in target cells: in animal studies, the result might be 5% uptake, or it might be 60% uptake, or anywhere in between. A lot of work has gone into trying to make things more reliable over the past decade, but for many years yet there will be questions as to whether any particular formulation works well enough to build upon. That said, the error bars are large in these measurements, and further data is definitely called for.

First Data from Anti-Aging Gene Therapy

Last year, Elizabeth Parrish, the CEO of Seattle-based biotech firm BioViva, hopped a plane to Colombia, where she received multiple injections of two experimental gene therapies her company had developed. One is intended to lengthen the caps of her chromosomes (called telomeres) while the other aims to increase muscle mass. The idea is that together these treatments would "compress mortality," by staving off the diseases of aging - enabling people to live healthier, longer. Last week, BioViva reported the first results of Parrish's treatment: the telomeres of her leukocytes grew longer, from 6.71 kb in September 2015 to 7.33 kb in March 2016. The question now is: What does that mean? The company announced Parrish's response as success against human aging, having "reversed 20 years of normal telomere shortening." Over the phone, Parrish was more measured in discussing the implications of the finding, which has not yet undergone peer review. "The best-case scenario would be that we added 20 years of health onto the leukocytes, and the immune system might be more productive and catch more of the bad guys. But we have to wait and find out. The proof will be in the data."

Much more data are needed before claiming success against aging, said Dana Glei, a senior research investigator at Georgetown University. "We haven't established a causal link between telomere length and health. If it's like gray hair, dying your hair won't make you live longer." An n of one won't give us the answer, but Parrish's personal trial is the start of what BioViva hopes to accomplish: the first clinical studies using a gene therapy to stall aging and increase health span. The company's approach is backed by preclinical evidence - in particular, that from María Blasco's group at the Spanish National Cancer Research Centre (CNIO). In 2012, Blasco's team reported the results of a telomerase gene therapy in mice. The enzyme telomerase, encoded by the TERT gene, lengthens telomeres. "We demonstrated that AAV9-Tert gene therapy was sufficient to delay age-related pathologies and extend both median and maximum longevity in mice," said Blasco, who is not involved with BioViva. "Many pathologies were delayed, including cancer."

There is another potential weakness of the BioViva data: measurement error. The 9 percent difference between Parrish's before and after telomere lengths is within the measurement error of most laboratories. Houston-based SpectraCell Laboratories conducted the telomere length assay for BioViva. Jonathan Stein, the director of science and quality at SpectraCell, said that most telomere-length assays have a variance of 8 percent, and his firm's test is in line with that number.

The other gene therapy Parrish received - the gene encoding the follistatin protein - is supported by human data, at least in the context of people with muscle disorders. (There are not yet data demonstrating the effects of follistatin gene therapy on aging-related muscle loss.) Follistatin inhibits myostatin, which puts the breaks on muscle growth and therefore makes it an attractive therapy for muscular dystrophies. Early clinical trials on six people with Becker muscular dystrophy, for instance, showed that four of them could walk longer distances after the follistatin gene therapy. Parrish said she expects MRI data on her muscles' response to the treatment in about a month. Working with regulatory agencies has been a sticking point for BioViva, hence Parrish's trip to Colombia. Her controversial move - to skirt oversight by the US Food and Drug Administration by receiving the gene therapies outside the country - prompted a member of the company's advisory board, the University of Washington's George Martin, to resign. Parrish said she is now traveling the globe to find a regulatory partner willing to approve human clinical trials. "When I started looking into this, it seemed like a crazy science," she said. "But it's a crazy science whose time has come."

If you read around online discussions of BioViva's work, you'll find opinions to be fairly polarized. It is clearly the case that a fair number of people in the sciences really, really don't like it when anyone departs from the standard regulatory script of spending a lot of money and time keeping various government agencies happy, and set off to do something adventurous and entirely legal in another jurisdiction that regulators disallow in their own. This might be something like crabs in a bucket, perhaps, but the scientific community has always fiercely attacked those who deviate from the orthodoxy. Maintaining the scientific method in the face of those who are in fact out to undercut its foundations is a constant battle, and this is understandable. Yet the present system of regulation is not the embodiment of the scientific method, and certainly not the only way to conduct technological development resulting from science. Someone has to be the first human subject after animal studies have proven promising, and medicine has a long and noble history of self-experimentation to prove safety and capability, or even for the purposes of discovery. Many of the people who did this, and in some cases suffered for it, and as a result succeeded in producing new and useful medicine are regarded as brave pioneers. Rightfully so, I think.

What do regulators add to this picture other than barriers and objections? It doesn't require a regulator to design and carry out ethical studies in human medicine, and the present state of medical regulation is so ridiculously overblown, costly, and constrained that if everyone went by the FDA book, it would be a decade or more before anyone could legally access gene therapies intended to compensate for aspects of aging. Even that would only happen after the expenditure of billions of dollars, ensuring that only very large entities could control and deliver this sort of therapy: Big Pharma and government work hand in hand to the tune of their perverse incentives, limiting rather than expanding opportunities for progress. If you want a dynamic market of many small competing groups, innovative and rapid, then the heavy hand of regulation has to go. At present the only realistic way to go about this is to embrace the medical tourism marketplace and transparency in development: fund small trials, make all the data public, license the technology widely, and let educated patients decide on their options.

Freedom to choose and differences of opinion on the utility of specific therapies are important. For my money, I'm happy to let someone else go first in the case of telomerase gene therapy, which seems riskier than myostatin or follistatin gene therapies given the current state of evidence. I would be made more comfortable by trials in something other than mice, a species that is quite different from us in terms of its telomere dynamics and thus cancer risk profile following this sort of treatment. While telomerase gene therapy actually reduces cancer risk in mice in some cases, perhaps by spurring greater immune activity, along with extending life and reducing incidence of disease, there is no guarantee that the various changes involved will balance in the same way in humans. The falling cost and increasing reliability of gene therapy these days means that there are enough interested people for this to move straight to human testing, however - which isn't unusual in many areas of medicine, I should add.

Even if the economics were different, it is clear that telomerase gene therapies would still be heading for human trials one way or another. There are research groups with enough data in mice and the interest to move forward: telomerase therapies appear to be in essence another way to spur greater activity in old stem cells, and thus improve health and extend life, and all such approaches are gathering attention these days. The established research groups may well continue to work within the regulatory gauntlet while those less impeded forge ahead much more rapidly. This will be a repeat of the development of the stem cell industry over the past two decades, parallel lines inside and outside the gilded cage of regulatory capture. It was just about a decade between the availability of stem cell therapies via medical tourism and the capitulation of the FDA allowing the first classes of treatment in the US, and it certainly would have been longer without the pressure of having these treatments available so widely elsewhere in the world.

Researchers here demonstrate a method of spurring microglia to attack amyloid in mice. It should be said that this is only the latest in a number of approaches shown to clear amyloid and improve symptoms in a mouse model of Alzheimer's disease. Alzheimer's research is an area in which a great many research results fail on moving from mice to people, but that said, there is a lot of independent evidence for microglia to be a useful target in Alzheimer's and other neurodegenerative conditions.

A study has discovered that a protein called IL-33 can reverse Alzheimer's disease-like pathology and cognitive decline in mice. "Alzheimer's disease currently has an urgent unmet clinical need. We hope that our findings can eventually be translated into humans. IL-33 is a protein produced by various cell types in the body and is particularly abundant in the central nervous system (brain and spinal cord). We carried out experiments in a strain of mouse (APP/PS1) which develop progressive AD-like disease with ageing. We found that injection of IL-33 into aged APP/PS1 mice rapidly improved their memory and cognitive function to that of the age-matched normal mice within a week."

The hallmarks of Alzheimer's include the presence of extracellular amyloid plaque deposits and the formation of neurofibrillary tangles in the brain. During the course of the disease, 'plaques' and 'tangles' build up, leading to the loss of connections between nerve cells, and eventually to nerve cell death and loss of brain tissue.‌ IL-33 appears to work by mobilising microglia (immune cells in the brain) to surround the amyloid plagues, take them up and digest them and reduces the number and size of the plaques. IL-33 does so by inducing an enzyme called neprilysin, which is known to degrade soluble amyloid. In addition, the IL-33 treatment worked by inhibiting the inflammation in the brain tissue, which has been shown earlier to potentiate plaque and tangle formation. Therefore IL-33 not only helps to clear the amyloid plague already formed but also prevent the deposition of the plaques and tangles in the first place.‌‌

"The relevance of this finding to human Alzheimer's is at present unclear. But there are encouraging hints. For example, previous genetic studies have shown an association between IL-33 mutations and Alzheimer's disease in European and Chinese populations. Furthermore, the brain of patients with Alzheimer's disease contains less IL-33 than the brain from non-Alzheimer's patients. Exciting as it is, there is some distance between laboratory findings and clinical applications. We are just about entering Phase I clinical trial to test the toxicity of IL-33 at the doses used. Nevertheless, this is a good start."

Link: http://www.gla.ac.uk/news/headline_456223_en.html

The Revolution Against Aging and Death (RAAD) Festival will be held in California this coming August. The list of speakers is a fascinating combination of the old and the new in the life extension advocacy community: people who have spent decades focused on supplements, health optimization, and the like on the one hand, representatives of the new field of rejuvenation biotechnology on the other, topped off by futurists and advocates whose efforts span these eras.

It is undeniably true that the "anti-aging" industry, for all that it is wall to wall fraud and lies, has built an enormous delivery network and megaphone, and that a lot of the people involved are genuinely passionate about the end goal of radical life extension and the end of aging. It is one of the many paradoxes of the broader community that despite this passion they spend their efforts on businesses and products that cannot make any real difference, and are probably doing more harm than good when you consider how their marketing affects public perception of legitimate work on extending healthy human lives. Nonetheless, there is an argument for engaging the more legitimate end of this industry in order to prepare the ground for a near future of actual, working treatments for aging, and increase the chances for a rapid transition of the first rejuvenation therapies into clinics worldwide. RAAD Festival is an example of that mindset in action, coupled with a determination to shift public discussions of longevity science and the bounds of the possible towards the goal of indefinite healthy life spans:

Join us for the largest ever gathering of radical life extension enthusiasts to learn the latest scientific advancements, connect with like minded people, gain vital insights to extend your health and wellbeing, become a more empowered and effective advocate, interact with leaders of radical life extension, and have a blast celebrating our unlimited future together with music and performances. This is our time to shine. It's time for us to come together, to learn about the newest life extending science and super longevity strategies, to take pride in our progressive views, and to be empowered to make our voices heard. RAAD Fest combines the energy and fun of a festival, the empowerment and interaction of personal development, with cutting edge science presented for a lay audience to create the first and best holistic radical life extension event ever. Hear from top scientists, entrepreneurs and thought-leaders addressing every aspect of radical life extension, from nutrition and new gene therapies, to the power of personal intention, the sociology of immortality and advancement in artificial intelligence. You will also have the opportunity to interact with our experts as well as share your own views.

We're at a unique turning point in terms of the plausibility of radical life extension. It's not a new idea. Taoists were interested thousands of years ago. 19th Century Russian philosophers talked about physical immortality. Books written in the 1950s and 60s predicted it would happen. But only now is the science starting to look solid. So this is a critical time for people to come together to learn what is happening now and to understand how they can make a difference both in their own lives and in the culture at large. This is the purpose of RAAD Fest, the largest radical life extension event ever.

It's not enough to just talk about possibilities. We need to take all possible actions, including improving diet, exercise, and adopting a positive-and-practical attitude. And we need to influence public opinion to drive more research investment in radical life extension. Action now can be the difference between living and dying. The idea that lifespans are not fixed is being taken seriously by serious people. But we need to bring together the diverse groups involved in radical life extension to have greater impact on public policy. We still spend ludicrous amounts of money on end-of-life care, which is basically extending misery and suffering, when we could be spending it on research that would prevent people from getting in that situation in the first place. We can't afford to have a passive mentality in which we agree in principle, but don't do anything about it. The stakes are too high. We need to come together to celebrate life and to inspire people to take more steps to live healthier lives now, and to take constructive action in society. There's so much that needs to be done. We need to push for changes in public policy, in corporate research funding, and in personal attitudes and cultural beliefs.

Link: http://raadfest.com/

Today I thought I'd point out a couple of interesting papers on the work of finding drugs to intervene in the aging process. This is far from a widespread undertaking, even now that more funding is arriving into the field. The majority of researchers focused on aging are not looking to intervene in the aging process at all, and their work is purely investigative. Equally, the majority of research into age-related disease is focused on working backwards from the disarray of a diseased metabolism, tracing molecular links in long chains of cause and effect that hopefully lead closer to causes rather than dead ends. At each new discovery, some groups stop to develop therapies, screening for drugs that can influence the newly uncovered link in a beneficial way, while causing few enough side-effects to be acceptable. Preference is typically given to existing drugs, even if they are much less effective than a theoretical new drug, because it is less expensive to push that through the regulatory system. The nature of this approach means that the resulting therapies largely involve tinkering with an already complex, failed metabolic state, without addressing the root causes of that failure, and are therefore only marginally effective. This is the story of most medical research: expensive drug development, massive regulatory costs, perverse incentives to create less effective treatments, and tiny gains at the end of the day.

There is a completely different approach to the problem of age-related disease, however, which is to start from the beginning and the known root causes of aging, and try to repair and revert these causes prior to a full understanding of the chain of cause and effect that drives the progression of aging. Don't try to work forward to full understanding of the process, just fix things where there is compelling evidence for their involvement in aging and see what happens. This should be much less challenging than the mainstream approach of working backwards from the disease state, and should produce far better results. It should also answer many questions as to the root causes of specific age-related diseases, and far more efficiently than working backwards through the complexity of late stage disease. How do researchers know what the root causes of aging are with such great reliability? Over the years, many, many research groups have compared old tissue and young tissue, and ruled out everything that has a direct cause other than the operation of normal metabolic processes. What is left is a consensus list of side-effects and molecular damage, the fundamental changes that are produced in the cells of normal, healthy, young individuals, and that slowly turn them into aged, diseased, and ultimately dead individuals. Unfortunately this better approach of repair has yet to gain more than a foothold in the research community. There is a long way to go yet before we can call rejuvenation research a mainstream, well-funded concern.

If you look through the SENS rejuvenation research programs, it is clear that there is a role for traditional or more modern drug discovery and development in a number of areas. There may prove to be good enough drug-based approaches to senescent cell clearance, for example, to compete in the marketplace with the more efficient and directed gene therapy techniques pioneered by Oisin Biotechnologies. Work on breaking down glucosepane cross-links will also no doubt settle down to some form of drug development once an initial class of compounds shows effectiveness. There are other examples, such as the work of Pentraxin Therapeutics or Human Rejuvenation Technologies that are both fairly standard issue drug development and relevant to the SENS vision. So all in all, I think you'll find the open access papers below interesting, even if they have little to say in and of themselves on the topic of rejuvenation research, being more focused on methods of altering metabolism to slightly slow aging.

Finding Ponce de Leon's Pill: Challenges in Screening for Anti-Aging Molecules

Several drugs have demonstrated great promise in the laboratory setting in enhancing the healthspan and lifespan of multiple species, including mice, raising the possibility that efficacious pharmacologic anti-aging therapy in people may be possible. However, screening for novel small molecules with anti-aging effects in mammals in an unbiased fashion represents an enormous, potentially insurmountable challenge. Alternatively, since it is clear that several cellular pathways affect longevity in an evolutionarily conserved manner, invertebrate models may be quite useful for such screening endeavors. However, some known molecular factors with major effects on mammalian lifespan are not well conserved between invertebrates and mammals. Consequently, small molecule screening efforts relying exclusively on the use of invertebrates will likely miss drugs with potent effects on mammalian aging. Moreover, many of the key physiologic features of humans and other mammals are not well modeled in invertebrates, as the latter lack specific tissues like heart and kidney and complex endocrine, nervous, and circulatory systems that are crucial targets of mammalian aging and age-related pathologies. Most invertebrate aging models possess limited regenerative capabilities and incompletely recapitulate processes such as stem cell renewal, which are required for tissue repair mechanisms that maintain tissue homeostasis in mammals, in order to sustain organ function over years and decades.

To date, the discovery of anti-aging compounds has so far been carried out via two basic approaches. One of these is phenotypic, defined as the screening of compounds in cellular or animal models to identify drugs conferring desired biological effects, i.e. lifespan extension. Although this approach has proven enormously valuable in many areas of biochemical research, identifying drugs that can modulate lifespan is more time consuming, complex, and expensive than for many other phenotypes. Moreover, elucidating the mechanism of action of agents identified in such phenotypic, "black box" screens represents a formidable challenge, though the powerful genetic tools available in invertebrate models can facilitate such efforts. A complementary approach involves target-based screening for modulators of pathways known or strongly suspected to modulate the aging rate. However, by definition, such efforts are unlikely to identify novel cellular factors and pathways involved in longevity.

A related challenge in aging research at present is the lack of primate model systems with reasonably short lifespan for preclinical testing of candidate anti-aging drugs. The most commonly used model, the rhesus monkey, lives for three to four decades. In Europe, the marmoset is used as a non-rodent species for drug safety assessment and toxicology. However, their maximal lifespan is ~17 years - shorter than the rhesus monkey, but still highly impractical for testing pharmacological interventions aimed at extending longevity. The development of new mammalian aging models besides the mouse would be extremely helpful to better elucidate the biological processes underlying mammalian aging and to expedite the translation of pharmacological interventions from the laboratory to actual clinical use in humans. One model to consider in this regard is dogs, which share their social environment with humans. Furthermore, dogs are relatively well understood with regard to aging and disease, exhibit great heterogeneity in body size and lifespan, and provide a large pool of genetic diversity. Testing candidate anti-aging compounds in humans represents an enormous challenge. It is highly unlikely that pharmaceutical companies can be persuaded to engage in decades-long clinical trials of candidate anti-aging medicines with lifespan as an endpoint. The evaluation of shorter-term surrogate phenotypes, such as molecular markers or age-associated defects such as impaired responses to vaccination, may permit initial clinical evaluation of candidate anti-aging compounds in a more reasonable timeframe.

Biology of Healthy Aging and Longevity

As a heterogeneous process, aging may occur at different rates across diverse organisms, and even organisms of the same species can age at variable rates. At the biological level, aging is characterized by the accumulation of molecular and cellular damage, which leads to structural and functional aberrancies in cells and tissues, such as loss of mitochondrial homeostasis, impaired intercellular communication, senescence (cell arrest that hampers growth and division), and decreased regenerative capacity. The ability of organisms to overcome stress and respond to external environmental challenges/insults is blunted within aged individuals when compared to younger counterparts. Healthy aging, however, refers to the warding off of molecular and cellular decline for the longest length of the lifespan. Not surprisingly, healthy aging has been associated with increased longevity. This claim is substantiated by the fact that genetic, dietary, and/or pharmacological interventions that promote cellular homoeostasis, stress resistance, and protection against age-related diseases also tend to extend lifespan and vice versa.

Overwhelming scientific evidence supports the claim that there is no single cause of aging. Indeed, notable advancements in the biology of aging, especially during the last few decades, have contributed to the identification of multiple mechanisms that modulate the aging process. Despite this progress, uncovering interventions that can achieve healthy aging in humans is challenging. The conserved molecular and cellular mechanisms that underlie aging, especially how these pathways interplay and how complex lifestyles and environments to which humans are exposed modify them, are not completely understood.

Despite the impressive advancements made towards understanding more about the molecular basis of aging, there is still no definitive intervention for ensuring healthy aging in humans. To uncover new therapeutic avenues, we need to gain deeper knowledge about how different internal and external factors regulate the cellular hallmarks of aging, and how their regulation changes across time and individuals. All molecular pathways exhibit complex communication known as "crosstalk." The genome, epigenome, organelles, proteome, and pathways such as those involving sirtuins, mTOR, AMPK, and insulin/insulin-like growth factor-1 signaling - all integrate and process signals that must act coordinately to promote homeostasis in cells and tissues. It is unclear, however, how these complex molecular networks are affected by diverse environmental challenges and how they become impaired with aging. Lastly, in an effort to find beneficial interventions to delay aging-linked deterioration, the search for small molecules that can mimic calorie restriction - and the dissection of their pharmacological modes of action in vivo - is a growing area of research that merits more attention. Collectively, through all of these scientific efforts, we may someday achieve the longstanding human dream of living a long and healthy life.

Cryonics is the low-temperature vitrified storage of at least the brain on clinical death, with good evidence for it to preserve the fine structures that store the data of the mind. For so long as the mind is maintained, there is a chance that future technologies and societies will become capable of restoration. A small non-profit industry offers cryopreservation services for the few people who choose to avoid the certain oblivion of the grave, but growth into a sizable competitive market has proven elusive. This is important because growth is largely agreed to be necessary for longer-term survival of cryonics organizations, and thus the preserved minds, into a future period in which restoration is plausible. A lot of people interested in cryonics have their opinions on what should be done, which strategies should be pursued for growth, and the open access paper linked here is one such, suggesting integration with the funerary industry.

A significant merger of cryonics with the funerary industry has not happened and will likely never happen on the part of present organizations, as the essence of cryonics and the culture of its community is predicated on the fact that preserved individuals are patients, and clinical death is distinct from final information theoretic death. Cryonics is an emergency medical service, not a funeral arrangement, and this distinction is vital to the community. The path presently taken by the cryonics industry to grow and gather more acceptance is through integration with the medical development community, such as via the development of reversible vitrification for use in the organ transplant field, a line of research that is gaining more interest and appears to be nearing realization.

Cryonics service providers offer their customers perpetual care. This care is meant to continue until medical technology has advanced to the point that their reanimation can be performed safely. While the most optimistic estimates are that reanimation may be possible in as little as fifty years, the time frame is normally considered to be hundreds of years. The poor quality of suspensions received by most persons, however, suggests that many will be reanimated only in the distant future, if at all. One of the greatest unknowns is whether these companies will be able to operate continuously over this period. The cryonics industry's offer of perpetual care is organizationally similar to the offer of perpetual care provided by the Catholic Church in England in the Middle Ages in the form of chantries. The first perpetual Mass was established by royalty in the 1180s. Most institutions providing this service were suppressed in 1547 as part of the Reformation. Therefore, the "perpetual" care lasted for less than 400 years. The chantries were established as part of the Roman Catholic Church or as institutions under its direction and control. During this period, the Roman Catholic Church was as powerful as a state and was considered by many to be the governing body of Europe. In contrast, cryonics organizations are very small businesses with extremely limited resources, and are subject to regulation by both State and Federal governments. The key question addressed here is whether and how such organizationally inferior institutions can achieve the longevity that the most powerful organization in Europe only barely achieved in earlier times.

According to the monthly data on the Cryonics Institute (CI) website, CI membership will not continue to increase indefinitely with the current strategy. Those figures show that paid-up memberships will never pass 2,200. At that point, members going into suspension will equal new signups. The Alcor Life Extension Foundation membership appears to be following a similar pattern, i.e. a fixed number of new members per month, which is a declining growth rate. This is in sharp contrast to the earlier growth rates seen at CI, which indicated a doubling in membership every three to five years. If this trend continues, then CI will reach its peak size in about 50 years. We can expect a long decline to follow, since long-term stability is an unknown phenomenon for organizations. CI would then be expected to disappear in less than a hundred years after this peak, about 150 years from now. Since about half of prearranged suspensions can be considered poor, due to delays in cooling, it is unlikely those cryonicists will be reanimated within this time frame. In fact, there is significant doubt that anyone cryopreserved with today's technology could be reanimated within the next 150 years. A hundred and fifty years would be an unusually long lifetime for a business organization, so this estimate is likely overoptimistic.

The mainstream view of cryonics is that it is an unusual interment practice. In fact, CI was, for a time, officially registered as a cemetery. Under the Uniform Anatomical Gift Act employed, persons must be declared dead prior to being processed for suspension. About half of all cases at CI are postmortems. Since no marketing is directed toward the funeral industry, we can conclude that marketing efforts are having no effect or that there is an unmet demand that is being made apparent. In fact, a cooperating funeral director recently requested that he be allowed to offer cryonics as a standard product. Therefore, we can conclude that both mainstream opinion - government - and the market are signaling the need for a strategy employing the funeral industry as a sales channel. Failure of the medical model has been attributed to the inability to demonstrate revival from the suspended state. However, survey data shows that attitudes would hardly be affected by such a demonstration. A majority of the public simply doesn't view aging as a disease and doesn't see death as a medical problem. Some funeral directors see cryonics as an option, suggesting the funeral industry as an appropriate sales channel.

There is no physical difference necessary between facilities for cryonic suspension and cryogenic interment, which could be considered an esoteric burial practice similar to having one's ashes launched into space. The difference amounts to an intent to revive. The major barrier to implementation of this new sales channel is the self-perception of the leadership of the cryonics organizations. They would have to accept that they were participants in the funeral industry. The entire future of the cryonics industry, of those in storage, and of the many that will never be suspended because suspension is not marketed via the funeral industry is being jeopardized to maintain this self-perception by the leadership of the cryonics organizations. From the standpoint of social movement theory, the industry is maintaining its isolation from the mainstream at a time when it is technically mature enough to become a mass movement. If local funeral directors acted as sales agents, a rapid response would be likely. This arrangement could lead to better suspensions and increased sales. The major barrier appears to be the self-perception of leaders in the cryonics organizations.

Knowledge of and acceptance of cryonics, as an interment practice, has become widespread. The discrepancy between the acceptability of cryonics and its adoption suggests that a new approach based upon existing social models is needed. One such model is conventional funeral provision. The key to survival of the cryonics industry appears to be a successful transition to the mainstream. However, continued isolationism appears to be essential to the maintenance of a preferred self-image by insiders. While insiders see themselves as "saving lives" by performing an advanced form of medicine, the isolationism of the industry is actually resulting in the "loss" of many lives that could be "saved."

Link: http://dx.doi.org/10.1080/23311886.2016.1167576

Initial data appears to show success for the telomerase gene therapy undergone by the BioViva CEO last year. Similar gene therapies extend life in mice, most likely though increased stem cell activity and thus improved tissue maintenance. It doesn't seem to raise cancer risk in mice, but there is a concern that this may still be an issue in humans, with our quite different telomere and telomerase dynamics. Measuring the length of telomeres as presently accomplished in white blood cells is a proxy metric of dubious value for the endpoint of improved stem cell function, unfortunately, but it is the technique presently available at reasonable cost and reliability. Average telomere length in immune cells is only tenuously related to age, statistically over large populations, and does tend to change over time in both directions in individuals due to changing health and other circumstances. The alteration here is large enough and rapid enough, however, to indicate that the gene therapy worked in the sense of delivering telomerase. Finding out whether it worked in other senses, producing a more youthful tissue environment, would require a biomarker of biological age, such as the DNA methylation measures presently under development.

In September 2015, then 44 year-old CEO of BioViva USA Inc. Elizabeth Parrish received two of her own company's experimental gene therapies: one to protect against loss of muscle mass with age, another to battle stem cell depletion responsible for diverse age-related diseases and infirmities. The treatment was originally intended to demonstrate the safety of the latest generation of the therapies. But if early data is accurate, it is already the world's first successful example of telomere lengthening via gene therapy in a human individual. Gene therapy has been used to lengthen telomeres before in cultured cells and in mice, but never in a human patient. Telomeres are short segments of DNA which cap the ends of every chromosome, acting as 'buffers' against wear and tear. They shorten with every cell division, eventually getting too short to protect the chromosome, causing the cell to malfunction and the body to age.

In September 2015, telomere data taken from Parrish's white blood cells by SpectraCell's specialised clinical testing laboratory in Houston, Texas, immediately before therapies were administered, revealed that Parrish's telomeres were unusually short for her age, leaving her vulnerable to age-associated diseases earlier in life. In March 2016, the same tests were taken again by SpectraCell revealed that her telomeres had lengthened by approximately 20 years, from 6.71kb to 7.33kb. This implies that Parrish's white blood cells (leukocytes) have become biologically younger. These findings were independently verified by the Brussels-based non-profit HEALES (HEalthy Life Extension Company), and the Biogerontology Research Foundation, a UK-based charity committed to combating age-related diseases.

"Current therapeutics offer only marginal benefits for people suffering from diseases of aging. Additionally, lifestyle modification has limited impact for treating these diseases. Advances in biotechnology is the best solution, and if these results are anywhere near accurate, we've made history.". Bioviva will continue to monitor Parrish's blood for months and years to come. Meanwhile, BioViva will be testing new gene therapies and combination gene therapies to restore age related damage. It remains to be seen whether the success in leukocytes can expanded to other tissues and organs, and repeated in future patients. For now all the answers lie in the cells of Elizabeth Parrish, 'patient zero' of restorative gene therapy.

Link: http://bioviva-science.com/2016/04/21/first-gene-therapy-successful-against-human-aging/

Today's news, linked below, comes from the Russian end of the longevity science community. If you've been following the work of the Science for Life Extension Foundation folk over the years, then you'll recognize many of the names involved, but this particular announcement involves a group that I wasn't aware existed. Before diving in, I should say that in comparison to the English language world the Russian public and longevity science community have always been far more enthusiastic and outspoken when it comes to the logical end goal for efforts to treat aging. That means the defeat of aging, the production of a cure for aging, to bring aging under the complete control of medicine, to end aging and thereby produce indefinite healthy life spans. There is probably an interesting anthropological study to be made of this difference between our cultures, but equally perhaps it is simply the consequence of a greater degree of engagement, respect, and support for the sciences one sees in Russia and the surrounding regions.

IVAO to announce plans to invest over $1 billion in aging and longevity projects at a conference in St Petersburg

IVAO is organizing an international conference titled "Biomedical Innovations for Healthy Longevity", where top thought academic thought leaders and industry executives from all over the world will convene for three days to present latest research results, discuss translational and commercialization opportunities, establish valuable collaborations, network and partner. The event features a business forum with one day dedicated to round table discussions on presenting favorably presenting aging research in the press, novel ways to attract funding and classifying aging and many age-associated conditions.

At the conference IVAO plans to announce a roadmap for investing over $1 billion into a broad range of projects, companies and financial instruments linked to longevity research. "After millennia of failed promises, we are finally reaching the point in human evolution, where major breakthroughs contributing to the body of knowledge in aging are happening almost every month in laboratories all over the world. We decided to combine the best features of mutual funds, venture capital firms and analytical companies in one place to build a reasonably conservative investment vehicle to take part in the coming longevity boom," said Andrey Fomenko, founder of IVAO.

"Since 1995 Andrey Fomenko and I monitored research activities in aging and longevity. When in 1996 we established our non-profit Eternal Youth Foundation, most people did not understand. But today these technologies are becoming mainstream and time horizons for many technologies are shrinking," said Lada Fomenko, the head of Eternal Youth Foundation and Director of IVAO. Scientists, industry executive, investors and students are invited to attend the conference and network with the most advanced professionals in aging and longevity to help advance the entire field.

Human organization friction is a very real thing. The larger and less familiar the endeavor, the longer it takes to pull people together, raise funds, and get going. You should assume that any new venture you read about in the press was at least a few years in the making, quietly and behind the scenes. When fields are especially young, it can take years of networking, advocacy, and happenstance for a community to evolve to the point at which formal ventures are even a possibility. So while the regular readers here at Fight Aging! have been involved in this modern rejuvenation research community for a while and are generally pretty bullish on longevity science, the rest of the world is only just opening its eyes.

It has been more than twenty years since the first compelling demonstrations of slowed aging in laboratory animals using modern technologies. Most of the time since then has been a beginning of sorts, the formation of a community, a war of persuasion and debate in the research community, a growing amount of bootstrapped funding, a few major failed projects seeking to find treatments for aging, and advocacy for better ways forward such as the SENS damage repair approach. In the grand scheme of things, the tens of millions of dollars devoted to new work on aging by a handful of foundations over the past decade, hard-won victories though they were, are still just faint echoes at the edges of the broader field of medical research. The mainstream is billions in funding for pure research, and hundreds of times that amount for the business of treatments.

Faint echoes are how every new mainstream paradigm begins, however. The end of the beginning was definitively marked by Google's high profile investment in interventional aging research in 2013. It was a sign that the comparatively quiet cultural war that took place in the aging research community over the past few decades was over, and those who favored public discussion and treatment of aging won decisively. Similarly, it was a sign that the overlapping networks of technology, philanthropy, and capital now understood medicine for aging as a promising frontier, something worthy of more than the largely small and faltering experiments in investment that had taken place in the decade prior, the now long-dead startups that suffered largely from being too early, struggling prior to the first wave of significant support for their goals.

Matters are accelerating now. It is rarely the case that more than a few months go by these days without an entirely new significant venture that I had never heard of coming to my notice. People in the philanthropic and investment communities are slowly but surely waking up to the prospects for treating aging and ultimately bringing aging under medical control, and some are becoming quite enthusiastic supporters of radical life extension along the way. Some have been building funds and connections for a few years now, largely isolated from the portions of the advocacy community we're familiar with. The community itself has broadened until its far nodes are well beyond my sight and awareness. This is all very promising, for all that I fully expect most of the new money, like that put in by Google, or that invested in Human Longevity Inc., to go to projects that will do nothing but add knowledge, or only incrementally improve the present inadequate approach to treatments for aging. That means work on therapies that do little or nothing to address the root causes of aging, and are usually only poor patches over the damage. Funding communities build upon themselves, however, and the more interested money in the ecosystem, the easier it will be to advance the state of SENS rejuvenation research - both the work that still must be done in the labs, and the startup companies that are launched or close to launch.

The presence of reactive oxidizing molecules in our tissues increases with age. These cause damage by reacting with proteins, all of which are important parts of the biological machinery in some portion of a cell. An oxidized protein has a different chemical structure and thus cannot perform its normal tasks. This contributes to disarray and dysfunction in a cell until the damaged protein is removed by quality control processes. High levels of oxidation are referred to as "oxidative stress," and this plays an important role in aging. It is, however, far from straightforward as to how this stress arises and then interacts with metabolic operations and damage repair systems, though mitochondria appear to play a number of important roles. It appears that oxidative stress is a later condition of aging, a fair way removed from primary causes, but a lot of researchers start at this point and consider how to intervene at this level:

Improved therapies for the treatment of idiopathic pulmonary fibrosis (IPF) and other fibrotic diseases are needed. It has been suggested that core pathways that mediate fibrosis in multiple organ systems may serve as targets for anti-fibrotic drug development, such as redox imbalance in the context of aging. Aging results in decreased resistance to multiple forms of stress, as well as increased susceptibility to numerous diseases. Progressive fibrosis is a hallmark of aging in various organ systems, including the liver, kidney, pancreas and lung. IPF, the most fatal and progressive fibrotic lung disease, disproportionately affects the elderly population and is now widely regarded as a disease of aging. The incidence and prevalence of IPF increase with age; two-thirds of IPF patients are older than 60 years at the time of presentation with a mean age of 66 years at the time of diagnosis. Further, the survival rate for IPF patients markedly decreases with age. Although the roles of specific aging hallmarks in the pathogenesis of IPF have not been fully elucidated, numerous studies implicate age-related alterations in cellular function in the pathogenesis of IPF.

Aging and fibrotic disease are both associated with cumulative oxidant burden, and lung tissue from IPF patients demonstrate "signatures" of chronic oxidative damage. The "oxidative stress theory" posits that a progressive and irreversible accumulation of oxidative damage caused by reactive oxygen species (ROS) impacts critical aspects of the aging process by contributing to impaired physiological function, increased incidence of disease, and a reduction in life span. Oxidative stress can lead to extensive modifications or damage to macromolecules including DNA, lipids and proteins and can also lead to increased production of cytokines. The lungs are particularly prone to insult and injury by oxygen free radicals given their direct exposure to the environment via inspired air. Further, environmental insults to lung may serve as a "second hit" which accelerate the aging process by promoting persistently elevated oxidative stress levels leading to increased susceptibility to disease. Oxidative stress may represent a core pathway by which other "damage" theories of aging are based. Examples include genomic instability as a result of DNA damage, and accumulation of glycated crosslinks during protein damage that can result in pathogenesis associated with cardiovascular and neurodegenerative disease. Recent studies of familial and sporadic cases of IPF have been associated with telomere shortening, further supporting the concept that IPF may represent an age-related degenerative disease process. The causes for the shortened telomeres in IPF patients without mutations in telomerase is currently unknown; however, oxidative stress represents one potential mechanism. A better understanding of the mechanisms that mediate oxidant-antioxidant imbalance in aging may be critical to the development of more effective therapeutic strategies.

Despite the well-recognized role of oxidative stress in fibrosis and aging, the ability to precisely target key mediators of this process has proved difficult. By definition, oxidative stress occurs when cellular ROS levels overwhelm the cellular antioxidant capacities, thus therapeutic strategies have been directed inhibiting oxidant generation as well as stimulating antioxidant capacity. A number of antioxidant therapeutic strategies have shown promise in various preclinical models, however, they have failed to demonstrate efficacy in the clinic. Although there may be several potential reasons for this observed lack of efficacy of anti-oxidants, one important consideration is the potential for ROS to function as redox signaling molecules for physiologic cell signaling. In fact, ROS may be viewed as "antagonistically pleiotropic" by mediating detrimental effects in the context of aging or an age-related disease. Based on its pleiotropic functions, it can be argued that targeting the primary enzymatic source of ROS (rather than anti-oxidant approaches) may offer a more promising strategy.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791330/

At the high level, the arguments for deploying telomerase-based therapies to lengthen average telomere length in various tissues and cell populations as a treatment for aging have not changed much over the past decade. The data and details have evolved with progress in investigative research, but the digest of the views held by the faction who think this way remains this: that average telomere length is enough of a cause of issues in aging, as opposed to being a reflection of other processes with few secondary effects of its own, to merit addressing. My view of the state of research is still that average telomere length looks very much like a signature of aging, not a cause of aging. It is a measure of some combination of stem cell activity, meaning the pace of delivery of new cells with long telomeres, and rates of cell division, as telomeres shorten a bit every time a cell divides. Since stem cell activity declines with age, so too does average telomere length - and the problem here is the loss of tissue maintenance by stem cells, not the length of telomeres per se.

Researchers have demonstrated that telomerase therapy can extend life in mice, most likely by improving stem cell activity in old age, one of the many ways in which it is possible to force old stem cells do more work than they have evolved to undertake at that stage in life. This approach to treating issues of old age is heading in the direction of human medicine, at the usual glacial pace of later stage research moving through the regulatory pipeline, barring a few brave outliers. There are concerns about cancer risk, given that the present consensus is that loss of stem cell activity with age most likely serves to reduce cancer incidence, extending life at the cost of frailty. In mice telomerase therapy has not shown increased cancer rates, which is a challenge to the consensus view, but mice have very different telomere dynamics in comparison to we humans. In any case, this paper is authored by one of the more prominent groups involved in this work, arguing for more of a focus on the field of telomerase therapies to treat aging:

Telomerase is a DNA reverse transcriptase polymerase (telomerase reverse transcriptase, TERT) which uses an RNA template (telomerase RNA component, TERC) for de novo addition of telomeric DNA onto telomeres, thus compensating for the telomere erosion caused by cell divisions. Indeed, overexpression of telomerase is sufficient to counteract telomere attrition and to indefinitely extend the replicative lifespan of primary cells in culture in the absence of genomic instability, transforming them into cancerous cells. However, high telomerase expression is normally restricted to early stages of embryonic development (i.e. the blastocyst stage in mice and humans) and to pluripotent embryonic stem cells. Thus, adult mammalian tissues including adult stem cell compartments do not express sufficient amounts of telomerase to maintain telomere length throughout organismal lifespan. Consequently, telomere shortening occurs along with physiological aging in humans and mice and this process is proposed to underlie aging and age-associated diseases as well as organismal longevity.

During recent years, a number of molecular pathways have been identified as main molecular causes of aging, including telomere attrition, cellular senescence, genomic instability, stem cell exhaustion, mitochondrial dysfunction, and epigenetic alterations, among others. Interestingly, telomere attrition is considered a primary cause of aging, as it can trigger all the above-mentioned hallmarks of aging, although the degree to which it is a principal cause of aging is under active investigation. Critical telomere shortening elicits the induction of cellular senescence or the permanent inability of cells to further divide, which in turn has been proposed to be at the origin of different disease states. In addition, telomere attrition in the stem cell compartments results in the exhaustion of their tissue- and self-renewal capacity, thus also leading to age-related pathologies.

A substantial number of companies are now aiming to harness the knowledge that has been generated, unveiling the molecular mechanisms of aging in order to develop a new class of drugs to prevent and treat the major age-related diseases. In this regard, telomerase overexpression studies in mice have been proof of principle that just modifying a single hallmark of aging, i.e. telomere shortening, this was sufficient to delay not one but many different age-associated pathologies in mice, including cognitive decline. Indeed, the use of telomerase activation in delaying aging-associated conditions has spurred the interest of commercial enterprises. However, potential off-target effects of compounds that activate TERT at a transcriptional level should be a concern. Such off-target effects may be circumvented through direct delivery of TERT, such as by means of systemic gene therapy using non-integrative AAV vectors, which showed a significant delay of age-related pathologies in mice and increased longevity. However, it should be mentioned that strategies for telomerase activation, indirect or direct, have raised safety concerns due to the close correlation of most cancers and constitutive reactivation of endogenous telomerase. This highlights that, in addition to proof-of-concept studies in mice, the development of safe strategies for transient and controllable telomerase activation in humans should be a future goal.

In this regard, TERT gene therapy with AAVs is particularly attractive for TERT activation, since the non-integrative and replication-incompetent properties of AAVs allow for cell division-associated telomere elongation and subsequent loss of TERT expression as cells divide, thus restricting TERT expression to a few cell divisions. It is likely that the first clinical use of a TERT-based therapy, such as the TERT gene therapy approach developed by us, will be for the treatment of the human telomere syndromes, including aplastic anemia and pulmonary fibrosis. However, this requires the development of appropriate preclinical models and the subsequent clinical trials in humans. Given that physiological aging is provoked, at least in part, by telomere shortening, a TERT gene therapy may be used not only for the prevention and treatment of telomere syndromes but also for the treatment of multiple age-related diseases. In this regard, short telomeres have been extensively associated with a higher risk for cardiovascular disease. In support of a potential use of TERT activation in the treatment of age-related diseases, we demonstrated that TERT gene therapy can efficiently rescue mouse survival and heart scarring in a preclinical mouse model for heart failure upon induction of acute myocardial infarction. Collectively, experiments in cell and animal models provide proof of concept for the feasibility of telomerase activation approaches to counteract telomere shortening and its consequences. In particular, the successful use of telomerase gene therapy in animal models of aging and short telomere-related diseases paves the way for the development of therapeutic telomerase treatments in human aging and associated disease.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815611/

It is fair to say that medicine, like much of our technology, is an expression of the urge to immortality. The rise to civilization is arguably a process of identifying and fixing the problems that kill people, starting with the most pressing and moving on until there are no more problems that kill people. Now that we are in an era in which age-related diseases - and aging itself given that it causes those diseases - collectively form the most pressing problem, it will be worked on. As the authors of the open access paper I'll point out today note, this whole business of medicine, technology, civilization is "based on the assumption that longevity is valuable and that an early death is worse than a late death." That assumption certainly appears to be the basis for the way in which people act when viewing the big picture, but I wish you luck in trying to get any randomly selected room full of people to agree that longevity is valuable and death is a terrible thing, always to be avoided.

A large part of the challenge facing the development of rejuvenation therapies, treatments for aging that can prevent and reverse age-related disease by repairing the cell and tissue damage that causes aging, is that most people don't appear to be particularly enthusiastic when it comes to avoiding natural aging and death. This in turn means that there is little funding, as over the long term and the large scale, public support and interest determines funding for research and development. It is puzzling when compared with the evident, overwhelming support for, say, cancer research or the defeat of other specific age-related disease. You'd be hard pressed to find someone who will say in public that cancer research should be halted, or is pointless, but that is exactly the response from most people regarding research aimed at extending healthy human life by treating aging. The views of the public at large, and many individuals, are incoherent and contradictory on this topic: the fellow who proudly states that he doesn't want to live longer than his parents, and that 80 is long enough for anyone, also thinks that cancer and heart disease should be cured. What is aging without age-related disease? It is youth, because the only way to remove the medical conditions is to remove the damage that causes them, and that damage is one and the same as aging.

The best explanation to date appears to be the widespread mistaken belief that treating aging to extend life would result in ever-increasing decrepitude rather than prolonged youth and health, stemming from all sorts of misunderstandings about what aging actually is under the hood. There are plenty of other theories, however. The modern culture of environmentalism probably has a role, coupled as it is to incorrect Malthusian beliefs about economic development and technology. Also the widespread view that limited funds should be devoted to the young or indeed any cause other than helping old people: in many ways older people are considered less valuable, or to have had their chance. These are pernicious and damaging viewpoints. Certainly, the need for advocacy to support research fundraising efforts is as great as ever.

Can we even all agree that death is bad and something should be done? Not so much, unfortunately, and a sizable fraction of any group of people dissent from that view in one way or another - though when compared with their actions the degree to which they mean what they say is always a question mark. The paper quoted below summarizes some of the philosophical underpinnings of medicine, down at the lower level of asking why we even undertake these efforts to save lives and avoid death, and why there is support for saving some lives but not others, curing some diseases but not treating aging. Like many of these discussions, the authors don't escape the idea that younger lives are worth more. This is unfortunate because it is the basis for a vicious circle: when less work is undertaken to save the lives of the old because they are considered to be worth less than the lives of the young, then there will be slower progress towards rejuvenation biotechnologies capable of granting a long and healthy future to everyone, and therefore equal value to all lives. Everyone loses. So I think it is potentially useful to consider these things occasionally, given the strange and inconsistent behavior and opinions voiced about aging and age-related disease. Somewhere in all of this lies a better way to persuade the world to fund rejuvenation research, and to speed up the slow bootstrapping process of reaching prototype therapies.

The badness of death and priorities in health

The business of saving lives works on the assumption that longevity is valuable and that an early death is worse than a late death. There is a vast literature on health priorities and badness of death, separately. Surprisingly, there has been little cross-fertilisation between the academic fields of priority setting and badness of death. Our primary aim is to connect philosophical discussions on the badness of death to contemporary debates in health priorities. All health care systems share two basic goals: saving lives and improving the quality of life. The first goal gives rise to two essential questions: (i) Why should we save lives? (ii) Which lives should we save first? In the health priorities literature, the second question has received the most attention. We believe (i) and (ii) are closely connected, and that an answer to (ii) presupposes an answer to (i). In order to make claims about which lives to save first, we need an account of why we should save lives in the first place. One justification for saving lives is simply that death is bad. Saving lives entails postponing death, which is justified on the assumption that an early death is worse than a late death. One could, however, argue that we should justify saving lives with reference to considerations of fairness. Although we do not deny this, our aim is a different one, namely that of investigating the reasons we have for saving lives that stem from considerations of the badness of death.

We will briefly clarify the concept of death before we proceed. "Death" can refer to at least four dimensions: "the prospect", "the process", "the incident" and "the loss". The prospect refers to our knowledge of being mortal, which as far as we know is unique to human beings. The process of dying is an event that may be filled with pain, as in some instances of cancer, or it may happen abruptly, as in a traffic accident. The incident of death is when someone goes from existence to non-existence. Finally, there is a permanent loss when death occurs because there is no future for that individual. Although many tend to focus on the process of dying, our focus will be on the loss. Arguably, if dying had not been followed by permanent non-existence, then perhaps dying would not be so bad after all. Interestingly, the loss dimension of death seems to play an important role in current health priorities debates. One example is the estimation of health loss due to both morbidity and mortality in traditional cost-effectiveness analyses; another is the Global Burden of Disease project. If the loss dimension is accepted, the question is for whom death represents a loss. There are two rival theories to this question: Epicureanism and Deprivationism. Epicureanism refers to a contemporary view on the badness of death inspired by the ancient philosopher Epicurus, which states that death is not bad for those who die. Both theories are compatible with the idea that death can represent a loss for others (such as family, friends, and society), but only Deprivationism accepts that death represents a loss for those who die.

The two arguments normally offered in favour of Epicureanism are the experience argument and the time argument. The experience argument is best illustrated by the expression, "What you don't know won't hurt you". One interpretation of this is that in order for something to be good or bad for us, we must experience its goodness or badness. But of course when we are dead, we cannot experience. Therefore, death cannot be good or bad for us. There are at least four views one can adopt in responding to this argument. One view is that death is bad before it occurs, another is that death is bad when it occurs, a third is that death is bad after it occurs, and a fourth is that death is bad at a time which cannot be easily identified. One can successfully object to the time argument on the basis of one of these four views. We believe the fourth view is the best strategy for responding to the time argument. Here are some cases of analogy in support of the fourth view. For example, never having an education, freedom, or children can be bad even if its badness cannot be ascribed to a specific time. Moreover, at times, people may be grateful for not being a victim of accidents or suffering from severe sickness, even if "the evils that they never suffered" cannot be so easily located in time. If one accepts either the experience- or the time argument, it follows that death cannot be bad for those who die. What does this imply with regard to health priorities? If death is no loss for those who die, it matters less whether we suffer a premature or a late death. Consequently, age will play a less significant role (if any role at all) to health priorities. With Epicureanism we are, however, left with the option that death is bad for third parties such as family, friends, and society. This implies a higher emphasis on saving lives for the sake of others. Moreover, this suggests that what matters from a moral point of view are things like the emotional attachments and investments of family, friends, and society. In addition, the death of individuals can be bad by virtue of being a loss of caring relationships, productivity, or simply in terms of the world being deprived of a person.

When it comes to Deprivationism, some things in life can be good or bad in themselves, such as pleasure and pain. Death, on the other hand, is a different kind of evil. Suppose you suffered from paralysis in both your legs as a result of an accident. This accident deprives you of the chance to do a lot of things, like walking or playing tennis. In a similar way, death deprives us of the opportunity to continue with our lives. And assuming that continued life contains value, death is bad for us. Deprivationism explains how we can make judgments concerning the badness of death by comparing at least two different outcomes: (a) how well off individuals would have been if they continued to live and (b) how good it is for individuals not to continue with their lives. As long as (a) is better than (b), death is an evil. Deprivationism is the standard view on the badness of death. We suggest that Deprivationism is relevant to health priorities in at least four areas. First, Deprivationism brings attention to the kinds of values that are lost when death occurs. Secondly, it emphasises that age matters. Thirdly, Deprivationism will favour a person-affecting theory. Fourthly, it may say something new about who the worst off are. Jointly these four areas can provide reasons for saving lives. Though the idea that age matters to health priorities has gained a certain acceptance, there is bound to be disagreement about which age groups to prioritise. This issue is the subject of contemporary debate. Our claim is that in order to prioritise between age groups, it is relevant to consider the question of when it is worst to die. To this end, Deprivationism can provide theoretical support.

At a given level of medical technology, as the average age of the population rises, the number of people suffering age-related diseases at any given time also tends to rise. The only way to offset that is improved prevention or improved therapies, with the former being more important in the past, and the latter becoming increasingly dominant as technological progress accelerates. The rates of incidence and mortality have fallen over the past few decades for many common age-related conditions, a trend that reflects some combination of prevention and better treatment, especially for cardiovascular disease. Given that there has been a large reduction in cardiovascular disease impact and mortality, and the aging of the cardiovascular system can drive the development of dementia, it isn't terribly surprising to see evidence for similar reductions in dementia incidence:

The UK has seen a 20% fall in the incidence of dementia over the past two decades, according to new research, leading to an estimated 40,000 fewer cases of dementia than previously predicted. Reports in both the media and from governments have suggested that the world is facing a dementia 'tsunami' of ever-increasing numbers, particularly as populations age. However, several recent studies have begun to suggest that the picture is far more complex. Although changing diagnostic methods and criteria are identifying more people as having dementia, societal measures which improve health such as education, early- and mid-life health promotion including smoking reduction and attention to diet and exercise may be driving a reduction in risk in some countries.

As part of the Medical Research Council Cognitive Function and Ageing Study (CFAS), researchers interviewed a baseline of 7,500 people in three regions of the UK (Cambridgeshire, Newcastle and Nottingham) between 1991 and 1994 with repeat interviews at two years to estimate incidence. Then 20 years later a new sample of over 7,500 people from the same localities aged 65 and over was interviewed with a two year repeat interview again. This is the first time that a direct comparison of incidence across time in multiple areas, using identical methodological approaches, has been conducted in the world.

The researchers found that dementia incidence across the two decades has dropped by 20% and that this fall is driven by a reduction in incidence among men at all ages. These findings suggest that in the UK there are just under 210,000 new cases per year: 74,000 men and 135,000 women - this is compared to an anticipated 250,000 new cases based on previous levels. Incidence rates are higher in more deprived areas. Even in the presence of an ageing population, this means that the number of people estimated to develop dementia in any year has remained relatively stable, providing evidence that dementia in whole populations can change. It is not clear why rates among men have declined faster than those among women, though it is possible that it is related to the drop in smoking and vascular health improving in men. The researchers argue that while influential reports continue to promote future scenarios of huge increases of people with dementia across the globe, their study shows that global attention and investment in reducing the risk of dementia can help prevent such increases.

Link: http://www.cam.ac.uk/research/news/new-cases-of-dementia-in-the-uk-fall-by-20-over-two-decades

This is an informative article from one of the Major Mouse Testing Project principals, covering at a high level the development of senolytic therapies, those capable of removing some fraction of the senescent cells that accumulate with age. Since senescent cells are one of the root causes of aging and age-related disease, removing them qualifies as a narrow form of rejuvenation therapy, one of the first to reach the point of clinical development. Work on senolytics reached its tipping point a couple of years ago, and progress has been rapid and promising since then, with the first study to show extension of life in mice via clearance of senescent cells published last year, and startup companies Oisin Biotechnologies and UNITY Biotechnology working on bringing treatments to the clinic.

As your body ages increasing amounts of your cells enter into a state of senescence. Senescent cells do not divide or support the tissue they are a part of, but instead emit a range of potentially harmful chemical signals, these encourage other nearby cells to also enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase levels of chronic inflammation, and can even eventually raise the risk of cancer. Senescent cells normally destroy themselves via a programmed process called apoptosis and they are also removed by the immune system, however the immune system weakens with age and increasing numbers of these senescent cells escape this process and build up. By the time people reach old age significant numbers of these senescent cells have accumulated in the body and cause havoc further driving the aging process.

The health and lifespan of mice have been demonstrated to improve by the removal of senescent cells using a transgenic suicide gene and later experiments showed the same could be achieved using small molecules. Senolytics are a relatively new class of drugs that focuses on the removal of senescent cells. Senescent cells comprise a small number of total cells in the body but they secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which together form the senescence-associated secretory phenotype or SASP. The resulting SASP is thought to significantly contribute to aging and cancer, and thus senolytics and removal of SASP is a potential strategy for promoting health and longevity.

It was discovered that senescent cells have increased expression of pro-survival genes, consistent with their resistance to apoptosis. Drugs targeting these pro-survival factors selectively killed senescent cells. Two such drugs were dasatinib and quercetin which were both able to remove senescent cells but were better in differing tissue types. However it was discovered that a combination of the two drugs formed a synergy that was significantly more effective at removing some senescent cell types. In other studies whilst only removing thirty percent of senescent cells there were improvements to age related decline. These results suggest the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of aging and promoting healthy longevity.

Even more recently a further study demonstrated the benefits of senolytics for certain aspects of vascular aging. This is the first study to confirm that clearance of senescent cells improves aspects of vascular aging and chronic hypercholesterolemia, and could be a viable therapeutic to reduce morbidity and mortality from cardiovascular diseases. Dasatinib and quercetin are already approved for use by humans too so the application of these drugs or improved drugs based on them could be developed relatively quickly. However to date the combination of dasatinib and quercetin has yet to be tested in relation to its potential to increase maximum healthy lifespan. Current senolytic studies have focused only on health improvements rather than the long term effects (either bad or good) of this type of approach. The Major Mouse Testing Project aims to address this missing and vitally important question, can these senolytics promote healthy longevity?

Link: http://hplusmagazine.com/2016/04/19/senolytics-seek-destroy/

Fortes fortuna iuvat, as they say. I'm pleased to see that the BioViva principals have attracted the support of Deep Knowledge Life Sciences as they continue to bootstrap their very intentionally disruptive gene therapy startup:

Deep Knowledge Life Sciences and BioViva announce partnership

"BioViva aims to make gene therapy affordable to everyone. Dmitry Kaminskiy, the founding partner of Deep Knowledge Life Sciences, is enthusiastically funding gene therapy, and is himself an early adopter." said BioViva CEO Elizabeth Parrish, adding "We both want to see a world where investors actually live their legacy instead of just leaving it", alluding to a possible future trend. Parrish made headlines in 2015 when she travelled to an undisclosed location outside the US and personally underwent two of her own company's experimental gene therapies: one to protect against loss of muscle mass with age, another to battle stem cell depletion. It was a gesture intended to prove the safety of the therapies and clear the road ahead for human trials in the US. Months later, BioViva are tracking her results and she has reported no negative side-effects. "I believed the biotech industry had become over-regulated and that the prevailing model was unlikely to bring new therapies to market in our lifetime. What we needed was a company that would treat diseased patients with no other options and then develop these treatments into preventative medicines. And thus was born BioViva in 2015."

For Dmitry Kaminskiy it's not all about the portfolio. He wants to shift the entire industry up a gear, and put an end to the lack of vision he believes has mired biotechnology for decades: "Millions of human lives are affected by diseases with a genetic component. The sooner we can bring affordable gene therapies and other cell therapies to market, the more needless deaths can be avoided."

I regard the shared vision of bypassing excessive regulation in medical development to be somewhat more important than the exact nature of the therapies under development today. Rapid, effective passage to the clinic will be the legacy here, the opening of a door that will see an increasing number of developers in every important field of medicine adopting a fast path to medical tourism and clinical availability outside the US and Europe, transparency of ongoing results, and a sensible degree of safely data. The stem cell field and countless patients benefited greatly from this sort of approach over the past fifteen years, and it really should be the standard, not the exception.

What constitutes a sensible degree of safety data? That should up to companies and patients to decide upon for themselves, but it is certainly far, far less than the FDA presently insists upon. The FDA leadership are not primarily concerned with safety at all, but rather the potential political fallout that might result from approving any any therapy, ever. There is no such thing as a safe medical treatment, but the media can pounce at random on any death, and the defense put up in advance by FDA career bureaucrats is to demand as much expense and data as possible from applicants. Few people seem to care about the potential therapies that never make it through the process, or are never submitted because there is no possible profit - those losses are invisible, but they are measured in lives, not money. These perverse incentives, rife in every government agency, is why the cost of developing drugs is huge, why the process is lengthy and drawn out beyond all common sense, and why the cost has doubled in the past decade. These imposes costs are pointless and unnecessary, and a huge burden on progress. It is long past time to evade the FDA and take the road of medical tourism, transparency from companies, educated customers, and sane levels of testing and development cost.

BioViva has demonstrated prototype follistatin and telomerase gene therapies in the first human volunteer. If successful, and with a enough uptake in cells, the former should provide increased muscle mass and thus compensate partially for the sarcopenia that accompanies aging, while the latter may globally increase stem cell activity, offsetting to some limited degree the decline that occurs with age. To my eyes follistatin and similar myostatin gene therapies are about as low risk as any genetic edit can be before it has been used by thousands of people. Myostatin blockers of various sorts have been trialed in humans with positive results, and scores of animal studies for follistatin and myostatin gene therapies have taken place since the turn of the century. There are natural human and animal myostatin loss of function mutants to study as well, and most seem to do pretty well with their extra muscle tissue. Telomerase gene therapy on the other hand strikes me as being more risky. It clearly extends life and improves health in mice, but mice have very different telomere and telomerase dynamics when compared to humans. There is the strong possibility that telomerase therapies will boost cancer incidence in humans, even though they don't do that in mice. At some point it has to be tried based on the intriguing animal study results, but I wouldn't want to be first in line.

There is no reason for gene therapies to be expensive once they are out of their initial phase of development and early adoption. This is the age of CRISPR, an basis for gene therapy that makes genetic editing so cheap and easy that near every life science laboratory can now undertake this research. A gene therapy treatment to enhance capabilities or compensate somewhat for one or more of the losses of aging, such as myostatin knockout or follistatin overexpression, will trend towards becoming a mass produced infusion, the same for everyone, administered by a bored clinician, and with limited need for followup attention from a physician. All of the complexity is baked into the manufacturing process, and the cost will scale down as the production runs grow large. Unlike drugs for medical conditions, the target market here is every adult human being: the economies of scale and competition will be more like like those for present day childhood vaccinations than other types of medication, and the price will accordingly fall to the same low level.

So, I hope to see BioViva prosper in their effort to shake up clinical translation, and demonstrate that no-one really needs the FDA in order to responsibly place the next generation of therapies in the hands of patients. They have picked a set of treatments likely to attract a lot of interested parties to the clinics that will provide them, and the advent of CRISPR-based gene therapies will make expansion to other very interesting therapies quite plausible. Things should become interesting in the years ahead, I believe.

In recent years, public and press interest in medicine to treat aging has been growing, and so more popular science and general interest articles - such as the one linked here - have been published. This is a new phase in the bootstrapping of longevity science, in which the media and the public conversation becomes more of a factor. Unfortunately people unfamiliar with the science, which means near all journalists, tend to pick random grab-bags of information for their articles and discussions. You never know just how coherent or correct or reflective of the current state of research any given piece will be, even if accurate within its narrow selection of research topics. There are a lot of differing opinions on how to proceed towards treatments for aging in the research community, and these approaches have enormously divergent expectation values: how much it will cost to get to a prototype treatment, and how many years of healthy life we can expect to gain from successful therapies. All publicity is good publicity when it comes to raising the water level for fundraising in all areas of aging research, but it matters greatly which lines of research gain greater support and funding.

This article, for example, looks only at classes of research initiative that are capable in principle of doing comparatively little for human longevity, and at great cost. The past fifteen years have demonstrated very well that is it is enormously challenging to alter human metabolism into safe new states in which aging is modestly slowed, even when we have the well-understood and well-studied example of the calorie restriction response to mimic. Billions have been spent on this, and with no result yet that is plausibly going to add more than a couple of years to human life expectancy. For that money, the research community could have completed prototypes for the full toolkit of SENS rejuvenation therapies that actually repair and remove the forms of cell and tissue damage that cause aging, not just slow down their accumulation. Repair can in principle create rejuvenation in the old, and is comparatively cheap. Slowing the pace of damage cannot do this, and is comparatively expensive. So, as I said, the type of research that prospers matters greatly.

"There is such a thing as 'biological age,' and it is distinct from chronological age," said Steve Horvath, a professor of human genetics at UCLA. "There is a huge debate about how to measure it. But everybody would agree 'biological age' should be a better predictor of how long you live than chronological age." Brian K. Kennedy, who heads the Buck Institute for Research on Aging, goes a step further. "I'm a firm believer that there is a 'biological age,' that it is different for different people, and that it can be manipulated," he said. "At least it can be manipulated in animals, and I think we will be able to manipulate it in humans, too." The idea that biological age is measurable and predictive only recently moved out of the mouse lab into human epidemiology.

A study published last year looked at roughly 1,000 New Zealanders who have been followed by researchers since their birth in the city of Dunedin in 1972 and 1973. In the Dunedin study, biological age was calculated for each person when the group was 26, 32 and 38 years old. Because the calculation was done repeatedly over a dozen years, the researchers were also able to estimate a "pace of aging" for each person. The results were startling. Even though all subjects had a chronological age of 38, their biological ages ranged from 28 to 61. There was a similarly wide range in the pace of aging. A few people showed virtually no aging over 12 years, a few showed three years of biological aging per year lived, and the rest fell in between. Cognitive and physical function tracked biological age.

A study last year found that people in their 70s whose biological age is five years greater than their chronological age have a 20 percent higher risk of dying over six years. Biological age appears to be real and able to predict the future, at least to some extent. But what is driving it? For a while it looked like the answer was: "Telomeres." The notion that telomere wear was the engine of aging had many adherents - until research revealed the story was much more complicated. "There's been 20 years of research, and the field has learned that telomere shortening plays a role in aging. But it is not the fundamental cause of aging," Horvath, the genetics professor, said. "We can debate how important it is."

A newer and more informative measure is known as the epigenetic clock. It keeps track of age-related changes in molecules, called methyl groups, that attach to the outside of our strands of DNA, like barnacles on a rope dangling off a dock. "DNA methylation" plays a part in regulating genes; its exact role is still being worked out. A person's methylation pattern is partly inherited and can be altered by lifestyle and environmental exposures. DNA damage, telomere shortening and cell senescence also change methylation patterns. But the biggest driver is the passage of time. "In my opinion, there is a fundamental aging process - the true root cause of aging," Horvath said. "We are currently designing a large human study that will test to what extent epigenetic changes underlie this process." Whatever the answer, it's clear that aging slowly, avoiding disease and living a long time are intertwined phenomena.

Link: https://www.washingtonpost.com/national/health-science/scientists-can-make-mice-live-longer-now-they-want-to-do-the-same-for-you/2016/04/18/473a84e6-ff4f-11e5-9d36-33d198ea26c5_story.html

To what degree does the age-related decline of the immune system contribute to mortality and loss of longevity? How important is it in comparison to other aspects of aging? This study offers one useful data point, as the authors describe a genetic alteration that can boost the supply of new immune cells in old mice. The decline in that supply with age is one of the factors leading to poor immune function - and that means more than just vulnerability to infections, as the immune system is also responsible for destroying potentially cancerous and senescent cells, as well as clearing out forms of damaged proteins and unwanted metabolic waste. Various possibilities for increasing the number of new immune cells already exist in principle, such as regenerating the thymus, or cell therapies in which a patient's immune cells are grown outside the body and regularly infused, but this genetic approach is a new discovery.

There's no other age group suffering more from infectious diseases than seniors. With growing age, the risk of chronic and cute infections increases. This is due to the diminishing potential of hematopoietic stem cells (HSC) to build blood and immune cells in an appropriate number. In particular, HSC's capability to build lymphocytes is strongly declining, which leads to imbalances in blood cell composition and, thus, to immune defects limiting overall fitness and organismal survival during aging. There is experimental evidence that the accumulation of DNA damage contributes to these aging-induced immune impairments. Researchers identified gene Per2 as a genetic switch for a better immune system in mice: Per2 gene deletion ameliorates DNA damage responses in HSC leading to stabilization of hematopoietic stem and progenitor cells in aging mice. Hence, mice were less prone to infections and exhibited an elongated lifespan by 15% without increases in cancer.

For their study, in vivo RNA-mediated interference (RNAi) screenings were conducted in mice. 459 putative tumor suppressor genes were targeted to identify genes that limit the self-renewal capacity of HSC in response to DNA damage and aging. This screen identified "period circadian clock 2 (Per2)"-gene - usually one out of various genes regulating sleep-wake cycle - to represent a major factor limiting the maintenance and repopulation capacity of HSC in the context of various types of DNA damage and aging. Interestingly, Per2 deletion was sufficient to maintain a balanced production of lymphocytes, and hence, to improved immune function in aging mice. A similar effect was also found for DNA damages caused by the shortening of telomeres - the protective caps at our chromosomes' ends - a mechanism thought to be relevant for human aging.

"All in all, these results are very promising, but equally surprising. We did not expect such a strong connection between switching off a single gene and improving the immune system so clearly". It will be of future interest to study if the results are transferable to humans. Although humans and mice are genetically quite similar, genes usually regulate myriad of processes in an organism, and possible side-effects of Per2 deletion will have to be elucidated very carefully. Interestingly, Per2 gene mutations in humans have been associated with advanced sleep disorders leading to advanced tiredness of the patients in the early evening hours. "It is not yet clear whether this mutation in humans would have a benefit such as improved immune functions in aging - it is of great interest for us to further investigate this question."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=163209&CultureCode=en

In this day and age, the biggest difference a billionaire can make to the near future is to fund medical research. The costs of that research are falling rapidly with progress across the board in biotechnology, and the foundation for transformative new medicine can be created with a fraction of one billionaire's net worth, if spent wisely. Perhaps a bigger incentive in some cases than making the world a better place is that research can move from start to finish rapidly enough for those who fund it to benefit. We all age and suffer from age-related disease in the same way, no matter what our net worth, and everyone wins or everyone loses together in the game of medical development. Thus there is every incentive for someone with enough money to make a difference to take aim at the medical conditions that he or she will likely suffer in the decades ahead, and in doing so fix the problem for everyone. In a way it is very surprising that so few people do this. That, I think, is changing slowly, however. A realization of the potential for near future medicine to effectively treat aging and age-related disease is spreading, even though most people pay little attention to this sort of thing until they need something done.

Of course while the cost of research in the life sciences has fallen dramatically, the cost of regulatory compliance and commercial development has gone the other way. There remain tremendous problems and costs once at the stage of clinical translation, all the result of the perverse incentives produced by heavy regulation and the consequent regulatory capture, but once a new class of therapy is prototyped and ready there are (a) plenty of groups in the Big Pharma industry willing to take a run at it with their own funds, and (b) other avenues beyond trying to gain FDA approval, such as overseas development and medical tourism. Solving the problem of any specific medical condition, and that includes aging itself, is almost entirely the challenge of producing a working therapy with sufficient animal data to gain the interest of established developers. Once over that hurdle, allies with deep pockets emerge and matters progress.

I'm sure you're all familiar with how some of the wealthier individuals in the English language world have chosen to channel significant resources into medical and life science research. Paul Allen picked understanding the human brain as his first goal and cellular metabolism as his second. Bill Gates aims at the worst of the remaining prevalent infectious diseases, such as malaria. Denny Sanford chose to reinforce later stages of stem cell therapy development. The Google cofounders are focused on aging, though of course everyone and their dog in this community has an opinion on how they are going about it in the wrong way. Aging was also the target for Paul Glenn. There are numerous other examples, and recently Sean Parker picked the growing field of cancer immunotherapy for his new research initiative:

The Parker Institute for Cancer Immunotherapy

The Parker Institute was created through a $250 million grant from the Parker Foundation. The Institute's goal is to accelerate the development of breakthrough immune therapies capable of turning cancer into a curable disease by ensuring the coordination and collaboration of the field's top researchers, and quickly turning their findings into patient treatments.

Over 40 laboratories and more than 300 researchers and immunologists from the country's leading cancer centers are part of the network. Each Parker Institute research center receives comprehensive funding, and access to dedicated research, clinical resources and the key technologies needed to accelerate development in cancer immunotherapy. In a unique agreement, the administration of all intellectual property will be shared, enabling all researchers to have immediate access to a broad swath of core discoveries. A scientific steering committee of the field's leaders will set a research agenda and coordinate world-class research teams focused on the most pressing and promising scientific questions.

The commonality in these initiatives is that they all set forth to reinforce or transform or finalize a field that had already become a part of the research mainstream. Each had gone through a long period of bootstrapping, validation, and development well before the high net work individuals came into the picture. Organizations do not commit nine-figure sums of money to anything other than mainstream, well-supported initiatives, and when thinking about these things, is probably best to consider a billionaire as being the figurehead in a sizable organization. All such large-scale decisions are much more political and collaborative than the naive viewpoint might imagine, no matter who allegedly has the final say over disposition of finances. High levels of risk tend to be ruled out pretty early in any decision process that involves more than three humans, and this is just human nature at work.

Why has no-one stepped in to put a few hundred million dollars into getting SENS rejuvenation therapies to the prototype stage? The answer to that question is that SENS rejuvenation research programs have not yet taken over the aging and broader medical research mainstream, but remain a small faction. They are clearly heading in the right direction, with a growing number of leaders in various field of research and medicine openly providing support for the SENS position of damage repair, and the first classes of therapy are under development in a few startups. Clearly more support, more study data, and more bootstrapping is needed, however. It will be very interesting to see this unfold over the next decade as, for example, senescent cell clearance moves from theory with good backing to "it extends life in mice" to clinical treatment for humans to robust data in humans showing reduced symptoms and risk of age-related disease. Concurrently, other SENS therapies, such as cross-link clearance will be following the same path, a few years behind. Eventually it will be impossible to ignore the fact that the damage repair approach works, and that is when very large donations will start to appear.

To look at the situation for cancer immunotherapy, it has been evident for the past twenty years or more that the next generation of cancer treatment would involve proficient targeting of cancer cells, so as to maximize impact to the cancer and minimize or completely remove side-effects for the patient. Immunotherapy has been a strong contending technology platform for a decade, and in the last five years or so it has been the obvious basis for most of the next generation of targeted cancer therapies. So consider that the Parker Institute arrives something like ten years after the people who mattered in cancer research and related funding institutions became convinced that immunotherapy was something to put serious effort into, the point at which it became mainstream. From this sort of fuzzy and very subjective view of history, I'd judge we are at least ten to twenty years from the similar final avalanche of support for rejuvenation research programs - which will make the time between now and then an era of increasing availability of early rejuvenation therapies after the SENS model, human trials, and a great deal of very interesting data on effectiveness. How long it actually turns out to be is very much up to us. The more we do now, the faster we progress to the point at which large-scale funding arrives to seal the deal.

It is interesting to note a growth in discussion of radical life extension as a goal, and this from groups entirely outside the established community of supporters and advocates that came into being a couple of decades ago. Progress in development and advocacy arrives in waves over longer periods of time, and we are in the midst of the start of a new wave. We should expect to see new ventures and new faces, disconnected from prior efforts and coming to this with their own ideas and preconceptions. This is the way in which the patchwork of human endeavor takes shape over the long term.

In connection with the recent funding round for Human Longevity Inc. and resulting coordinated publicity, it is interesting to see the comments below from one of the involved groups, an established incubator-slash-fund focused on healthcare. As I've noted in the past, Human Longevity Inc. is a personalized medicine and genetics company, and not set on a road that can contribute to radical life extension. Other approaches are needed for that, but if people are genuinely interested in the goal of far longer healthy lives - as opposed to merely saying whatever will talk up their positions - then eventually they will gravitate towards the approaches with potential, such as the SENS research and development programs.

StartUp Health, a global organization leading the movement to transform health by building the world's largest community of Healthcare Transformers, today announced the launch of StartUp Health's Longevity Moonshot, a mission to extend and enhance healthy life by 50+ years and change the face of aging. Marked by StartUp Health's recent investment in Human Longevity, Inc (HLI), the genomics-based, technology-driven company led by co-founder and CEO J. Craig Venter, PhD., HLI was selected to be the founding partner of the Longevity Moonshot. "Aging is the biggest risk factor for every significant human disease. We are excited to be launching The Longevity Moonshot with Human Longevity, Inc. as the founding partner because we believe that together we can inspire a global community of Healthcare Transformers to join our mission to extend and enhance a healthy lifespan and ultimately improve the health of billions. By collaborating as a networked community, we can change the face of aging forever."

"Human Longevity, Inc. is honored to partner with StartUp Health and collaborate with their global community of Healthcare Transformers committed to transforming health," said Dr. Venter, co-founder & CEO, Human Longevity, Inc. "Our goal is to solve diseases of aging by changing the way medicine is practiced. Having the opportunity to actively network and engage with other innovators with the same mission will help us all revolutionize healthcare." The StartUp Health Longevity Moonshot is the first moonshot that StartUp Health is organizing for its community of Healthcare Transformers to focus on, with additional moonshots set to be announced throughout the year. StartUp Health is already working to support the White House Cancer Moonshot and The Cancer Moonshot 2020.

Link: http://www.prweb.com/releases/2016/04/prweb13334849.htm

Human Longevity Inc. (HLI) is a young company with a lot of funding that will be using genetics to produce a platform for personalized medicine and investigation of disease mechanisms, with a focus on age-related disease. Unfortunately, as I've noted in the past, this sort of use of genetics in the present research mainstream, which is to say the entirely correct scientific impetus towards building a comprehensive and complete map of human molecular biochemistry, is not the road towards effective extension of human life spans. Some of the Human Longevity principals have in the past talked a good game when it comes to the desire to meaningful extend human life span, but that simply isn't an outcome that is possible or plausible given what they are doing. What is plausible and possible is incremental progress in the expensive and futile approach of patching over age-related disease without addressing root causes, better diagnostics, and a great deal of new information about the details of the overlap of metabolism, genetics, and aging - how and why natural variations in longevity exist.

Understanding natural variations in longevity doesn't give researchers the ability to create radical life extension, people living to 150 and beyond in excellent health. Neither would even perfect diagnostic ability, a complete and transparent view of what is going on in our biochemistry. The only way to control, prevent, and reverse aging to fix the causes of aging, the molecular damage that accumulates to cause dysfunction, damage, and disease. The research community knows how to do this, and classes of potential therapies are outlined in great detail in the SENS research programs and elsewhere. For entirely cultural reasons, however, work on such rejuvenation treatments is a minority field and little funded. We can hope that as it produces results, as is the case for the senescent cell clearance component of SENS at the moment, and as the mainstream approach of tinkering and understanding metabolism continues to fail to produce results, SENS will take over the mainstream. It is a slow and frustrating process, however.

Now that a large funding round for Human Longevity Inc. has been completed, we are seeing more articles on their technology; VCs and founders tend to like to talk up their positions. This is one of the more informative pieces:

So far, HLI has amassed the sequences of around 20,000 whole genomes, says Craig Venter. But, of course, he wants even more. The company has room for more sequencing facilities on its third floor and is considering a second center in Singapore, planning to rapidly scale to sequencing the genomes of 100,000 people per year - whether children, adults or centenarians, and including both those with disease and those who are healthy. By 2020, Venter aims to have sequenced a million genomes. Despite the scale of its ambitions, HLI would be just another company offering DNA sequencing and testing if it were not for the fact that Venter is systematically linking DNA information to a diverse range of other medical data about each patient, gathered in what he calls a Health Nucleus. With this, Venter wants to move from basic genetics to impacting individual lives "very directly," he says. "The most important part of that is nothing to do with the genome directly, but measuring phenotype and physiology and understanding their medical risk. That is what the Health Nucleus is all about."

The Health Nucleus adds yet more data using non-invasive tests. My tour begins with the room where HLI conducts a total body scan to create the avatars that inhabit its app. We pass through a succession of white rooms. There's one where magnetic resonance imaging (MRI) scans are shown, revealing visceral fat (which is linked to type 2 diabetes and cardiovascular disease), muscle volume, grey matter, white matter and more. Venter is happy for his "age-related atrophy" report to be displayed here on a screen, given the good news about how young his brain looks.

So far, Venter and a handful of patients have passed through the Nucleus. Targeted initially at self-insured executives and athletes, a full health scan will be priced at $25,000. "We will be developing the evidence around this to make the case for preventive medicine." Criticisms of such extensive screening stem from the conservative nature of the medical community, notably when it comes to keeping the costs of screening under control. "That is the medical establishment saying: we want to keep doing what we do, we want to see people after they develop symptoms and have something wrong with them. The human longevity approach is the exact opposite."

Ray Kurzweil is one of HLI's advisors. Does Venter buy into his visions for radical life extension? No. Kurzweil's view is interesting but does not change a thing Venter does on a daily basis. Though Venter wants to see the kind of step change in health last witnessed between 1910 and 2010, when improvements in medicine and sanitation increased the average lifespan from around 50 to 75 years, life extension is not the primary objective, he stresses. As his 70th birthday approaches, Venter is only too aware of his own mortality. While his mother, aged 92, is "still pretty bright" despite a stroke, his father only lived to 59 as a result of sudden cardiac death. "I am now ten years beyond that," he says with a chuckle of satisfaction. But if you really want immortality, he adds, "do something meaningful with your life".

Link: http://qz.com/663528/biotechs-quest-to-put-a-new-spin-on-old-age/

The latest edition of the Rejuvenation Biotechnology Update arrived today. This newsletter series is a collaboration between the Methuselah Foundation and SENS Research Foundation, two of the most important organizations involved in advocacy and research to speed the defeat of aging and age-related disease. The newsletter goes out to members of the Methuselah 300, a long-standing group largely made up of ordinary philanthropists of modest means. Over the years these donors have collectively helped to fund many of the important projects carried out at the Methuselah Foundation: the Mprize for longevity science; the initial set of SENS rejuvenation research programs; seed funding tissue engineering startup Organovo and senescent cell clearance startup Oisin Biotechnologies; the establishment of the New Organ prize series; and much more.

If you want to see how everyday people with entirely ordinary incomes can band together to make a real difference to progress in the sciences, look no further than the Methuselah Foundation and the Methuselah 300. This is how it is done: persuade the core supporters, build a network of connections in the research community, and make smart, targeted investments in research and advocacy. On the back of this simple formula, and with the help of hundreds of supporters, the Methuselah Foundation has played a strong role in the significant, pivotal change that has taken place in the aging research community in the past fifteen years. Over the lifetime of the Methuselah Foundation the environment has gone from one in which talking about life extension through medical science was to risk your career to one in which the leaders of the field - and pretty much everyone else - openly advocate for greater human longevity. That didn't happened by chance, and it wasn't inevitable: it took a lot of hard work, both openly and behind the scenes, to bring about this important cultural change.

One of the great secrets of our time is that early stage medical research has become very cheap over the past few decades. The pace of progress in tools and knowledge is staggering. Any number of important, small, discrete projects at the cutting edge of the medical life sciences can be accomplished for a few tens of thousands of dollars, given an established lab to work with and smart young researchers to carry out the work. For a few hundred thousand dollars, a biotechnology company can be established, complete their prototype therapy, and carry out animal studies needed to attract greater investment. This is an age of communication, and research funding is in the process of becoming extremely transparent and collaborative: we can choose the projects to learn about and support, and we can see exactly what the organizations we trust to do this for us, such as the Methuselah Foundation and SENS Research Foundation, are doing with our donations. Every twist and turn of the race is there to be cheered on - and make no mistake, it is very much a race. Scientific progress and funding on the one hand, and aging on the other. We'll all win together in the best of worlds, in which rejuvenation therapies are developed soon enough, but lot of work remains in order to get to that goal. So consider joining the Methuselah 300 or donating to support SENS research programs. It is the smart thing to do.

Rejuvenation Biotechnology Update for April 2016 (PDF)

Because it doesn't take a scientist to understand the vital importance of investing in healthy life extension, these newsletters strive to report three significant studies from the past 3-6 months accessibly and approachably, describing how each one fits into the broader landscape of rejuvenation biotechnology research.

Announcing the $500,000 Vascular Tissue Challenge Under Development at NASA and Methuselah Foundation

The deadline for comments is only a few weeks away. The Vascular Tissue Challenge is a $500,000 prize purse to be divided among the first three teams who can successfully create thick, human vascularized organ tissue in an in vitro environment while maintaining metabolic functionality similar to their in vivo native cells throughout a 30-day survival period. NASA's Centennial Challenges Program is sponsoring this prize to help advance research on human physiology, fundamental space biology, and medicine, taking place both on the Earth and the International Space Station National Laboratory. The Vascular Tissue Challenge rules are currently open for public comment. If interested in this challenge, please provide your feedback. We encourage readers to attempt to submit comments even if they received this newsletter after April 15th.

Naturally occurring p16Ink4a-positive cells shorten healthy lifespan

Senescent cells have accumulated DNA damage or other abnormalities, have lost the ability to divide, and may create cancer-prone environments locally to where they reside in tissues through the secretion of growth factors, as well as may inflame the immune system through the secretion of cytokines. These cells also appear to have detrimental effects on tissues in which they reside. Senescent cells accumulate in all tissues with age and are a concern to longevity researchers; it is hypothesized that these cells contribute to aging and that removing them from an aged person could have rejuvenation effects. In this study, researchers chose a protein marker of senescent cells, and used a genetic system to induce programmed cell death in their mice when a drug was administered, but only in cells that express the marker at high enough levels to be considered senescent cells. They found that elimination of the senescent cells ameliorated the dysfunction that typically occurs with age in multiple organs and tissues, including fat, cardiomyocytes (heart), and the glomeruli of the kidney (which are involved in filtering the blood). Furthermore, the removal of senescent cells reduced early deaths in the mice and decreased the incidence of cancers, leading to an increase in median life expectancy.

This paper was met with a lot of excitement. The results are indeed impressive, showing that the normal function of several different organs - fat tissue, kidney, heart - can be restored, and healthy lifespan can be prolonged, without apparent side effects, simply by ablating a key subset of senescent cells. This study provides a clear and important piece of evidence to support the idea that senescent cells shorten lifespan, and conversely, that their elimination extends it. With this study, it became clear that, yes, eliminating senescent cells in otherwise healthy aged mice is a net benefit without any apparent downsides. Getting rid of senescent cells is one of the seven key rejuvenation biotechnologies of SENS.

Lanosterol reverses protein aggregation in cataracts.

Cataracts develop due to changes in the lens of the eye, which must be transparent and maintain its optical properties within narrow parameters for proper vision. The major protein which constitutes the lens of the eye is called crystallin, and disruptions to its structure on a molecular level can cause the normally clear lens to become opaque. Currently the only treatment option for cataracts involves surgery. The researchers in this group started by examining some families who had severe cataracts, and found that many of them carried rare gene mutations in the gene that codes for an enzyme called lanosterol synthase. This research group then found that the normal version of lanosterol synthase, but not the mutant versions, were able to prevent the mutant crystallin proteins from forming aggregates. Then they moved to an in vivo study in dogs with age-related cataracts. Cataract scores improved in the dogs treated with lanosterol eye drops.

This is a very interesting result, and of particular relevance is the in vivo portion of the study in dogs, showing that lens clarity could be improved in living organisms with real cataracts by treatment with eye drops alone, with no requirement for surgery. Lanosterol is a naturally occurring compound, which bodes well for its safety if it is effective at doses within the normal range for youthful people without cataracts, and it could potentially be very inexpensive to produce, although the actual price to consumers might be determined more by intellectual property claims and marketing factors rather than by manufacturing costs. Cataracts definitely qualify as an important disease of aging, especially when considering how much impaired vision can affect quality of life and independence.

The mechanism for how lanosterol may reverse cataracts is still uncertain. The authors suggest that the amphipathic (in-between water and oil soluble; like a detergent) nature of lanosterol could allow crystallin proteins which have undergone changes in folding/conformation to return to their normally folded state, which restores clarity of the lens on a macroscopic level. If there is a treatment that works for reversing aging damage, we don't necessarily need to know the mechanism of how it works to benefit from it. However, it might be important to link this new information about lanosterol and cataracts to what occurs in aging. Does lanosterol synthase activity decline with age? How long does lanosterol treatment keep lenses clear? More broadly, a very common theme in diseases of aging is the aggregation of proteins. Removal of crosslinked protein aggregates is one of the main planks of SENS Research Foundation's focus. Protein crosslinking and aggregation is apparently what occurs in cataracts, and according to this study may be at least partially reversible with lanosterol. Could lanosterol, or similar amphipathic molecules, be used to untangle other types of protein aggregates besides crystallin?

Researchers recently published evidence for variants in the FOXO3 gene to correlate with modestly reduced mortality due to cardiovascular disease. FOXO3 is one of the very few longevity-associated genes in which the statistical associations have been replicated in different human study populations. In the vast majority of cases there is no replication, which suggests that the genetic contribution to longevity is very complex, made up of thousands of individually tiny contributions that strongly interact with one another and environmental circumstances. This effects in one group of people do not appear in another, even within the same region and heritage:

FoxO3 is an evolutionarily conserved transcription factor in the insulin signaling pathway. It regulates expression of genes controlling a multitude of processes that could enhance health and lifespan. A previous study of American men of Japanese ancestry was the first to find an association of three single nucleotide polymorphisms (SNPs) of FOXO3 with human longevity. The association was replicated in 11 other independent studies of populations of diverse ancestry. The mechanisms by which the protective alleles reduce mortality to promote human longevity are also not known. Identifying the cause of death in longevity-allele carriers vs. noncarriers may provide clues as to why FOXO3 SNPs strongly protect against mortality.

We hypothesized that the longevity-associated FOXO3 genotype would be associated with a sizable risk reduction for mortality and with one or more major age-associated clinical causes of death, such as coronary heart disease (CHD), cancer, and stroke. To test this hypothesis we utilized an extensive, prospectively collected dataset from our long-lived cohort of American men of Japanese ancestry, well characterized for aging phenotypes, drawn from the Honolulu Heart Program prospective cohort study. We genotyped this study population to prospectively assess the following: (i) the effect size of the protective (longevity-associated) FOXO3 genotype on total (all-cause) mortality in 17 years of follow-up; and (ii) the effect of the protective FOXO3 genotype on cause-specific mortality. We then attempted a replication of major findings in a suitable cohort of elderly white and black Americans of both sexes in the Health Aging and Body Composition cohort study, which had 17 years of follow-up.

we demonstrated a large (10%) protective effect against all-cause mortality and 26% for CHD mortality over 17 years of follow-up. The protective effect was, moreover, observed in three genetically different populations. Our study contrasts with the vast majority of prior investigations of FOXO3 variants and longevity, which have been case-control studies that did not quantify risk over time, but rather simply tested for association with an outcome. The magnitude of the impact of an absence of the protective FOXO3 G allele was comparable to the increase in risk of death from smoking a pack of cigarettes a day for 25 years in Japanese men. In black males and females, it was equivalent to having a 20 mmHg higher systolic blood pressure, and in white men and women to a 20 mg dL-1 elevation in fasting blood glucose. The data suggest a possible mediator role for hypertension, which we found to be less prevalent in middle-aged women carrying the FOXO3 G allele.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12452/

Researcher S. Jay Olshansky is one of the principals behind the Longevity Dividend initiative, a long-running lobbying and advocacy initiative that seeks to push a great deal more government and philanthropic funding into aging research. The specific focus is on modestly slowing aging via near term interventions with the goal of adding five to seven years to healthy life spans over the next few decades, something I regard as far too unambitious. The TAME metformin study is an example of the Longevity Dividend portfolio, for example. Olshanksy is perhaps the canonical example of a researcher who advocates for longevity science, but thinks that radical life extension of decades or more or the outright defeat of aging is not achievable within our lifetimes, and doesn't think that the SENS approach of damage repair is any better than the mainstream approach of slowing aging. His views are well known within the research community, but it is always interesting to see him talk informally on this topic:

I study the upper limits of longevity and ask which populations are living longer and why, and what that means for society. Living a longer life is a monumental achievement of public health and modern medicine - it is exactly what we set out to achieve more than a hundred years ago when life was short. More people today are living to 65, 85, and 100 and beyond than ever before, but it has created a Faustian trade. In exchange for our longer lives, we now live long enough to experience heart disease, cancer, sensory impairments, and Alzheimer's disease. The fact is that our bodies were not "designed" for long-term use. While improved lifestyles can enhance health and quality of life, the aging process marches on unaltered beneath the surface - leading to the diseases and disorders we fear most. My research focuses on investigating ways to extend the period of healthy life and compress sickness and disease as much as possible to the very end. Recently I have teamed with a group of researchers to study the ability of the diabetes drug metformin to do just that; although metformin is just one of many research pathways scientists are pursuing to slow biological aging. My research suggests that slowing down aging will be the next great public health advance in this century because it targets multiple age-related chronic diseases. Importantly, this approach to public health can save far more health care dollars than treating one disease at a time. The time has arrived to take a new approach to chronic fatal and disabling diseases.

When will an aging intervention come online? No one can know the answer to this question in advance since it takes years to study the safety and efficacy of potential interventions. However, we're no longer talking about something theoretical here. We can observe decelerated aging today in people that, in many cases, may be your friends, relatives, or even yourself. Centenarians today are in all likelihood living that long because their bodies and minds are not really 100+ years old - they might very well be 10, 20 or even 30 years younger. Scientists are studying the genetics of these long-lived subgroups in order to discover (and perhaps recreate) their genetic advantage for the rest of us. It's an exciting time to be involved in aging science, and I'm optimistic that an intervention that slows aging in people will arrive in time to positively influence most people alive today. However, the short answer is no, we're not ready for metformin as the next equivalent of a baby aspirin. We can't know the answer to this until the research is done and the data thoroughly analyzed. While I would encourage everyone to remain excited about this work, keep in mind that no intervention of this kind should be taken today without approval and evaluation by your personal physician. There is a tendency in this field for the entrepreneurs to try and take over as soon as the science offers a glimmer of hope, so I would urge extreme caution. In the interim, please try and help out the world of aging science by following the work and encouraging the effort.

By 2050 I'd be surprised if we could achieve anything more than a few years of additional healthy life, even with a breakthrough in aging science. This may not sound like much, but keep in mind that in long lived populations, it takes very large reductions in death rates to achieve even a 1 year increase in life expectancy. A 1 year increase in healthy life expectancy is even more difficult to achieve. My personal view here is that if we continue with the current medical model of attacking one disease at a time, we will not see an extension of healthy, but instead, the exact opposite - a prolongation of the period of frailty and disability. This is the very reason we're working so hard now to change the culture of thinking on this topic.

The idea that the first person to live to 150 or 200 or 1,000 or 10,000 years has already being born is hype cooked up by some who want to advocate for radical life extension. All of these numbers are made up out of thin air - they're designed to get the attention of the media, and frankly, this makes it more difficult to get funding for aging science because funders have no interest in creating a new set of challenges that would come with people living for hundreds or thousands of years. Keep in mind that life extension is not the primary goal of aging science; health extension is the primary goal. Aubrey de Grey is a friend, but we do have healthy disagreements. We need this kind of open dialogue in science, and it should be conducted with respect and decorum. Having said that, don't expect radical life extension any time soon. Think about it for a moment. Even if you had an intervention in hand that could make people live for 1,000 years, how could anyone prove that using the tools of science? You would have to wait for 1,000 years to make that statement, which is why I say that anyone making these claims is making up numbers out of thin air. The fact is, even if a genuine magical elixir found its way into anyone's lab, the scientist who discovered it wouldn't know its effect - even if the intervention could talk and declare its effectiveness. Our goals in aging science must be measurable using the tools of science!

I've listened to my friend Aubrey de Grey speak many times. He's quite good, right up until the last 15 minutes when he starts talking about escape velocity and 1,000 year lifespans and made up numbers. It's somewhat difficult to ignore the very point that Aubrey emphasizes. With regard to his effort to reverse or repair the damage caused by aging rather than delaying it, I'm hopeful that he's right. No one can know whether his approach will work until it's tested, which is what I like about Aubrey. He's not selling anything yet - he's operating within the bounds of science and setting forth testable research hypotheses. I think Aubrey's work, or at least the 7 deadlies idea he supports, should be one of the projects pursued by the Longevity Dividend Initiative, but like everyone else, this science would have to survive peer review.

I'm actually pleased that Google's Calico and Venter's Human Longevity have come into the mix. Competition is good; the presence of funds to accelerate aging is good; there are a lot of outstanding scientists already in this field, and I expect we'll soon attract many more. It's the next great frontier of human biology. Having said that, I'm very careful about claims that are made here, which is why I shy away from exaggeration and I think the rest of us should as well. Someone will eventually develop a breakthrough in the field, and when that happens, it will fundamentally change the way in which we think about aging, disease and longevity. Someone will win the race, and perhaps there will be more than one winner, but when that happens, we all win. The fact that there is a race at all is what is so exciting now. While I don't expect 120 is in the cards, I do expect many of us to benefit from an intervention that extends our healthy life and preserves our youthful vigor for a longer period of time. I expect the competition to go on even after the first intervention makes its way into the marketplace. I see a healthy sector moving forward.

This may very well become the next great public health paradigm - we made the case for this in 2008. We are in fact going to high net worth individuals with the suggestion that they can get in on the ground floor of what could prove to be one of the most important accomplishments in medicine in the modern era. Just as Bill Gates has made his impact in public health by attacking infectious diseases in the developing world - and there are very few examples like this - we expect someone to step up to the plate and make a declaration just like President Kennedy did years ago when he decided to send someone to the moon and return them safely. The time has arrived to fundamentally change the way in which we attack disease, and once done, it's fairly easy to make the case that the modern era will have witnessed one of its greatest accomplishments. I don't think the money for this effort will come from governments (not enough funds and too slow); it's going to come from a high net worth individual with a vision and the funds to back it up. The question now is, who will it be?

Link: https://www.reddit.com/r/science/comments/4eqnyf/im_s_jay_olshansky_an_epidemiologist_at_the/

The staff at the SENS Research Foundation, who coordinate and carry out scientific programs aimed at speeding up progress towards rejuvenation therapies, have for some years referred to their work as a branch of regenerative medicine. When most people think of regenerative medicine, stem cell therapies to treat injuries and age-related diseases are the first thing to spring to mind, but that is just the most visible, energetic, and highly funded part of a much broader field. Wherever there is loss or degeneration in our physiology, a treatment that can even partially reverse that state of affairs, restoring some fraction of normal function to tissues, can reasonably be called a regenerative therapy.

Aging is defined by degeneration and failure. The most straightforward definition and measure of aging is that your risk of death due to intrinsic causes rises over time. Those intrinsic causes are the slow accumulation of molecular damage as a side-effect of the normal operation of cellular metabolism, and a resulting loss of function and resilience in damaged organs and systems. To pick one example, degeneration of the heart and cardiovascular system means an ever greater risk of abrupt failure and consequent death, and that degeneration can be traced back to root causes ranging from cross-links in the extracellular matrix that stiffen arteries, leading to high blood pressure and all of its unpleasant consequences, to growing numbers of senescent cells that produce inflammation and all sorts of other tissue damage, to increasing quiescence and lower rates of activity on the part of the stem cells that maintain heart and blood vessel tissues. These are degenerative changes, marked by decline. Just as delivering stem cells as a therapy can somewhat reverse the loss of tissue maintenance, a way to turn back the clock a little on some of the consequences of that issue, clearing cross-links or senescent cells will help in similar ways. These are all early forms of induced regeneration.

The article linked below skips from one end of the longevity science community, SENS rejuvenation research, to the other, attempts to modestly slow aging with existing drugs. I'm very much more in favor of the former than the latter: the costs are lower and the potential gains far larger. In the middle there is a look at regenerative medicine in the sense of cell therapies and their infrastructure, but it is interesting to see that more people are picking up on the unification of medicine now that the treatment of aging is a realistic prospect for the near future. Aging is not stuck out on the edge on its own, as something somehow out of bounds or different from the treatment of age-related disease. It is all a part of the same tapestry, and the more focus put on aging, the more likely that real progress will be made in bringing the clearly identified causes of aging under medical control.

Regenerative Medicine Comes of Age

Induced pluripotent stem cells (iPSCs) and genome-editing techniques have facilitated manipulation of living organisms in innumerable ways at the cellular and genetic levels, respectively, and will underpin many aspects of regenerative medicine as it continues to evolve. An attitudinal change is also occurring. Experts in regenerative medicine have increasingly begun to embrace the view that comprehensively repairing the damage of aging is a practical and feasible goal. A notable proponent of this view is Aubrey de Grey, Ph.D., a biomedical gerontologist who has pioneered an regenerative medicine approach called Strategies for Engineered Negligible Senescence (SENS). He works to "develop, promote, and ensure widespread access to regenerative medicine solutions to the disabilities and diseases of aging" as CSO and co-founder of the SENS Research Foundation. He is also the editor-in-chief of Rejuvenation Research, published by Mary Ann Liebert.

Dr. de Grey points out that stem cell treatments for age-related conditions such as Parkinson's are already in clinical trials, and immune therapies to remove molecular waste products in the extracellular space, such as amyloid in Alzheimer's, have succeeded in such trials. Recently, there has been progress in animal models in removing toxic cells that the body is failing to kill. The most encouraging work is in cancer immunotherapy, which is rapidly advancing after decades in the doldrums. Many damage-repair strategies are at an early stage of research. Although these strategies look promising, they are handicapped by a lack of funding. If that does not change soon, the scientific community is at risk of failing to capitalize on the relevant technological advances.

For decades, an urge to discern the secrets of unusually long-lived people has animated the work of Nir Barzilai, M.D., a researcher who is currently the director of the Institute for Aging Research at Albert Einstein College of Medicine. The Targeting Aging with MEtformin (TAME) study is focused on the concept that multimorbidities of aging can be delayed by metformin, a commonly used drug for the prevention and treatment of type 2 diabetes. Studies have demonstrated a decreased risk of not only cardiovascular disease but also cancer risk and cancer mortality in type 2 diabetic individuals taking metformin.

The TAME study hypothesis is that delaying aging is the only effective way to delay age-related diseases and compress morbidity. Sponsored by the American Federation for Aging Research, the study will recruit elderly subjects and, in a double-blind, placebo-control study, will test if metformin can put off the onset of multimorbidities including cancer, cardiovascular disease, type 2 diabetes, cognitive decline, and mortality. As the study's principal investigator, Dr. Barzilai hopes to convince the FDA to approve aging, as measured by multiple disease endpoints, as an indication. There is a great benefit for healthy lifespan, not only to the individual, but also for society in the form of cost savings, which is often referred to as the longevity dividend.

A developmental process responsible for fine-tuning nervous system connections to muscle fibers may inappropriately reactivate in later life, becoming an important contributing cause of the characteristic loss of muscle strength and control that occurs in aging:

Proteins in the family MHCI, or major histocompatibility complex class I, "prune" the connections, or synapses, between motor neurons and muscle fibers. Pruning is necessary during early development because at birth each muscle fiber in humans, mice and other vertebrates receives signals from dozens of neural connections. Proper motor control, however, requires that each muscle fiber receive signals from only a single motor neuron, so without the pruning carried out by MHCI proteins, fine motor control would never emerge. It is not known why more synapses are made during development than are needed. One possibility is that it allows the wiring diagram of the nervous system to be precisely tuned based on the way the circuit is used. MHCI proteins help limit the final number of connections so that communication between neurons and muscles is more precise and efficient than would be possible using just a molecular code that produced a set number of connections.

Researchers also found that MHCI levels can rise again in old age, and that the proteins may resume pruning nerve-muscle synapses - except that in a mature organism there are no extra synapses. The result is that individual muscle fibers become completely "denervated," or detached from nervous system control. Denervated muscle fibers cannot be recruited during muscle contraction, which can leave older people weaker and more susceptible to devastating falls, making independent living difficult. However, the researchers discovered that when MHCI levels were reduced in mice, denervation during aging was largely prevented. The mice actually lacked a protein known as beta-2 microglobulin, which forms a complex with MHCI and is necessary for MHCI expression on the surface of cells. This could be beneficial from a clinical perspective because beta-2 microglobulin is a soluble protein and can be removed from the blood. "Our studies raise the possibility that targeting one protein could help with both motor and cognitive aspects of aging." Because MHCI proteins are important in the immune system, however, such an approach could result in compromised immunity. Future work will include exploring the effectiveness of other approaches to reducing the proteins' synapse-eliminating activity in older nervous systems, ideally while leaving their immune functions intact.

Link: http://blogs.princeton.edu/research/2016/04/11/same-immune-system-proteins-may-first-giveth-then-taketh-away-motor-control-brain-behavior-and-immunity/

This article profiles Samumed, who are producing regenerative therapies based on manipulation of Wnt signaling, presently at various early stages in the pipeline. Wnt signaling is implicated in cancer, aging, and regeneration, but like many protein networks it is involved in a large number of very fundamental cellular processes, making precise control of outcomes a challenge. This is something that the Samumed researchers claim to have solved to a large enough degree to produce drugs that target this pathway, with Wnt-based regenerative treatments in the works for a range of tissues:

Samumed has raised $220 million and is halfway through raising another $100 million. The target Samumed researchers went after was obvious: a gene called Wnt, which stands for "wingless integration site," because when you knock it out in fruit flies, they never grow wings. It's a linchpin in a group of genes that control the growth of a developing fetus - whether you're a fly or a person. Together these genes are known as the Wnt pathway. Trigger the right ones and you might revive old flesh. Some cancers do their dirty work by hijacking Wnt, and blocking it might stop tumors. Most other researchers who had searched for Wnt drugs used one of biomedicine's workhorses: a cell line derived from an aborted fetus in the Netherlands in 1973. Those fetal cells are easy to use in the lab, but over the intervening decades they have become very different from normal cells in humans. The Samumed team opted to look for drug targets in colorectal cancer cells that expressed Wnt, comparing them with healthy colon cells that didn't. It took almost three years. Exactly what did they find? Samumed isn't quite saying. Normally a patent explains which chemicals a drug targets. But in 2013 the Supreme Court said that genes aren't patentable, a ruling Samumed interprets as saying the company can have its patents while keeping those biochemical pathways under wraps.

What the company will show is the animal and human data for its baldness and arthritis treatments. In mice and mini-pigs that have had hair removed, it grows back. Experiments in arthritis involve cutting the ligaments in the knees of rats so that the cartilage is destroyed. Samumed's drug regrows the cartilage, and the rats can walk again. So what happens in people? In March Samumed presented data on the use of its baldness drug, code-named SM04554, in 300 patients. Hair-loss specialists who saw the data were not blown away. Those results aren't big enough to be certain they're not occurring by chance or that men will really feel that the product is making their hair grow back. When it comes to Samumed's valuation - and medicine as a whole - the arthritis data are far more important. The largest study of Samumed's arthritis drug, SM04690, included only 60 patients. Even for small numbers the results line up alluringly: Patients who got SM04690 scored better than those on placebo on two questionnaires that measured how well they functioned and whether their pain improved. On X-rays of patients' knee joints, the space between the bones seemed to have increased, indicating cartilage might really have grown back. Still, again, even Samumed's own consultants say the data are preliminary. More proof will come from a 445-person trial that Samumed aims to complete by the end of the year.

Viewed under the microscope, Samumed looks like a company with a pair of drugs that have not been proved and, if trends in drug discovery hold true, will probably not make it to market. But its investors obviously see something far more wonderful, world-changing and potentially lucrative. If these drugs work, it becomes a better bet that some of Samumed's other medicines will work, too. There's a treatment for scarring of the lung, known as idiopathic pulmonary fibrosis. And for macular degeneration, which causes blindness.

Link: http://www.forbes.com/sites/matthewherper/2016/04/13/the-god-pill/

Today's open access paper focuses on albumin and is a great example of the role played by oxidation of proteins in aging, the way in which it can act as a link between fundamental damage and secondary damage, and between damage in one location in the body and consequences in another. Oxidation of many common proteins increases with advancing age, firstly because more oxidation is taking place due to damaged or overactive cellular processes, and secondly because the systems intended to clear out oxidized proteins become damaged and less efficient themselves. All proteins are in effect small machines, or interchangeable parts of larger assemblies of machinery, and when altered by oxidative reactions they tend not to work properly, causing a chain of localized malfunctions. Cells react to the presence of this type of damage with increased housekeeping or calls for help to the immune system, but higher levels of such damage can tip matters over into serious dysfunction, chronic inflammation, and the creation of senescent cells, among other consequences, contributing to the progression of aging and age-related diseases.

Oxidation of proteins that are carried far and wide in the blood stream, like albumin, is one of the ways in which localized age-related cellular damage can produce global consequences throughout the body. Take damage to mitochondrial DNA, for example. As we age, a small but significant fraction of our cells become taken over by dysfunctional mitochondria as a result of rare mutational damage to their DNA. Most such damage is repaired very rapidly, but large deletions can cause a form of malfunction that makes mitochondria more resistant to removal by quality control mechanisms. Cells packed full of these broken mitochondria become dysfunctional themselves, exporting reactive oxidizing molecules in large volumes into the surrounding tissues. Some will react with proteins in the bloodstream, and those oxidized proteins will most likely end up stuck in a blood vessel wall somewhere, irritating the local environment. This is how atherosclerosis starts and is reinforced: damaged proteins to start with, followed by an overreaction on the part of local cells, then immune cells pile in, and a growing local disaster zone of inflammation, dying cells, and continued signals for help is created. Ultimately this creates fatty plaques that remodel and narrow blood vessel walls, causing cardiovascular disease at best, and which at worst can fragment to block vital blood vessels, causing death or serious injury.

This unfortunate set of circumstances is one of the reasons why repairing broken mitochondria is an important component of any comprehensive future toolkit of rejuvenation therapies. There are numerous possible approaches to that goal, most of which are either nearly or actually possible today, at least in cell cultures. For a decade or so the SENS Research Foundation has championed allotopic expression, creating copies of mitochondrial genes in the cell nucleus as backups, so that the necessary protein machinery will be created and delivered to mitochondria regardless of damage to the mitochondrial genome. Today Gensight is developing this technology for a single mitochondrial gene, while the SENS Research Foundation is moving more slowly, and with much less funding, towards completing the necessary groundwork for all thirteen genes of interest.

Aging-associated oxidized albumin promotes cellular senescence and endothelial damage

Aging is associated with well-known changes in protein conformation that are involved in aging-related disease. Among this modification, probably the protein oxidation is the most relevant mechanism of pathogenesis in the elderly subjects. Oxidative modifications generally cause loss of catalytic or structural function in the affected proteins; it is likely that the level of oxidatively modified proteins observed during aging will have serious deleterious effects on cellular and organ function. Proteins are major targets for reactive oxygen species (ROS) because of their abundance in biological systems. In addition, proteins are primarily responsible for most functional processes within the cells. The major protein present in the plasma is albumin, which constitutes ~55% of the plasma proteins. As a result, it is most susceptible to suffer an oxidative process. In this manner, the oxidation of albumin may cause endothelial damage. Nevertheless, there are no studies analyzing the effects of oxidized albumin in aging, and as a consequence endothelial damage.

It is now recognized that the oxidative modification of proteins by reactive species, especially ROS, is implicated in the progression of an important number of diseases. Compared to control samples, proteins are more oxidized in tissues of animals and patients suffering from many of the age-related diseases. Cardiovascular diseases show a significantly elevated mortality in elderly patients and have been associated with endothelial cell injury. Furthermore, cardiovascular diseases have been proven to cause a decline in endothelial function. In addition, oxidized proteins have been demonstrated to be a critical contributor to the development of atherosclerosis, contributing to the formation, progression, and complications of atherosclerotic plaques. Noteworthy, in another study, oxidized proteins lead to endothelial dysfunction. As a result, there is great interest in studying new target therapies to prevent or reverse the aging-induced oxidative stress in endothelial cells.

The mechanism by which endothelial cells undergo senescence is still largely unclear and yet to be discovered. Although this mechanism probably involves a multifactorial response, oxidative stress has been proposed as a mediator to explain the process of cellular senescence. Oxidative stress is characterized by excess free radical activity and plays an important role in the oxidation of proteins. Several studies have implicated the oxidation of low-density lipoprotein (LDL) in atherosclerosis. However, there is no evidence that relates the oxidized albumin, which is the most abundant protein in serum, with endothelial injury. Therefore, in this study, we investigated whether aging induced an increase in oxidized protein and whether oxidized albumin may be involved in aging-related endothelial damage.

Endothelial microparticles (EMPs) have been used as biomarkers of cell damage and activation. These are a heterogeneous population of small membrane fragments shed from various cell types. The endothelium is one of the primary targets of circulating microparticles, and microparticles isolated from blood have been considered biomarkers of vascular injury and inflammation. In this study, oxidized albumin-treated human umbilical vein endothelial cells (HUVECs) cause the release of EMPs and an increment of apoptosis levels. These findings support the idea that the endothelial cells are suffering from an endothelial activation, which is an apoptosis phenomenon not observed with native albumin treatment. Recent evidence also suggests that the endothelial cell is damaged as a consequence of cardiovascular disease. Furthermore, released EMPs are considered a marker of endothelial damage in patients. Several studies have demonstrated that adhesion molecules are secreted by activated endothelial cells and contributed to endothelial cell injury. Supporting this, our results demonstrate an increase of VCAM-1 and ICAM-1.

In addition, other studies have indicated the increase of modification proteins may be associated with oxidative stress development in aging. In this regard, there is a wealth of data evidencing the fact that protein modifications cause ROS production. As the results showed, oxidized albumin results in ROS production increment in endothelial cells as well as in the amount of ROS per cell. The enhancement of oxidative stress is considered a key mechanism in cellular senescence development. In this study, the upregulation of ROS induced by oxidized albumin is correlated with an increase in the number of senescent cells. These data support the idea that the oxidized albumin may be considered a cardiovascular risk factor to induce oxidative stress. As a consequence, the cell may suffer senescence processes to prevent a possible damage due to oxidative stress. Research is needed to explore the possibility of utilizing oxidized albumin as a potential therapeutic target.

A research team investigating the mechanisms of regeneration has assembled the TiRe (Tissue Repair) database, a catalog of genes known to be involved in skin healing in a variety of mammals. There are several hundred such genes at this point, indicative of the complexity of the processes involved. Among the questions explored in this open access paper is whether or not more rapid healing corresponds with greater longevity in, for example, genetically varied lineages of laboratory mice: is there any overlap in the genes known to be relevant in healing and aging, and what exactly do those relationships mean?

Wound healing is an inherent feature of any multicellular organism and recent years have brought about a huge amount of data regarding regular and abnormal tissue repair. Despite the accumulated knowledge, modulation of wound healing is still a major biomedical challenge, especially in advanced ages. Some species from diverse taxa (such as salamander, axolotl, hydra, and several others) and early mammalian embryos are able to fully regenerate damaged tissues/organs. In mammals, however, this ability is drastically reduced after birth and continues to decline with age. For most organs, this reduced regenerative capacity is in fact a normative response, favoring speed over functional restoration, so that regular tissue repair results in scar formation. Deviations from regular tissue repair may lead to diverse pathological conditions, from slow or ineffective wound healing to hyper-fibroproliferative responses, both of which are often observed in advanced ages. Thus, factors that govern tissue repair are strongly associated with aging and age-related pathologies, and as such are potential targets for intervention in aging.

Is accelerated wound healing "good" for longevity? In an attempt to address this question, we have compared the list of wound healing-associated genes (WHAGs) with those reported as being involved in the control of lifespan. The comparison yielded 17 genetic mouse models of extended lifespan (longevity phenotype), or reduced lifespan (premature aging phenotype), which were also tested for skin wound healing. It is important to note that many studies used the rate of skin wound closure as a biomarker, assuming a priori that slower skin wound healing is indicative of an aging phenotype. Yet, our analysis shows that a slower or faster skin wound healing is indicative of an aging or longevity phenotype, respectively, only when assessed in advanced ages, but not in the young. For example, Agtr1a knockout resulted in slower wound healing in young mice but also in an extended lifespan. In contrast, Cav1 knockout, which accelerated wound closure, was accompanied by reduced longevity.

This means that pro- or anti-longevity effects of genetic interventions manifest in accelerated or delayed skin wound healing only in advanced ages, but not in young animals. Moreover, it seems that the association between the rate of wound healing and longevity is primarily attributed to an overall effect of the target gene on organismal aging rather than to its skin-specific action. This assumption is strongly exemplified by our study on the long-lived αMUPA mice, which preserve their skin wound healing capacity up to an old age (at least 25 months). In this unique model, the uPa transgene is expressed in the ocular lens and the brain stem but not in the skin, thus excluding the gene-specific effects on wound healing. Overall, the results emphasize that the age factor should be taken into account when evaluating the links between skin wound healing, aging and longevity.

To better understand these links, including older animals in the analysis is encouraged while using only young animals might yield confusing or misleading results. In particular, the opposite effect between the rate of skin wound healing in young age and the effect on life span could be explained by the links between wound healing and cancer, and the role of cancer in the determination of mouse longevity. Indeed, cancer has been considered as "an overhealing wound". This could be especially relevant to mice as cancer is the main cause of death for a variety of murine strains. For example, Tert overexpression in the young leads to accelerated wound healing, a high incidence of cancer, and increased mortality. Another example is the tumor suppressor gene Pten, known to negatively regulate the activity of the PI3K/mTOR pathway, which is involved in various cancers. Knockout of this gene resulted in accelerated wound healing in young age but a decreased lifespan, which is most likely associated with increased tumorigenesis.

Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=8501&path%5B%5D=25258

Researchers here suggest that regenerative therapies for the heart need to specifically address the lymphatic system in addition to the normal targets, as lymph drainage is as impacted as other processes following a heart attack, and this contributes to the harms done:

Although the blood system is the first to have been explored for the purpose of improving heart function, a study has revealed the potential of a secondary system that had previously received scant attention. The researchers analysed the heart lymphatic system in an animal model. They showed that this system was highly impaired following a myocardial infarction. Using a biotherapy based on the injection of microparticles, they succeeded in regenerating lymphatic vessels in a targeted manner. This treatment promotes lymphatic drainage, thus limiting post-infarct oedema and inflammation. Heart function is thereby improved.

When the heart is no longer able to provide an adequate blood supply to meet the body's needs, we speak of heart failure. This is due to an abnormality of the heart muscle that may be associated with injuries, a filling defect associated with a lung disease, deformation of the heart valves, etc. Fatigue, breathlessness and oedema are the main symptoms. While the blood system is involved in supplying blood to the organs and providing them with oxygen and nutrients, the lymphatic system transports fluids together with cells of the immune system, and drains away cellular wastes. The heart lymphatic system is especially well developed, but its role in cardiovascular diseases had received very little attention until now.

The research team used biodegradable microparticles, containing growth factors, previously developed during work on the creation of blood vessels. The researchers injected rats with a new biotherapy agent, based on the release of an encapsulated growth factor specific for lymphatic vessels (VEGF-C). "When administered to rats, the treatment accelerates the post-infarct cardiac lymphangiogenic response, and improves the lymphatic drainage of the heart in 3 weeks. As a direct effect, it reduces cardiac oedema, inflammation and fibrosis. This work, the result of 4 years of research, shows the strong involvement of this system in cardiovascular diseases. Indeed, research on these lymphatic vessels has only been developed in the last 10 years at most, and their role in physiopathology is often ignored." Lymphangiogenesis (the process that guides the formation of lymphatic vessels) thus represents a significant new therapeutic approach to explore in cases of heart failure and myocardial infarction.

Link: http://presse.inserm.fr/en/an-invisible-system-to-rescue-the-heart/23414/

One of the research advocates with the Major Mouse Testing Program recently wrote a popular science article on cellular senescence in aging, and more importantly the growing interest in methods of removing senescent cells. You'll find it linked below. Growing numbers of senescent cells is one of the root causes of degenerative aging, contributing to declining tissue function, progression of age-related disease, and ultimately death. Just this year researchers published results from a study of mice genetically engineered to destroy their own senescent cells, and which lived 25% longer than their unaltered peers. Other drug-based approaches to destroy senescent cells have not yet been used in full life span studies, but have been shown to improve health markedly in rodents, even after a single treatment in old age. Two startup companies are presently in the early stages of working on senescent cell clearance therapies, Oisin Biotechnologies and UNITY Biotechnology, and as more evidence accumulates there will no doubt be other players in this field.

Senescence is a cellular state of arrested replication, and is accompanied by many other altered behaviors, such as secretion of inflammatory and damaging molecules into surrounding tissues, a phenomenon called the senescence-associated secretory phenotype, or SASP. Cells become senescent in response to internal damage or a toxic environment - which can include the SASP of nearby senescent cells. At least initially senescence probably serves to reduce cancer risk, removing the ability to replicate from the cells most likely to suffer cancerous mutational damage. Most senescent cells are destroyed shortly after entering this state, either by their own programmed cell death processes, or by roving immune cells attracted by signals in the SASP. Some linger, however. Growth in the number of these persistent senescent cells occurs throughout life, but speeds up in later years: the level of damage to cells and tissues is higher, so more cells become senescent in response, and at the same time the immune system declines in effectiveness. As the presence of senescent cells increases, their collective SASP becomes a real issue, and actually makes cancer risk and progression worse than would otherwise be the case.

Researchers are still engaged in cataloging all of the ways in which senescent cells interact with important functions in our tissues. This is a slow and expensive process, just like all such work aimed at fleshing out the grand map of human metabolism and how it changes with age. The beauty and simplicity of aiming to destroy senescent cells, however, is that the scientific community doesn't need a full understanding of the detrimental effects, all the way down to the detail level of molecular interactions. All that is needed is to periodically remove these cells and validate the resulting benefits to health and longevity, a much easier prospect, as demonstrated by the numerous approaches presently under development or illustrated in animal studies.

The Two Faces of Aging: Cancer and Cellular Senescence

Aging, inflammation, cancer, and cellular senescence are all intimately interconnected. Deciphering the nature of each thread is a tremendous task, but must be done if preventative and geriatric medicine ever hope to advance. A one-dimensional analysis simply will not suffice. Without a strong understanding of the genetic, epigenetic, intercellular, and intracellular factors at work only an incomplete picture can be formed. However, even with an incomplete picture useful therapeutics can and are being developed. Depending on the context in which they are operating a single gene can have positive or negative effects on an organism's phenotype. Often the gene is exerting both desirable and undesirable influences at the same time. This is called antagonistic pleiotropy. Cellular senescence is a protective measure; it is a response to damage that could potentially turn a healthy cell into a malignant one. By halting its own division a senescent cell removes itself as an immediate tumorigenic threat. Yet the accumulation of senescent, non-dividing cells is implicated in a host of pathologies including, somewhat paradoxically, cancer.

Our bodies are bombarded by insults to their resilient but woefully vincible microscopic machinery. Oxidative stress, DNA damage, telomeric dysfunction, carcinogens, assorted mutations from assorted causes, necessary or unnecessary immunological responses to internal or external factors, all take their toll. In response cells may repair themselves, they may activate an apoptotic pathway to kill themselves, or just stop proliferating. After suffering these slings and arrows, p53 is activated. Not surprisingly, mice carrying a hyperactive form of p53 display high levels of cellular senescence. Abnormalities in p53 are found in most, if not all, cancers. Knocking out p53 altogether produced mice unusually free of tumors, but find themselves prematurely past their prime. There is a clear trade-off here. SASP (senescence-associated secretory phenotype) is associated with chronic inflammation, which itself is implicated in a growing list of common infirmities. Many SASP factors are known to stimulate phenotypes similar to those displayed by aggressive cancer cells.

p53 and mTOR interact with one another in ways that make mTOR inhibitors potentially useful, but since mTOR inhibitors such as metformin and rapamycin have their share of unwanted side effects, more and better drugs capable of destroying senescent cells - known as senolytics - must be explored in greater detail. Starting with a simple premise, namely that senescent cells rely on anti-apoptotic and pro-survival defenses more than their actively replicating counterparts, researchers created a series of experiments to find the Achilles' Heel of senescent cells. After comparing the two different cell states, they designed senolytic siRNAs. Of 39 transcripts selected for knockdown by siRNA transfection, 17 affected the viability of target senescent cells more than healthy cells. Similarly, dasatinib, a cancer drug, and quercitin, a common flavonoid found in common foods, have senolytic properties. The former has a proven proclivity for fat cell progenitors, and the latter is more effective against endothelial cells. Administration together into elderly mice resulted in favorable changes.

There are other senolytic approaches under development. Please embark on your own journey through the gallery of encroaching options for those who would prefer not to become chronically ill, suffer immensely, and, of course, die miserably in a hospital bed soaked with several types of their own excretions - presumably, hopefully, those who claim to be unafraid of death have never seen this image, or naively assume they will never be the star of such a dismal and lamentably normal final act. There is nothing vain about wanting to avoid all the complications that come with time. This research is quickly becoming an economic and humanitarian necessity. The trailblazers who move this research forward will not only find wealth at the end of their path, but the undying gratitude of all life on earth.

Among the less attractive aspects of human nature are a fixation with what is rather than what can be, the tendency to limit the definition of success and desired outcomes to whatever the best of the present options might be, and a burning desire to tear down those who have more than you rather than work to create more for everyone. Even in an age of rapid, radical change driven by advancing technology, the vast majority of people focus entirely on the distribution of present assets and opportunities, giving little to no thought to the much larger set of assets and opportunities that we could create for tomorrow.

You see this in the vastly greater attention given to any evidence for distributions and correlations in life expectancy between populations today, and the tiny amount of attention and support given to the production of rejuvenation therapies to greatly increase life for everyone at a modest cost. Given the realization of SENS rejuvenation treatments, the first of which are already under development in startup companies, and most of which will take the form of comparatively low-cost, mass-produced infusions, ten year variations in longevity due to lifestyle choices or access to medicine will be swamped, made irrelevant and small.

The study shows that in the U.S., the richest 1 percent of men lives 14.6 years longer on average than the poorest 1 percent of men, while among women in those wealth percentiles, the difference is 10.1 years on average. Over roughly the last 15 years, life expectancy increased by 2.34 years for men and 2.91 years for women who are among the top 5 percent of income earners in America, but by just 0.32 and 0.04 years for men and women in the bottom 5 percent of the income tables. In addition to reporting the size and growth of the income gap, the study finds that the average lifespan varies considerably by region in the U.S. (by as much as 4.5 years), but that the sources of that regional variation are subtle, and, like the aggregate national gap, subject to further investigation. That regional variation in longevity does not seem strongly correlated with factors such as access to health care, environmental issues, income inequality, or the job market. "We don't find those to be as highly correlated with differences in longevity as we find measures of health behavior, such as smoking rates or obesity rates."

The researchers looked at 1.4 billion anonymized income tax filings from the federal government, and combined that with mortality data from the years 2001 through 2014 from the Social Security Administration. This represents the most complete geographic and demographic landscape of mortality in America. Among other things, the growth of the gap in mortality rates - by nearly three years - struck the researchers as noteworthy. To put it in perspective, they note that federal health officials estimate that curing all forms of cancer would add three years to the average lifespan. At the same time, the researchers are quick to point out that the findings cannot immediately be reduced to simple cause-and-effect explanations. For instance, as social scientists have long observed, it is very hard to say whether having wealth leads to better health - or if health, on aggregate, is a prerequisite for accumulating wealth. Most likely, the two interact in complex ways, something the study cannot resolve.

A new puzzle emerging from the study, the authors note, is that differences in lifespan exist along the entire continuum of wealth in the U.S.; it is not as if, say, the top 10 percent of earners cluster around identical average lifespans. "As you go up in the income distribution, life expectancy continues to increase, at every point." And then there are the new geographic patterns in the findings. For instance: Eight of the 10 states with the lowest life expectancies for people in the bottom income quartile form a contiguous belt, curving around from Michigan through Ohio, Indiana, Kentucky, Tennessee, Arkansas, Oklahoma, and Kansas. So while average lifespans for everyone are lower in some Southern states, the poor do not fare worse in those places than they do in other regions. "The Deep South is the lowest-income area in America, but when we're looking at life expectancy conditional on having a low income, it's not worse to be poor in the Deep South than it is in other areas of America. It's just that there are far more poor people living in the South."

Link: http://news.mit.edu/2016/study-rich-poor-huge-mortality-gap-us-0411

There is considerable growth in omics fields deriving from slices of proteomics, the study of the proteome, the proteins generated by a cell, and genomics, the study of the genome, the DNA that encodes those proteins. This means that the naming convention these days for areas of interest in molecular biochemistry, a particular subsection of the overall set of genes and proteins, is to coin new portmanteau terms ending in -ome and -omics. So here we have an open access paper that attempts a start on unifying on the one hand programmed aging theories in which aging is caused by genetic programs and on the other hand the more mainstream views on aging as an accumulation of damage that occurs as a side-effect of the normal operation of metabolism. In this paper the conceptual collection of genes, proteins, and alterations relevant to the regulation of aging or damage of aging are termed the deleteriome - relating to deleterious changes.

Different theories posit that aging is caused by molecular damage, genetic programs, continued development, hyperfunction, antagonistic pleiotropy alleles, mutations, trade-offs, incomplete repair, etc. Here, I discuss that these ideas can be conceptually unified as they capture particular facets of aging, while being incomplete. Their respective deleterious effects impact fitness at different levels of biological organization, adjusting progression through aging, rather than causing it. Living is associated with a myriad of deleterious processes, both random and deterministic, which are caused by imperfectness, exhibit cumulative properties, and represent the indirect effects of biological functions at all levels, from simple molecules to systems.

From this, I derive the deleteriome, which encompasses cumulative deleterious age-related changes and represents the biological age. This term encompasses molecular damage, consequences of additional deleterious processes, as well as increased disorder at all levels, from simple molecules to cells and organs. The organismal deleteriome consists of the deleteriomes of cells, organs, and systems, which change along roughly synchronized trajectories and may be assessed through biomarkers of aging. Aging is then a progressive decline in fitness due to the increasing deleteriome, adjusted by genetic, environmental, and stochastic processes.

Contributions of various factors to biological aging can be illustrated by the metaphor of an aging car. Here, the length of an organismal lifespan is analogous to the mileage driven over the car's lifespan. It is influenced by the make/model of the car (analogous to the effects of genetics) and road conditions, weather, and fuel quality (representing the effects of environment). Better built cars, like better road conditions, milder weather, and better fuel, will be associated with longevity. In addition, random processes influence lifespan. These stochastic events include internal processes of the car leading to damage accumulation, gradually increasing the chance the car breaks, as well as random events associated with driving (stopping, accelerating, turning, accidents, etc.). For example, a car driven on highways is expected to accrue more miles than when it is driven in city. Likewise, biological aging is influenced by genetics, which is a major contributor when aging is considered across species and genetically heterogeneous populations, environment, and stochastic processes.

As the deleteriome consists of diverse forms of damage and other deleterious processes, it is currently not accessible in its entirety. Difficulty in measurement notwithstanding, the deleteriome may be viewed as a measure of biological age of the cell, organ, or system. This implies that the best markers of aging would be the measures of the deleteriome. Such markers have not been well defined, as the focus of previous research has been on particular age-related changes, such as telomere length, oxidative damage, and expression of a limited number of genes. But such limited assays would be misleading in representing organismal aging and comparison across organisms and cell types. However, recent research shows that the candidate markers that best represent the deleteriome, because they include measurements of many diverse age-related parameters simultaneously, for example, genomewide epigenetic changes, mutations, nontargeted metabolite profiling and gene expression, offer the best predictive models of the progression through aging.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12480/

Today I'll point out a couple of recent studies covering some of the consequences that result from the long-term damage done by letting yourself become overweight. There are great many such studies, for all the good it seems to do in this era of cheap calories and diminished exercise. When talking about the harms done by excess visceral fat tissue, I'm sure I'm largely preaching to the choir. While I haven't checked, I'm fairly certain that the audience here is well aware of the ways in which we can sabotage our health. Based on the robust evidence from a small mountain of study data, if you want to struggle with illness in later life, spend more on medical services, and die sooner than you would otherwise have done, then the most effective way to engineer that outcome is to take up smoking, stop exercising, and put on weight. Smoking is probably the worst of those, taking everything into account, but when you look at the life expectancy numbers one of the more surprising results is that a sedentary lifestyle and obesity are each about as bad for you as a smoking habit.

How does being fat do enough damage to knock years from your life expectancy? The problems are largely caused by the visceral fat around the organs, rather than by subcutaneous fat deposits. Visceral fat cells are very active, sending all sorts of signals out into the body at large. Some of those trigger the immune system, which leads to raised levels of chronic inflammation. Further, given a high enough sustained intake of calorie and visceral fat deposition, fat cells start dying in large numbers, and this also attracts immune cells and creates inflammation. Recently researchers have noted that DNA fragments from dead fat cells grow in number in the bloodstream with age, again capable of producing inflammation, but also capable of causing abnormal behavior in other cells throughout the body. As you can probably tell, it has been clear for quite some time that inflammation is a primary connection between visceral fat tissue and ill health.

Chronic inflammation will occur in aging no matter how well we take care of our health, at least given the limited capabilities of medical technologies available today, none of which yet meaningfully address the underlying causes of aging. The immune system suffers structural issues after a lifetime of exposure to pathogens, and in addition its cells and sustaining tissues accumulate molecular damage just like all other portions of the body. The result is a weakened immune system that is constantly overactive, inflamed but doing little good in that active state. That is bad enough, but the extra inflammation that comes with excess fat tissue and other outcomes of poor lifestyle choices is a considerable and entirely avoidable additional burden. To be in a state of greater inflammation for years on end is very harmful. Inflammation is demonstrated to raise the risk of suffering all of the common fatal age-related conditions: it speeds progression of the underlying cell and tissue damage that gives rise to those conditions, and then continues to accelerates the pathology of a condition once established, for all the same reasons. This is why the relationships outlined below exist:

Heart failure risk increases with waistline

A body mass index (BMI) over 30 is considered obese, and the connection between obesity and the risk of heart failure has been established in several studies. Now, researchers have conducted a new meta-analysis that shows that a BMI between 25 and 30 kg/m2, which is considered overweight, is also associated with increased risk. "Overweight individuals had a 35 per cent increased risk of heart failure as compared with normal weight individuals, and our findings indicate that overweight should be considered a clear risk factor for heart failure."

Body mass index (BMI) shows the relationship between weight and height and is used internationally as a measure of body fat. The risk of heart failure rose on average by 41 per cent for an increase of five BMI units, and the increase in risk accelerated the further up on the BMI scale you scored. Obesity increased the risk two to three times compared with normal weight. The researchers found no differences between men and women in the analysis, which included 23 studies with a total of almost 650,000 participants. Four studies looked at the link between BMI and the risk of death from heart failure, and the results suggested a 26 per cent higher risk for an increase of 5 BMI units. Meanwhile, the researchers saw that every ten-centimeter increase in waist circumference was linked to a 29 per cent higher risk of heart failure. These analyses were based on twelve studies with a total of just over 360,000 participants.

New study: Waist circumference is stronger predictor of heart disease than BMI

Researchers found that abdominal obesity - or having an apple-shaped body - is a strong predictor of serious heart disease in patients who have type 1 or type 2 diabetes, and haven't displayed any symptoms of heart disease. Apple-shaped bodies are already associated with metabolic syndrome (which includes high blood pressure, high sugar levels and high cholesterol), as well as coronary artery disease and heart failure, but this new study found that waist circumference is also a strong predictor of left ventricular dysfunction in patients. Metabolic syndrome is often accompanied by excess body fat around the abdomen. "This study confirms that having an apple-shaped body - or a high waist circumference - can lead to heart disease, and that reducing your waist size can reduce your risks."

The results of the new research expands on the results of a previously published study called FaCTor-64, which showed that the greater a person's body mass index, the greater their risk of heart disease. FaCTor-64 enrolled patients with diabetes who were considered to be at high risk for heart attacks, strokes, or death but had no evidence of heart disease as of yet. Study participants completed randomized screening for coronary artery disease by CT coronary angiography, then received recommendations to change their care or their lifestyles, or continue routine standard diabetes care, based on their results. They were then followed to track future adverse heart events.

Double-stranded RNA activated caspase oligomerizer (DRACO) is an antiviral technology that works by destroying infected cells rather than directly attacking viral particles themselves, thus disrupting viral replication. It has proven effective against numerous viruses, and should in principal work against near all viral infections in a broad range of species, including the many persistent viral infections that presently lack any effective treatment. The technology finds itself in a similar position to SENS rejuvenation research however, with little support from the funding mainstream, and needing to raise funds from philanthropists to bring the technology to the clinic. Potential radical improvements over the existing status quo are often in this situation, unfortunately. Following on from an initial crowdfunding effort last year, and a growing group of supporters, the Rider Institute is the latest step in the organization of fundraising and advocacy for DRACO research and development:

Currently there are relatively few prophylactics or therapeutics for viruses, and most that do exist are highly virus- or even strain-specific or have undesirable side effects or other disadvantages. We have developed a radically new, broad-spectrum antiviral therapeutic/prophylactic that has the potential to revolutionize the treatment of viral infections. Our Double-stranded RNA Activated Caspase Oligomerizer (DRACO) approach selectively induces apoptosis (cell suicide) in cells containing viral double-stranded RNA (dsRNA). DRACO should recognize virus-infected cells and rapidly kill those cells without harming uninfected cells, thereby terminating the viral infection while minimizing the impact on the host.

When tested in human and animal cells, DRACOs have been nontoxic and effective against 18 different viruses, including rhinovirus (the common cold) and dengue hemorrhagic fever. We have also demonstrated that DRACO is nontoxic in mice and rescues mice from lethal challenges with H1N1 influenza, Amapari arenavirus, Tacaribe arenavirus, and Guama bunyavirus in preliminary trials.

DRACO research has entered what is known as the "Valley of Death." Modest amounts of funding from the National Institutes of Health have enabled the previous proof-of-concept experiments in cells and mice, but that funding grant is now over. Major pharmaceutical companies have the resources and expertise to carry new drugs like DRACO through the manufacturing scale-up, large-scale animal trials, and human trials required for FDA approval. However, before committing any of their own money, those companies want to see that DRACOs have already been shown to be effective against major clinically relevant viruses (such as members of the herpesvirus family), not just the proof-of-concept viruses (such as rhinovirus) that were previously funded by NIH. Thus the Valley of Death is the financial and experimental gap between the previously funded NIH proof-of-concept experiments and the threshold for convincing major pharmaceutical companies to advance DRACOs toward human trials.

We are now raising funds to test and optimize DRACOs against the herpesvirus family, which contains many major clinical viruses such as Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2), Cytomegalovirus (CMV), Varicella Zoster Virus (VZV, chickenpox and shingles virus), Epstein-Barr Virus (EBV), and Kaposi's Sarcoma Herpesvirus (KSHV). If we can raise enough funding, we also hope to test and optimize DRACOs against the family of retroviruses, which includes Human Immunodeficiency Virus (HIV) and Human T-Lymphotropic Virus (HTLV). In principle, the DRACO approach should be effective against virtually all known viruses, or potentially even against new viruses that may appear.

This campaign has been set up to raise the funding necessary to bridge the Valley of Death for DRACO research. With your assistance, we hope to raise enough funding to provide a total of $2 million dollars over four years, in order to test and optimize DRACOs against clinically relevant viruses in human cells. If successful, the results of those experiments should persuade pharmaceutical companies and other major sponsors to commit their own resources to advance DRACOs through large-scale animal trials and hopefully human trials. Without your assistance, DRACOs may never progress further, and their potential to revolutionize the treatment of viral infections may remain unfulfilled.

Link: https://riderinstitute.org/

George Church is an important figure in the field of genetics, and in recent years has become more vocal in his support for rejuvenation research. He is presently on the advisory board of the SENS Research Foundation, and in this broad article on the near future of medical research you'll find some of his thoughts on aging research:

Aging reversal is a big project both in my lab and in one of our startup companies. This is not about wellness or drugs that affect diseases of aging, which are effects rather than causes; it's trying to get at the causes of aging and reverse them. And there are a fair number of precedents for this in animals, but the idea is to get it transferred to humans.

Reversal of aging: Some examples of this are if you take blood from a young mouse and exchange it with an old mouse. The small molecules, macromolecules, and cells in the blood result in a variety of biomarkers of aging being reversed. You can affect the vasculature, the blood vessels, the nerves, skeletal and cardiac muscles, and there are measures of these that indicate that it's not just prolonging a very aged state or going for longevity; you're actually reversing it.

This is a much better target, in any case, than prolonging longevity because, A, it takes years to decades to even prove that you have extended longevity. Also, if you've done it on somebody that's quite old, the economic consequences are dire; that's the part of your life where you spend huge amounts on medicine and don't improve the quality of life tremendously. If you can reverse it to an age where you essentially don't use any medicine, this will be much more cost effective.

Link: https://www.edge.org/conversation/george_church-the-augmented-human-being

An interview with Aubrey de Grey of the SENS Research Foundation appears in the latest edition of the Actuary. This is in connection with forthcoming appearances at actuarial conferences, something that has long been a regular occurrence in de Grey's schedule as one of the more important advocates for rejuvenation research. The actuarial community is a good target for all advocacy relating to aging research, not least because they are already half-way bridging the gap with their own projects, aiming to better quantify the prospects for extended life spans through progress in medical science.

The profession of actuary is a node that connects medicine as practiced today, medical research and development for tomorrow, and the staggering sums of money that move through the global insurance and pensions industries. They are among the most ready to hear the story that great uncertainty lies ahead for the trend of increasing life expectancy, with the potential for radical gains should rejuvenation research programs like SENS move to the next stage of funding and pace of progress. SENS or something like it will happen, but the timing is very uncertain because the bootstrapping process that ends with taking over the medical mainstream is still in its early stages. At this point a couple of rejuvenation technologies are in early commercial development, but research funding is sparse for the rest and they remain years away from realization even if all goes well. The other uncertainty is that no-one has yet deployed SENS-like therapies based on repair of damage in humans: the effectiveness of the first of these, such as senescent cell clearance, at the outset, or five years in, or after a decade of improvements, is a question mark. One of them could add five or ten years to human life expectancy, a very large outcome for a treatment undertaken every few years, or it could improve health but do nothing meaningful to life span because other causes of aging lead people to die on about the same schedule.

While far from all actuaries are paragons of rationality when it comes to rejuvenation research and the prospects for change, a sizable fraction have become increasingly willing to hedge their predictions over the past decade, and industry voices have warned that a time of uncertainty lies ahead. Technological progress, and the great sweeping change now underway in the research community, from trying to patch over the consequences of aging to trying to repair the causes of aging, will make twenty year and longer life expectancy trend predictions meaningless. Actuaries have been speaking on this topic for some time now, but it isn't a message happily received in all quarters. Change in the insurance industry will come but slowly, and there will no doubt be entirely unnecessary chaos and destruction as we progress towards the medical control of aging and the greatly increased healthy longevity that will accompany it. No tears should be shed for that outcome, achieved by those betting against progress, save for the fact that losses will no doubt be socialized and the taxpayers will wind up footing the bill.

Dr Aubrey de Grey is a prominent biomedical gerontologist and chief science officer of the SENS Research Foundation. He is editor-in-chief of Rejuvenation Research, a Fellow of both the Gerontological Society of America and the American Aging Association, and sits on the editorial and scientific advisory boards of numerous journals and organisations. "You know, people have this crazy concept that ageing is natural and inevitable, and I have to keep explaining that it is not." His views on ageing are simple. "The human body is a machine with moving parts and like a car or an aeroplane, it accumulates damage throughout life as a consequence of normal operation."

Historically, efforts to postpone the ill health of old age have focused on finding ways to clean up our metabolism so that we accumulate damage to the body more slowly. About 15 years ago, de Grey had a 'Eureka!' moment upon realising that the most practical way to achieve this would be to find ways to repair the damage rather than looking to slow it down. "I realised we can classify different types of genetic damage into seven major categories, for each of which there is a different repair approach". This is the focus of the SENS Research Foundation. "We have all these diverse projects across various strands of research that we think need to be done, and because we are an independent non-profit charity, we have the luxury of being able to work on the hardest problems."

Although some of his views are met with scepticism and disbelief, he feels that the scientific community is become more accepting of his ideas, citing a recent breakthrough publication in one of the world's leading scientific academic publications. "As time goes on, our progress becomes more significant in proving the feasibility of my ideas. When I first started talking about these, people found them heretical and there was a lot of denigration from the scientific community, but I've gradually won them over. Other people are also making progress in actually implementing what we're doing. Just recently, an important US paper came out that showed you could extend the lifespan of mice using a particular type of damage repair that we'd been talking about for a decade."

If de Grey's predications are solid, what does he think this means for the actuarial profession? "I sympathise with the actuarial profession, because the fact is, the people who pay you to do your jobs really don't want to know the truth." Obviously, if his predictions come to fruition, there would be enormous implications for our industry; life and pensions in particular. Giant changes in life expectancy are likely to spark a renegotiation of pension contracts, as well as the way we approach our healthcare system, state benefit system and provide insurance. De Grey refused to be drawn on the wider impact that successfully achieving his goals could have, commenting: "I think it is foolish to speculate on what society is going to be like, even in 20 years, let alone 200 years from now. So many things are going to be different. The only thing we can do is prepare for as many alternative possibilities and consider how we might minimise any problems that might be created as a consequence of solving the problem of ageing." He believes dwelling on the bioethical considerations is missing the point: "We have to recognise that the problem we have today is enormous. Therefore it's critical not to be intimidated by the prospect that we have too many people, or living longer might be boring, and not let those considerations actually slow us down in terms of the development of medicines that get ageing under control."

De Grey readily admits that the likelihood of his research successfully extending his own lifetime is low. "As for any pioneering technology, the timeframe is extraordinarily speculative. Nobody has the faintest idea how long it's going to take. I put it at 20-25 years from now when we have a 50-50 chance of getting to a decisive level of comprehensiveness that works, which I've called longevity escape velocity. If we do get there by then, I've got a fair chance of benefiting. But I have absolutely no doubt there's at least a 10% chance we won't get there for another 100 years because we hit new problems that we haven't thought of. So if I look at my own personal prospects, or the prospects of any other particular person, the timelines and uncertainty result in this all being very speculative."

The conventional wisdom is that common genetic variations have only a very small impact on mortality and health across the majority of the present human life span, but as the molecular damage of aging accumulates in later life, a time of frailty, disability, and high risk of age-related disease, genes make an increasingly significant contribution to determining remaining life expectancy. Here is a very readable open access paper on this topic, covering at a high level a range of the mainstream work on genetics, lifestyle, and aging from the past few decades:

Before the 1990s it was largely considered that aging is ineluctable and that genetics does not control it. It was important, in this view, the idea that aging occurs after reproduction, and then there is no need, but also no opportunity, for selection to act on genes that are expressed during this late period of life. Thereafter studies clearly demonstrated that genetic variability could indeed affect lifespan. This triggered many studies in model organisms in order to disentangle the different biochemical pathways which could affect lifespan, and to highlight the genes coding for the proteins involved in such pathways.

It is of note that some authors suggested the molecular mechanisms modulating lifespan could be due to a pleiotropic effect of genes which have evolved for different purposes (such as the genes in the IGF-1 pathway which have evolved to face presence/absence of nutrients) but can, ultimately affect lifespan; others proposed that some genes may have evolved to program aging and avoid "immortality", as this would hamper the continuous substitution of old subjects with new, younger, ones. It was obviously inevitable that the research of the genetic basis of longevity turned to human beings and investigated whether the common genetic variability of human populations could affect inter individual differences in lifespan but also whether the genes found to prolong lifespan in model organisms, on turn, were correlated to human lifespan.

As to the first question (does common genetic variability affect lifespan, and in particular does it affect longevity?), this has been studied by two approaches. The first one was the reconstruction of the sibships of long-lived subjects and the comparison of their survival curves with those of the birth cohorts born in the same geographical area. This approach demonstrated that brothers and sisters of the long-lived subjects had a clear survival advantage (at any age) with respect to the general population. The second approach, with intrafamily controls, was started in order to distinguish the genetic from the "familiar" effect. Researchers compared the survival function of brothers of centenarians with those estimated for their brothers in law, that is with the men who married their sisters; these men were supposed to share with the brothers of the long lived subjects the familiar environment. By using this second approach, it has been found that the survival advantage of siblings of long-lived subjects was not completely shared by their brothers in law, despite they shared the same environment for most of their life. This suggested that beyond the family environment, there are genetic factors influencing survival and, consequently, lifespan. The genetic component of lifespan in humans has also been analyzed by comparing the age of death of monozygotic and dizygotic twins. This has allowed the estimate that about 25% of the variation in human longevity can be due to genetic factors and indicated that this component is higher at older ages and is more important in males than in females.

Link: http://dx.doi.org/10.1186/s12979-016-0066-z

Low doses of lithium have been shown to modestly extend life in nematodes, and a Japanese study suggested a correlation between human life expectancy and natural variations in lithium in tap water - a small and uncertain effect, as are most when it comes to human longevity. So it is interesting to find a similar outcome in flies, and here researchers have linked the effects of lithium intake to genes that are already targets of interest in aging research, NRF-2 and GSK-3, involved in regulation of cellular responses to stresses:

Fruit flies live 16% longer than average when given low doses of the mood stabiliser lithium. When the scientists investigated how it prolongs the lives of flies, they discovered a new drug target that could slow ageing - a molecule called glycogen synthase kinase-3 (GSK-3). The team found that lithium delays ageing by blocking GSK-3 and activating another molecule called NRF-2, which is found in worms, flies and mammals (including humans) and is important for defending cells against damage. According to the scientists, GSK-3 could be a target for drugs to control ageing. The study shows that male and female flies live longer than average when given low doses of lithium during adulthood or later in life, regardless of their genetic make-up. At low doses, few adverse effects were seen in the flies as they continued to feed normally and produce healthy offspring.

Different doses of lithium chloride were given to 160 adult flies to measure the effect on lifespan. Higher doses reduced lifespan but lower doses prolonged life by an average of 16% and maximum of 18% compared to a control group given sodium chloride. The benefits of lithium were also seen when it was used as a transient and one-off treatment. Flies that received a one-off dose near the end of their lives lived a maximum of 13% longer and young flies given low doses of lithium chloride for 15 days before switching to a control for the remainder of their lives also lived longer. "We studied the responses of thousands of flies in different conditions to monitor the effects of lithium and how it extends life. We found low doses not only prolong life but also shield the body from stress and block fat production for flies on a high sugar diet. Low doses also protect against the harmful effects of higher, toxic doses of lithium and other substances such as the pesticide paraquat."

Link: http://www.ucl.ac.uk/news/news-articles/0416/070416-fruit-flies-live-longer-on-lithium

Below you'll find linked a few papers on the biochemistry of extremely old individuals, those who are in the portion of life in which they are heavily damaged by the processes of aging, most of their former peers are dead, and genetic variations become significant in determining quality of life and remaining life expectancy. A great deal of data is arriving on the biochemistry of the aged. The capacity of the research community to accumulate data on molecular biochemistry, in genetics, in epigenetics, and in the growing diversity of "omics" fields, of which genomics was only the first and least specialized, has for years greatly exceeded the capacity to analyze that data. Those fractions of the community concerned with making sense of it all will be playing catch-up for decades, I believe, given the pace of growth in data on the operation of human cellular metabolism - and given that productive and useful analysis is fundamentally a harder, more expensive, and more uncertain problem than collecting the data in first place. The ongoing revolution in biotechnology means that mountains of omics data are assembled today, and there is every sign that tomorrow's mountains will be an order of magnitude larger. So when you pick papers to read from the ongoing river of new studies that build upon human metabolic data, bear in mind that if the influx of new data stopped tomorrow, there would probably still be enough to productively occupy the research community for years yet. It is an interesting situation, to be sure.

When it comes to aging, it all becomes deeper and more uncertain, of course. Researchers still have a long way to go to completely fill in the high level sketch of how human metabolism works in an ordinary, healthy adult, to turn that high level sketch into a comprehensive accounting of living molecular biology at the detail level. The task of understanding how that vastly complex and poorly understood system then changes over time, and how it goes wrong, and how it behaves in the seemingly endless variety of damaged states that accompany aging rather than in its normal, proper modes of operation in youth ... well, that is a much bigger project. The sheer complexity of our biochemistry is why researchers have struggled to produce safe and effective ways to alter cellular metabolism to slow aging, even when the goal is replicate aspects of well-known and easily studied states such as the responses to exercise or calorie restriction. Producing a slow-aging human by following this path is not a project for our era, but something that will require the far greater resources of biotechnology and computation that will emerge much later this century. Even then, why do this? Aging more slowly because you have a better biochemistry is not rejuvenation, and it doesn't much help those already old and damaged.

Thus to my eyes the best way to look upon the study of human longevity and human genetic and metabolic diversity is as an interesting but presently less important field of scientific endeavor. Extension of healthy life will not come from these studies, but rather from efforts to repair and reverse the molecular damage that causes aging. Given therapies that can achieve that goal sufficiently comprehensively, people will not enter the state of being very damaged and frail, and age-related diseases will not arise. The study of the resilience of some older people in the face of frailty will become a historical curio, in the same way as there is little study of the impact of genetic variations on smallpox survival rates today. That is the future we want to see, and it is one that researchers can work towards today, given present knowledge of the causes of aging, sidestepping our ignorance of the intricate chain of cause and effect linking root cause molecular damage to end result age-related disease. Just as the Romans could use engineering and empiricism to build imposing and functional structures that lasted for centuries, without modern materials science and computational modeling, in a state of comparative ignorance, the very same conceptual approach can be applied to rejuvenation therapies: revert the well-known and well-cataloged differences between old and young tissues, and observe the results, adjusting course as needed.

A Stress-Resistant Lipidomic Signature Confers Extreme Longevity to Humans

Plasma lipidomic profile is species specific and an optimized feature associated with animal longevity. In the present work, the use of mass spectrometry technologies allowed us to determine the plasma lipidomic profile and the fatty acid pattern of healthy humans with exceptional longevity. Here, we show that it is possible to define a lipidomic signature only using 20 lipid species to discriminate adult, aged and centenarian subjects obtaining an almost perfect accuracy (90%-100%). Furthermore, we propose specific lipid species belonging to ceramides, widely involved in cell-stress response, as biomarkers of extreme human longevity. In addition, we also show that extreme longevity presents a fatty acid profile resistant to lipid peroxidation. Our findings indicate that lipidomic signature is an optimized feature associated with extreme human longevity. Further, specific lipid molecular species and lipid unsaturation arose as potential biomarkers of longevity.

Improved lipids, diastolic pressure and kidney function are potential contributors to familial longevity: a study on 60 Chinese centenarian families

Last year, we managed to recruit 60 longevity families from Hainan province, a well-known longevity region in China, and performed a complete physical examination on all subjects. Based on this population, we found that the thyroid function was associated with longevity and could be heritable. In this study we expanded the study by investigating associations of the rest blood parameters with age, and associations between generations, aiming to seek candidate factors associated with familial longevity. Associations of blood parameters in centenarians (CEN) with their first generation of offspring (F1) and F1 spouses (F1SP) were analyzed.

In this study, using association and further comparison analyses we identified several blood parameters that may contribute to longevity. First, total cholesterol (TC) and triglyceride (TG) increased with age until 80 years, but decreased in centenarians, indicating that lipid metabolism was improved in the oldest old. A similar trend was observed for LDL-C, although it was not associated with age before 80 years. The changes in lipid levels were consistent with that in other studies. Increased TC, TG and LDL-C concentrations are the most important independent risk factors for cardiovascular disease, the leading cause of adult death worldwide. In this regard, we can assume that the CEN may be less susceptible to cardiovascular disease, and hence, live longer. To understand why the CEN have such a favorable lipid profile, we analyzed the expression of genes involved in lipid metabolism and found some differentially expressed genes between the CEN and F1SP. Based on their known functions, they may confer both beneficial and detrimental effect on regulating lipid profiles, suggesting there is a balance in the regulation of the lipid metabolism in the longevity subjects. However, the overall outcome seemed to reduce lipid levels and thus accounted for the favorable lipid profile in centenarians.

More importantly, we observed for the first time that diastolic blood pressure rather than systolic pressure was improved in CEN compared to the elderly. Blood pressure is a well accepted cause for age-related diseases, not only for the cardiovascular disease, but also for cerebrovascular and/or neurodegenerative diseases, such as cerebral hemorrhage and senile dementia. Indeed, a number of studies have noticed that diastolic blood pressure exerts stronger influence than systolic blood pressure on the occurrence and development of cardiovascular and cerebrovascular diseases. Our results expand the knowledge by extending the age range to over 100 years. Likewise, we managed to identify several candidate genes associated blood pressure. Of notice is the CST3 gene, it has the most significant difference between the CEN and F1SP, and it codes a protein called cystatin c which has been positively associated with systolic pressure but inversely with diastolic pressure, which was well consistent with our observation.

Methylomic predictors demonstrate the role of NF-κB in old-age mortality and are unrelated to the aging-associated epigenetic drift

Changes in the DNA methylation (DNAm) landscape have been implicated in aging and cellular senescence. To unravel the role of specific DNAm patterns in late-life survival, we performed genome-wide methylation profiling in nonagenarians (n=111) and determined the performance of the methylomic predictors and conventional risk markers in a longitudinal setting.

The consequences of aging-accompanied DNAm alterations for late-life health and functional abilities are largely unknown. A recent epigenome-wide association study (EWAS) demonstrated that the association between age-related DNAm changes and healthy aging phenotypes in individuals 32-80 years of age is negligible. The results of this study also reveal that the DNAm regions associated with aging phenotypes are distinct from those associated with chronological age. These findings suggest that the CpG sites involved in health-related outcomes in later life are largely regulated by sites other than the established age-related DNAm regions. In addition, using an EWAS approach, we have recently demonstrated that the CpG sites that are associated with aging-related inflammation are largely different from the sites associated with age. This phenomenon is also observable in regard to gene expression profiles and old age mortality. We have previously demonstrated that the genes exhibiting aging-related changes in expression levels are predominantly different from those that predict mortality in late life. These findings underscore the complexity and unknown nature of the genomic factors that control the human health span and late-life events.

Nevertheless, the mortality-predicting genes in our previous study were found to be functionally connected to the nuclear factor kappa B (NF-κB) complex, which is a central mediator in immunoinflammatory responses and has been advocated as the culprit in aging and cellular senescence. Aberrant activation of NF-κB has been reported in various age-associated conditions, such as neurodegeneration, immunosenescence, inflammaging, sarcopenia and osteoporosis, whereas studies involving mouse models have observed that NF-κB activation is a key determinant of accelerated aging and longevity. The results of this study corroborate the role of NF-κB in all-cause elderly mortality; the molecular network constructed from the genes harboring the mortality-associated CpG sites displayed the NF-κB complex as a central mediator. We hypothesize that our findings could relate to the recent observation of a programmatic role of hypothalamic NF-κB and IκB kinase-β activation in the control of the life span in experimental mouse models. Adhering to the conclusion of this mouse study that the decisive role of hypothalamic NF-κB is exerted systemically level through immune-neuroendocrine crosstalk, we suggest that our findings on immune cells might represent the peripheral correspondence of hypothalamic NF-κB activation. However, establishing the systemic-level events that connect NF-κB function to all cause-mortality in aged humans will require further research.

Here I'll point out one of numerous studies providing evidence to illustrate that telomere length isn't all that useful as a biomarker of aging. Telomeres cap chromosomal DNA, a length of repeated sequences that shortens every time a cell divides. This forms a part of the limiting mechanism that stops ordinary somatic cells from dividing indefinitely. Stem cells and cancer cells maintain their ability to divide by periodically extending their telomeres via various mechanisms. At present telomere length is usually measured from a blood sample, taking the average of lengths in immune cells. This will reflect some combination of cell division rates, cell replacement rates, and the immune status of the individual.

Statistically, considered over large populations, average telomere length in immune cells trends downward with aging, indicating that cell populations are dividing more frequently, or not receiving as great an influx of new cells with long telomeres as they were in youth, or both. The latter is a part of the well-known decline of stem cell activity with age. Unfortunately telomere length is nonetheless a terrible measure of biological age on a practical, individual basis, as the correlation just isn't that good, and measures can vary greatly over time for reasons that have little to do with aging, such as ill health due to infectious disease. This all ties in with the idea that the age-related statistical trend towards diminishing telomere length in cell populations is a reflection of the effects of damage on other processes, as well as the influence of numerous other environmental circumstances, and not a cause of aging in and of itself.

Advances in technology allow scientists to measure intricate details about the human body that greatly enhance understanding of health, disease and aging. Yet, when it comes to predicting death, more rudimentary measures - like a person's age or a person's ability to climb stairs or walk a short distance - are much more powerful predictors of survival than certain biomarkers. Using data from the United States, Costa Rica and Taiwan, researchers compared a broad set of predictors of death - like age, smoking habits and mobility - with the length of telomeres, DNA sequences that generally shrink with age.

Decades ago, researchers discovered that telomeres - which are protective caps on the ends of our chromosomes - act as a 'molecular clock' in human cells. Every time cells divide, telomeres shorten until they become critically short and signal the cell to stop dividing. Telomere length is typically measured in white blood cells (leukocytes), and shorter leukocyte telomeres have been associated with disease, aging and death. For these reasons, there has been great interest in the ability of this biomarker to predict mortality.

After evaluating data, the research team found that using telomere length to predict a human's death was only marginally better than a "coin toss." Chronological age was, by far, the single best predictor of death in all three countries. "Scientific evidence on telomere length has been sensationalized and, in some cases, exaggerated by the media and by companies that have capitalized on the research to market products that may promise more than they can deliver. This is what fueled our research. We wanted to determine whether telomere length could predict mortality better than other well-established predictors of survival, most of which are less invasive and much less costly to measure."

The researchers note some potential limitations of the findings. People who are critically ill might exhibit changes in the distribution of different types of leukocytes that makes their telomeres appear longer. In this study, telomere length is measured in leukocytes, which is common across most research. But some types of leukocytes tend to have longer telomeres than others. "Telomere length tends to be longer in the type of leukocyte that becomes more dominant when a person is ill. Therefore, a sick person might appear to have 'longer' telomere length, but that is deceptive. In fact, these critically ill individuals may be much more likely to die in the short-term despite the appearance of 'longer' telomeres."

It also is plausible that telomere length is a better predictor of long-term mortality, compared to short-term survival, since it reflects the gradual process of cellular aging. "Alternatively, telomere length might be a predictor of mortality only for certain groups of patients, such as those with cancer. An interesting possibility is that telomere length might not be a good predictor of mortality, but it could be a good predictor of healthy aging. Increasing evidence demonstrates that shorter telomeres are associated with cardiovascular disease, but additional research is needed to clarify the association between telomere length and other diseases of aging such as cancer."

Link: http://wws.princeton.edu/news-and-events/news/item/age-and-mobility-predict-death-better-one%E2%80%99s-%E2%80%98molecular-clock%E2%80%99

Despite some promising results, such as the one linked here, it remains an open question as to whether the mechanisms necessary for regeneration of limbs and organs, a feat that species such as salamanders and zebrafish are capable of, also remain buried in mammals, such as mice and humans. Have we lost that ability entirely over the course of evolutionary history, did our branch of the tree of life never have it, or does it remain, dormant, and possible to reactivate? Since mice, humans, salamanders, and zebrafish all grow from embryos, and since the process of organ regrowth at least superficially resembles embryonic development, there is hope that the third option is in fact the case, and that this is a path to enabling profound regeneration in our species.

"We want to know how regeneration happens, with the ultimate goal of helping humans realize their full regenerative potential." Over the last decade, researchers have identified dozens of regeneration genes in organisms like zebrafish, flies, and mice. For example, one molecule called neuregulin 1 can make heart muscle cells proliferate and others called fibroblast growth factors can promote the regeneration of a severed fin. Yet what has not been explored are the regulatory elements that turn these genes on in injured tissue, keep them on during regeneration, and then turn them off when regeneration is done. In this study, researchers wanted to determine whether or not these important stretches of DNA exist, and if so, pinpoint their location. It was already well known that small chunks of sequence, called enhancer elements, control when genes are turned on in a developing embryo. But it wasn't clear whether these elements are also used to drive regeneration.

First, the researchers looked for genes that were strongly induced during fin and heart regeneration in the zebrafish. They found that a gene called leptin b was turned on in fish with amputated fins or injured hearts. They scoured the 150,000 base pairs of sequence surrounding leptin b and identified an enhancer element roughly 7,000 base pairs away from the gene. They then whittled the enhancer down to the shortest required DNA sequence. In the process, they discovered that the element could be separated into two distinct parts: one that activates genes in an injured heart, and, next to it, another that activates genes in an injured fin. They fused these sequences to two regeneration genes, fibroblast growth factor and neuregulin 1, to create transgenic zebrafish whose fins and hearts had superior regenerative responses after injury. Finally, the researchers tested whether these "tissue regeneration enhancer elements" or TREEs could have a similar effect in mammalian systems like mice. They attached one TREE to a gene called lacZ that produces a blue color wherever it is turned on. Remarkably, they found that borrowing these elements from the genome of zebrafish could activate gene expression in the injured paws and hearts of transgenic mice.

Eventually, the researchers think that genetic elements like these could be combined with genome-editing technologies to improve the ability of mammals, even humans, to repair and regrow damaged or missing body parts. "There may be strong elements that boost expression of the gene much higher than others, or elements that activate genes in a specific cell type that is injured. Having that level of specificity may one day enable us to change a poorly regenerative tissue to a better one with near-surgical precision."

Link: https://today.duke.edu/2016/04/genetrees

Skin aging is a fixation in the broader community beyond the sciences, perhaps the more so because there is no effective treatment to slow or turn back skin aging. Life-long exercise and calorie restriction are the only thing that works. When looking at what you can go out and buy, all that does exist are a few marginal cosmetic approaches that don't address the actual underlying processes, and beyond that a very large number of people lying through their teeth about what their products are capable of achieving. An enormous amount of money changes hands on the basis of those lies, enough to sustain sizable industries. The degree to which people know they are being taken and are engaged in purchasing "anti-aging" products for reasons other than believing it will do any good is an open question. Still, this is a great example of the way in which outright fraud can become both respectable and sizable enough to solidify a place in society, which in turn is one of the many reasons why we should question everything around us rather than taking any it for granted. Change is coming in this case, however, in the form of therapies that do in fact address the underlying root causes of skin aging, and will be capable of actually, measurably, undeniably rejuvenating old skin.

If we look at the root causes of aging, assembled from the gathered evidence of dozens of fields of research and expressed as the SENS research proposals, those most relevant to the aging of skin appear to be (a) declining stem cell function, (b) the formation of persistent cross-links in the extracellular matrix, and (c) growth in the number of long-lasting senescent cells. However, no-one today can tell you which of those is most important, nor the relative levels of importance. The only practical way to find out is to fix one of those problems and see what happens. They are all fairly independent of one another, and will be addressed by entirely different research groups and sections of the research and development communities. If pushed for an educated guess, I'd say that we'd have heard by now if it was the case that stem cell infusions produced noticeable differences in skin in older individuals, so beyond wound healing this seems likely to be a smaller effect than the other two. As for the ordering of those other two, I really have no idea and no intuition. One could argue coherently for either: the extracellular matrix is the basis for skin elasticity, and cross-links definitively affect that elasticity, but senescent cells cause a very wide range of harms, and are thought to exist in aged skin in sizable numbers.

Cells become senescent in response to internal damage or a toxic environment, among other reasons. This shift in state removes them from the cycle of cell division, and it is thought that this is primarily an evolved defense against cancer, blocking the most vulnerable cells from running amok should they suffer just the wrong combination of mutational damage. Most senescent cells destroy themselves via programmed cell death mechanisms, or immune cells are drawn to the secreted signals of senescent cells and dismantle them. Some senescent cells linger indefinitely, however, and over a lifetime substantial fractions of many tissues become composed of cells in this state. A study some years back found as many as 20% of the cells in aged baboon skin showed signs of senescence, for example. These lingering cells generate a mix of signals called the senescence-associated secretory phenotype, which boosts inflammation, can harm the surrounding tissue structures, and make nearby cells more likely to become senescent themselves. In turn higher levels of chronic inflammation contribute to the progression of all of the common pathologies of aging.

The present state of ignorance on the relevance of senescent cells in skin aging won't last much past the next two years. Two companies are presently working on senescent cell clearance therapies, Oisin Biotechnologies and UNITY Biotechnology. In the former case, the technology has been demonstrated in rats. I have to imagine that for both companies, somewhere on the to-do list is the simple experiment in which one administers the treatment to aged animals and then measures the effects on skin elasticity and other physical measures impacted with age. That would be well within the capabilities of the Major Mouse Testing Project as well, using the recently discovered senolytic drug combinations if nothing else. If an approach can clear even a quarter of senescent cells in skin, that should be enough to draw conclusions on the impact to skin function. Beyond the knowledge gained, I can think of little better bait for publicity or potential funding from the big names in cosmetic science.

In the open access review linked below, the authors cover the approaches of destroying or altering the biochemistry of senescent cells as a class of approaches that could be used to delay skin aging. These researchers are associated with some of the existing groups working on the harmful biochemistry of senescent cells, as well possible methods to remove those cells or alter that biochemistry, such as the Buck Institute, and so they scrupulously avoid use of the word "rejuvenation." Removal of senescent cells is absolutely a very narrow form of rejuvenation, however. The presence of senescent cells is one of the defining features of old tissue, and they contribute to many of the processes of degenerative aging: inflammation, remodeling of surrounding tissues, failing tissue function, and so forth. Remove those cells and it is not unfair to say that the tissue in question is now closer in character to young tissue - a degree of rejuvenation has occurred, in other words. Of course that tissue still has amyloids, cross-links, failing stem cell populations, cells overtaken by damaged mitochondria, and so forth, but that is why we need a toolkit of various rejuvenation therapies, not just one tool.

Targeting Senescent Cells: Possible Implications for Delaying Skin Aging: A Mini-Review

Cellular senescence is a tumor-suppressive mechanism wherein cells are permanently growth arrested. Cells are induced to senescence by a wide variety of cellular perturbations, including nuclear DNA damage and mitochondrial dysfunction. Senescent cells are characterized by the secretion of several proinflammatory factors, a phenomenon called senescence-associated secretory phenotype (SASP). The accumulation of senescent cells with age is thought to contribute to impaired tissue homeostasis and to different age-related diseases. Lack of cell proliferation in senescent cells hampers the ability of tissues to regenerate after chronic and persistent injury, resulting in tissue damage. The proinflammatory and tissue-remodeling activities of the SASP also create chronic inflammation and alter tissue structure, which are the two main causes of age-related pathology. One fascinating hypothesis is that senescent cells might contribute in a cell and non-cell autonomous fashion to skin aging. Skin aging is associated with several pathologies, including lower protection from pathogens, increased irritation, loss of insulation, delayed wound healing and susceptibility to cancer, among others. Here, we summarize the evidence of the presence of senescent cells in the skin, and the potential for pharmaceutical interventions that eliminate the negative effects of senescent cells as methods to delay skin aging.

The impact of senescent cells on animal pathology was directly demonstrated when eliminating senescent cells through a suicide gene in a premature aging mouse model reduced selected age-related pathologies such as sarcopenia, cataracts, and loss of subdermal adipose tissue. Interfering with senescent cells may be beneficial for the overall health of the animal, and the development of specific interventions that target senescent cells may serve as a therapy to delay aging, including skin pathologies. This strategy can be achieved using three different approaches: (1) selective induction of cell death; (2) improvement of the immune system, and (3) inhibition of the SASP. The decline in immune function with age is consistent with the high number of senescent cells at old age, supporting the idea that the immune system may limit the number of senescent cells through clearance of these cells. Hence, it may be worth developing a strategy that boosts the immune cells capable of specifically eliminating senescent cells.

Removal of senescent cells and reducing the SASP are being considered as therapeutic strategies to delay the onset of age-related pathologies. Several drugs have already been identified that selectively target senescent cells. Some of them might have toxic effects when administered systemically for a long period of time: for example, ABT263 can cause thrombocytopenia in patients treated with an oral form of the compound. However, the toxicity might be highly reduced by developing drugs for topical treatment, an approach that would be suitable for skin interventions. The contribution of senescent cells to skin function is complex because they may be both beneficial and detrimental depending on the context; it is still unclear whether senolytic drugs will delay skin aging. Senescent cells are important for proper wound healing through their secretion of the SASP factor PDGF-AA and through their capacity to limit fibrosis, while chronic induction of cellular senescence through mitochondrial dysfunction may contribute to stem cell loss with age. Hence, proper testing of dosage and timing must be investigated to determine if these drugs would indeed reduce the negative impact on skin aging. Nonetheless, the possibility of selectively targeting senescent cells through pharmacological interventions posits a potential new solution to the functional decline associated with skin aging.

Starting with the earliest efforts to produce stem cell therapies, repairing damage and dysfunction of the heart has always been a primary goal. At present only very partial repair is possible in human cell therapies, for reasons that include the fact that cell therapies cannot address the buildup of important metabolic wastes such as cross-links, but improvement towards more optimal outcomes in this class of therapy is an incremental process of finding and refining methodologies of production and delivery of cells. With this in mind, researchers have recently achieved a very promising result in an animal study:

A new study shows that weeks after infusions of cardiosphere-derived cells (CDCs), the heart-pumping function returned to normal in laboratory rats with hypertension and diastolic heart failure. Formerly known as diastolic heart failure, the diagnosis now called heart failure with preserved ejection fraction is a condition in which the heart muscle becomes so stiff that its pumping chambers cannot properly fill with blood. Even though the heart's ability to pump blood to the body remains normal, its inability to fill with blood over time can lead to fluid buildup. This affects other body organs and causes fluid congestion, especially in the lungs. The hard-to-treat condition leads to extreme fatigue and difficulty breathing.

In the new research study, 34 laboratory rats with hypertension and heart failure with preserved ejection fraction were given infusions of cardiac stem cells. A second group of 34 laboratory rats were given a placebo. Four weeks later, the rats in the stem cells group had normalized heart function and their hearts were able to fill normally. Those in the placebo group became progressively sicker and died prematurely. "When patients with preserved ejection fraction get sick, they might be hospitalized and they might be prescribed medications like diuretics, which reduce the buildup of fluid in the lungs. The patients might get better symptomatically, but we haven't really treated the underlying condition. This research suggests that cardiac stem cells could be effective as a therapeutic agent, and there is a specific treatment we can try when everything else has failed." On the basis of these findings, the researchers have recently obtained clearance from the FDA to use cardiospheres to treat humans with heart failure with preserved ejection fraction. These stem cells, manufactured by Capricor as their product CAP-1002, have already been used in other human clinical trials.

Link: http://cedars-sinai.edu/About-Us/News/News-Releases-2016/New-Research-Shows-Cardiac-Stem-Cell-Infusion-Could-Be-Effective-Therapy-for-the-Most-Common-Type-of-Heart-Failure.aspx

Researchers have recently provided evidence for a correlation between levels of CXCL5 and progression towards coronary artery disease in aging. The more CXCL5 present, the better the state of the arteries in the study group:

For many people, coronary artery disease (CAD) - the buildup of plaque in the heart's arteries - is an unfortunate part of aging. By studying the genetic makeup of people who maintain clear arteries into old age, researchers have identified a possible genetic basis for the disease, as well as potential new opportunities to prevent it. "Our main goal was to try to understand why some people develop CAD and some people with similar risk factors do not, and we found that older people give us a great model to understand the natural disease process." Researchers analyzed blood samples and heart scans from 143 people over age 65 who were referred for cardiovascular screening. The analysis revealed that people with clear arteries had markedly higher levels of a protein called CXCL5, as well as genetic variants near the CXCL5 gene, compared with people with more plaque.

Previous studies linked CXCL5 with inflammation, leading some researchers to assume the protein was harmful. But recent research in mice suggested the protein could help limit plaque buildup by changing the composition of fat and cholesterol deposits in the arteries. The new finding offers the first evidence that CXCL5 could play a protective role in people, at least in the context of CAD. In addition to offering clues about how CAD develops, the study opens new possibilities for prevention and treatment. For example, it may be possible to develop a drug that mimics the effects of CXCL5 or that increases the body's natural CXCL5 production to help prevent CAD in people at high risk. The protein could even potentially be leveraged to develop a new, nonsurgical approach to help clear clogged arteries. One limitation of the study is that because all participants were referred for a heart scan, the study did not include healthy patients. Further research is needed to confirm the role of CXCL5 in CAD and explore drug development opportunities.

Link: http://news.unchealthcare.org/news/2016/april/new-clues-in-the-quest-to-prevent-clogged-arteries

Today I'll point out the availability of Alcor's book Preserving Minds, Saving Lives, a collection of some of the better writing on cryonics set down over the years. Much like research into rejuvenation therapies after the SENS model of repair of molecular damage, it is sadly the case that cryonics receives neither the attention nor the funding it merits given the plausible scope of benefits that might be realized. This is slowly changing in both cases, but much faster for rejuvenation research after the SENS model. Bootstrapping cryonics from its present state of a small non-profit industry and tiny scientific community into a much larger, capable, and more mainstream concern is proving to be a slow process indeed, but I think it will have its own tipping point in the years ahead.

Cryonics is, in short, the low-temperature preservation of at least the brain as soon as possible following clinical death. With the use of cryoprotectants, a glass-like state of vitrification is achieved in which ice formation is minimal to non-existent, cell damage is minimal, and the fine structure of the brain is preserved. It is a reasonable assumption that, if performed well, this also preserves the data of the mind, which present evidence strongly suggests is encoded somewhere in the dendrites and synaptic structures linking neurons. Lower animals have shown signs of retaining memory following vitrification and revival, and initial proof of concept experiments have demonstrated that internal organs can be vitrified and restored for transplantation, though currently the best restoration methodologies are fragile and failure-prone, still many years from clinical use. Still, it is through the organ transplant industry that cryonics will likely reach its tipping point: there is growing interest in the use of vitrification to store donated organs, or the seed tissues that grow into organs. When reversible vitrification of donor organs is possible, then preservation of the brain, the mind, and the self is a logical next step. For so long as the mind remains intact, the possibility remains for future restoration in a time of more capable medical technology. Death is not absolute or irreversible until that structure is gone.

This is why cryonics is important. It, like rejuvenation research, is all about saving lives, stemming the flood of death that passes us by every day. We live in a madhouse world in which more than 150,000 lives end daily, each one an invisible tragedy, while billions more march to an oblivion that might be avoided. Most are unaware of the alternative offered by cryonics, and of those who have heard of cryonics or given it some thought, most reject it out of hand. As a species, and judging by our actions, we are not as much in love with life as might be thought given our conversations and literature.

Preserving Minds, Saving Lives

Cryonics is an experimental medical procedure that uses ultra-low temperatures to put critically ill people into a state of metabolic arrest to give them access to medical advances of the future. Since its inception in the early 1960s, the practice of cryonics has moved from a theoretical concept to an evidence-based practice that uses emergency medical procedures and modern vitrification technologies to eliminate ice formation.

Preserving Minds, Saving Lives offers an ambitious collection of articles about cryonics and the Alcor Life Extension Foundation. From its humble beginnings in 1972, and its first human cryonics patient in 1976, Alcor has grown to a professional organization with more than 1,000 members, more than 140 human patients, and more than 50 pets, all awaiting a chance to be restored to good health and continue their lives.

This 570-page book presents some of the best cryonics writings from Cryonics magazine from 1972 to 2012. There are clear expositions of the rationale behind cryonics, its scientific validation, and the evolution of Alcor procedures. Also covered are repair and resuscitation scenarios, philosophical issues associated with cryonics, and debates within the cryonics community itself.

Why you want to read Alcor's new book

So perhaps you're fairly new to Alcor and cryonics. You're pretty sure this technology might be worth investigating; maybe you've even gotten signed up. But there's a lot you don't know. When your friends and relatives ask you those awkward questions about WHY you're doing this and what makes you think it will work, you haven't figured out solid answers yet. Especially if you live in an area without many other people involved in cryonics, you may really need solid ideas. You may even wish you have a book you could hand some of them, something that might make all of these ideas clear.

We have that book - Preserving Minds, Saving Lives: The Best Cryonics Writings from the Alcor Life Extension Foundation. We have been working on those answers for more than 35 years, often in the pages of our magazine, Cryonics. This book takes many of those great answers and puts them together in one volume for you. Why do we preserve patients in liquid nitrogen? How might that change in the future? What is the difference between freezing and vitrification? Why is vitrification better? How did this odd idea get started in the first place? What has Alcor gone through to get to this point? What mistakes were made along the way and how do we know cryonicists have learned from those mistakes? Why the heck isn't cryonics wildly popular? It's all here, along with many other discussions, by the best writers Alcor has had to offer for more than three decades. There are a handful of technical articles, because we want to make sure that the bases for this technology are readily available for future researchers. But most of the articles are accessible to anyone.

Results were recently published for a trial of ixmyelocel-T, a therapy consisting of the delivery of a mix of cell types generated from a patient sample, including mesenchymal and immune cells. This produced modestly promising results in a trial for limb ischemia a few years back, and here the focus is on heart failure, with a similar modestly promising outcome. To take a glass half empty view, the results suggest that in advanced cases of disease the present generation of regenerative therapies are too little, too late. Far greater rebuilding and reconstruction will be needed to do more than slow the decline, but equally these same present generation therapies would no doubt achieve more if used earlier and more often in the disease process, all the way back to preclinical stages. That would require something of a paradigm shift in the way mainstream medicine is practiced, however. The idea of treating people for prevention with therapies of this sort is not yet a popular one, sad to say, and the state of regulation makes it hard to start down that path within the bounds of the system.

Among 109 patients randomized to receive the cell therapy or a placebo, those receiving the cell therapy, which involved extracting stem cells from a patient's own bone marrow, showed a 37 percent lower rate of the trial's primary endpoint, a composite of deaths, cardiovascular hospitalizations and clinic visits for sudden worsening of heart failure symptoms, over a 12-month period. "To date, this is the largest double-blind, placebo-controlled stem cell trial for treatment of heart failure to be presented." The study was a phase 2 clinical trial for a new stem cell therapy known as ixmyelocel-T. Using this technique, a doctor extracts a sample of bone marrow from a patient, processes it for two weeks to "enhance" it by increasing the number of beneficial stem cells, and then injects the processed bone marrow product into the same patient's heart muscle. The goal of the procedure is to strengthen the heart by increasing the number of functioning heart muscle cells, an approach known broadly as regenerative therapy.

The trial enrolled 109 patients with class III or IV heart failure resulting from ischemic cardiomyopathy, a type of heart failure that is related to restricted blood flow from a heart attack or coronary artery disease. Roughly half, 58 patients, were randomly assigned to receive intramyocardial ixmyelocel-T treatment, and 51 patients were assigned to receive a placebo. Patients in the control group underwent a bone marrow extraction and received a placebo injection two weeks later. Among patients given stem cell therapy, 3.4 percent died and 37.9 percent were hospitalized with cardiovascular problems, as compared to 13.7 percent and 49.0 percent, respectively, in the placebo group. Patients given stem cell therapy also had, on average, a longer amount of time until their first adverse event. Other measures of heart function and quality of life, including a walking endurance test and a measurement of the amount of blood pumped out of the left ventricle with each contraction, also suggested improvements in the group receiving ixmyelocel-T.

Link: http://www.eurekalert.org/pub_releases/2016-04/acoc-sct040416.php

A group of researchers is claiming the creation of induced stem cells reprogrammed from adult somatic cells that, unlike the current standards for stem cell therapies, create daughter cells that participate in building tissue rather than affecting regeneration through signaling only. The claim is that this method recapitulates one of the primary mechanisms of limb regeneration seen in salamanders, in which which ordinary adult cells dedifferentiate to become multipotent stem cells capable of constructing multiple tissue types. The paper is to the point, but the publicity materials indicate that the authors think this is a very big deal. Given that they've not completed animal studies to prove the point, this may be premature, but we shall see.

Stem cell therapies capable of regenerating any human tissue damaged by injury, disease or ageing could be available within a few years. "This technique is a significant advance on many of the current unproven stem cell therapies, which have shown little or no objective evidence they contribute directly to new tissue formation. We are currently assessing whether adult human fat cells reprogrammed into induced multipotent stem cells (iMS) cells can safely repair damaged tissue in mice, with human trials expected to begin in late 2017. This technique is ground-breaking because iMS cells regenerate multiple tissue types. We have taken bone and fat cells, switched off their memory and converted them into stem cells so they can repair different cell types once they are put back inside the body."

The technique involves extracting adult human fat cells and treating them with the compound 5-Azacytidine (AZA), along with platelet-derived growth factor-AB (PDGF-AB) for approximately two days. The cells are then treated with the growth factor alone for a further two-three weeks. AZA is known to induce cell plasticity, which is crucial for reprogramming cells. The AZA compound relaxes the hard-wiring of the cell, which is expanded by the growth factor, transforming the bone and fat cells into iMS cells. When the stem cells are inserted into the damaged tissue site, they multiply, promoting growth and healing. The new technique is similar to salamander limb regeneration, which is also dependent on the plasticity of differentiated cells, which can repair multiple tissue types, depending on which body part needs replacing.

Along with confirming that human adult fat cells reprogrammed into iMS stem cells can safely repair damaged tissue in mice, the researchers said further work is required to establish whether iMS cells remain dormant at the sites of transplantation and retain their capacity to proliferate on demand.

Link: http://newsroom.unsw.edu.au/news/health/medical-scientists-develop-%E2%80%98game-changing%E2%80%99-stem-cell-repair-system

The big move of platform finally happened for Fight Aging! this past weekend. I've been putting this off for quite the while, five years at least. For the past twelve years, Fight Aging! ran on the Movable Type blog platform, and now it is on WordPress. While I have no regrets regarding missing out on the early and chaotic years of WordPress, picking Movable Type was certainly one of the more personally consequential wrong choices on technology I've made over the years. Sadly, it is never easy to pick the platform that will turn out to succeed, or at least the one that won't collapse into unsupported irrelevance all too rapidly, as was the case for Movable Type. Hence, a decade down the line, I had to run a large migration of years of encrusted features and additions, approaching a rewrite in places, fleeing a platform that has so fallen out of favor that even the migration tools have vanished or no longer work. There is probably a metaphor for aging and the human condition as it stands today buried in there somewhere.

The purpose of my sharing this is primarily to note that a lot of work has been done under the hood in order to, ideally, keep everything much the same at the surface. Near everything has changed. The tires have been kicked, and numerous last-minute problems identified and fixed, but ideally you should see few differences. I've rearranged some of the site sections and most of the URL paths have changed, yes, but all of the old URLs should automatically redirect to the new locations. This should also be true for those of you using the content feeds in various ways. They should all continue to just work, though you might consider updating the URLs at some point. If anyone finds broken links, broken pages, or other things that are not as they should be, please do let me know. This is a site of, at this point, more than 12,000 posts, so it is hard to check them comprehensively, even with automation. Beyond the posts, the site is something of an iceberg; the pages you see are generated and served by about a tenth of the code that is actually important and in use under the waterline.

It has to be said that security is an increasingly important concern on any modern platform. Being on Movable Type was very constraining from the point of view of adding features, true, but it at least provided the benefit of being a small target, the recipient of little in the way of automated attacks and spam. WordPress, in comparison, is arguably one of the biggest targets online today thanks to its popularity as a platform. Glancing at the metrics, the defenses put in place have blocked something like 3,000 drive-by spam submissions in the past day or two, and the intrusion logs are just as voluminous. One of the time-consuming parts of this migration was the need to lock things down to a much greater extent than was the case in the past. WordPress is a palace of a thousand doors, half of which are hidden away, all of which need their locks and guards, and few of which are either locked or guarded when set up out of the box. While that does to a certain extent mean that you only have to run a bit faster than the other guy to stay ahead of of the proverbial bear, it is still necessary to do it right and plug all of the holes.

As a final note, the real benefit of this migration is that I'm now in a far better position to tinker and change and update Fight Aging! in ways both small and large. If you have ideas or features you'd like to see, this would be the time to mention them. I make no promises that any particular change will definitely happen, or that it will happen rapidly, but much more is now possible than was the case last week.

Experiments based on exposing old tissue to a young environment, and vice versa, have been gaining much more attention in recent years. The most common are the heterochronic parabiosis studies in which the circulatory systems of an old and a young individual are linked, with the result that the older individual benefits in a modest reduction in many measures of age-related decline, such as stem cell activity. This has led research groups to focus on the effects of signal molecules in the bloodstream as a proximate cause for some age-related changes in biochemistry. There are many other approaches to mixing old and young biochemistries, however, and in this open access paper the authors report on the results of taking an easily transplanted structure within skin, the hair follicle, and moving it between old and young individuals:

Recently, parabiosis experiments pairing old and young mice have suggested that some features of aging organs in old mice, in particular stem cells, can be reversed by factors in blood of young mice, including brain, spinal cord, and heart. The hair follicle, which cycles through telogen (resting), anagen (growing), and catagen (regression) throughout the life of mammals, undergoes obvious age-related changes including hair loss. The hair follicle contains hair-follicle-associated pluripotent (HAP) stem cells, which may also deteriorate during aging. Instead of using complex parabiosis surgery, we used hair-follicle subcutaneous transplantation in order to determine if the hair follicle, including its ability to produce hair shafts, and its HAP stem cells, can be rejuvenated.

We transplanted young hair follicles subcutaneously into both young and old nude mice. We also transplanted old hair follicles into young and old nude mice. In young nude mice, the transplanted young hair follicles started to establish blood vessel connections and hair shafts began to grow by week 2. The old hair follicles transplanted to young nude mice also established blood vessel connections by week 2. The growth rate of old hair follicles in young nude mice was somewhat slower than young hair follicles. In contrast, in old nude mice, both transplanted young and old hair follicles failed to regrow extensive hair shafts. At week 2 and week 4, both the young and old transplanted hair follicles had less blood vessel connections with old host mice, in contrast to blood vessel connections in young mice.

Therefore, our results showed that both young and old hair follicles can regrow extensive hair shafts when transplanted to young nude mice, while neither young nor old hair follicles can regrow extensive hair shafts when transplanted to old nude mice. These results suggest that young nude mice can provide a more suitable environment to subcutaneously-transplanted hair follicles, both young and old, than old nude host mice. These results also suggest a large influence of the host nude on the donated hair follicles, due to the fact that both young and old hair follicles fail to regrow long hair shafts in old host mice. Old hair follicles had the capability to regrow long hair shafts when transplanted to young host mice, suggesting that old hair follicles can be rejuvenated by young host mice. In young nude host mice, HAP stem cells in the transplanted follicle were active throughout the 8-week experimental period as can be seen by their expression of nestin-driven green fluorescent protein (ND-GFP). ND-GFP expressing cells were widely distributed in both young and old hair follicles transplanted to young host nude mice. HAP stem cells were located in various areas of the follicle, including the follicle sensory nerve, hair matrix bulb and outer-root sheath. HAP stem cells surrounded the hair bulb at week 8 suggesting their role in hair-shaft regrowth. In old hair follicles of old nude mice, most of the ND-GFP expressing cells were located in the attached sensory nerves but not in the center of the hair follicle as they were in old follicles transplanted to old mice. Thus the subcutaneous environment has a strong influence on the HAP stem cells of young and old hair follicles.

Link: http://dx.doi.org/10.1080/15384101.2016.1156269

DNA methylation is a form of epigenetic alteration to DNA, influencing the rate at which specific proteins are produced from their blueprint genes. The pattern of methylation shifts constantly in response to circumstances, but since the damage that causes aging is much the same in everyone, it is possible to identify patterns that correlate well with age. Here researchers investigate DNA methylation changes in aging skin:

Epigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age-related changes in DNA methylation at the genome scale have been termed 'epigenetic drift', but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age-related epigenetic changes because of its substantial cell-type homogeneity and its well-known age-related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N = 108) using array-based profiling of 450,000 methylation marks in various age groups. Data analysis confirmed that age-related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy.

In agreement with our previous studies that were carried out either at lower resolution or with smaller sample sizes, we find that age-related methylation changes appear rather moderate and do not compromise the overall integrity of the epidermis methylome. Nevertheless, we identified a variety of specific age-related methylation changes. In contrast to prior work by others, where whole-blood samples and different tissues were used to develop a predictive signature of biological age, we achieved significantly improved prediction accuracy by training the prediction algorithm on epidermis samples. In agreement with previous analyses, we observed a significant age-related hypermethylation of CpG island-associated probes. Interestingly, this effect was strongly enriched during two specific age windows, at 40-45 and 50-55 years. Considering that our samples were exclusively derived from female volunteers, it seems reasonable to link the latter window to menopause, which is also known to distinctly accelerate skin aging. The high temporal and spatial specificity of these methylation changes suggests that defined signaling pathways, such as estrogen signaling, may be involved in their establishment.

Our results also describe an age-related erosion of DNA methylation patterns that is characterized by two distinct features: (i) While the topology of young methylomes is characterized by sharply demarcated regions of (almost) complete and (almost) absent methylation, old methylomes appeared to be less clearly defined, which is reflected by the significantly reduced variance and spatial correlation within methylomes. (ii) While young methylomes are highly similar among each other, old methylomes appeared to be substantially more heterogeneous. Hence, while methylation patterning within an individual becomes more homogeneous with age, the differences between individuals increase. The effects of age-related methylation changes on gene expression patterns have been analyzed in several previous studies. Somewhat surprisingly, however, no global correlations could be established and methylation-related expression changes generally appeared very limited. These findings support the notion that age-related methylation changes function to stabilize pre-existing gene expression patterns. Alternatively, age-related gene expression changes might also be too subtle to achieve statistical significance in classical differential expression analyses. The analysis of gene co-expression networks provides an opportunity to analyze transcriptional deregulation at a higher level of complexity, and our findings demonstrate a reduced connectivity of gene expression in old samples. These results are in agreement with earlier findings in aging mice and suggest that the age-related erosion of methylation patterns is accompanied by a reduced fine-tuning in the transcriptional circuitry, possibly through methylation-dependent changes in transcription factor binding.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12470/

Over the past decade, promising inroads have been made in the production of "good enough" engineered skin tissue, and it has advanced to the point at which production methodologies can be automated, building skin from a patient's own cells. The varied forms of tissue generated by these approaches differ from natural skin in many ways: they do not have the same layering of specialized cell types, and lack blood vessel networks and other features of skin such as hair follicles, sweat glands, and lymphatic systems. Still, they can successfully replace lost skin and integrate with a recipient patient's tissues. This represents a big improvement in the quality of treatment and the prognosis for burn victims and other patients who have lost large sections of skin.

As is usually the case, the technologies at the end of the research pipeline closest to realization are considerably less advanced than the work still in progress in the laboratory. We live in an age of rapid progress, and the newly launched technology is already heading towards obsolescence. Even as forms of first generation tissue engineered pseudo-skin become available as an option for hospitals and clinics, the research community is closing in on the production of much more natural and fully-featured skin, again produced from a patient's own cells. Once realized and deployed, this will represent another leap ahead for the treatment of injured and lost skin. In the publication and publicity materials noted here, researchers report on achieving the goal of complex, more fully featured skin in mice:

This Lab-Grown Skin Grows Hair and Can Sweat

Scientists have developed a new method to grow 3D layers of skin and hair cells from stem cells - which are genetically engineered from adult tissue. The scientists' lab-grown skin includes all three layers of skin cells, as well as sweat glands, hair follicles, and your skin's oil-producing glands called sebaceous glands. That's far and away more complex than the next best attempt to artificially regenerate skin, which only includes two types of skin cells. To test their new skin, the researchers took a DNA sample from an adult nude mouse, built a chunk of skin with it, and successfully implanted skin back in the mouse, where it thrived and grew hair. The skin and hair prospered over the entire 70 day period it was meant to last.

To build their multi-layered suite of skin cells, the researchers first collect a small sample of adult tissue. This can be as simple as taking a drop of blood. Although, for their mice, the team scrapes away a tiny bit of mouse's gums. The scientists are then able to genetically engineer those adult cells to revert into stem cells that share the donor's DNA, called induced pluripotent stem cells, or iPS cells. The team found a way to nurture those iPS cells to generate into a package of skin and hair cells. This is done by growing the stem cells in en environment infused with the right combination of chemical signals. This tricks the iPS cells into thinking they need to start forming skin, which can then be harvested in chucks containing between one and two dozen hair follicles. Using this same adult-derived stem cell process, the researchers are also now looking at ways to regenerate various parts of your mouth, including teeth and salivary glands.

Bioengineering a 3D integumentary organ system from iPS cells using an in vivo transplantation model

The integumentary organ system is a complex system that plays important roles in waterproofing, cushioning, protecting deeper tissues, excreting waste, and thermoregulation. The integumentary organs include the skin and its appendages (hair, sebaceous glands, sweat glands, feathers, and nails). We developed a novel in vivo transplantation model designated as a clustering-dependent embryoid body transplantation method and generated a bioengineered three-dimensional (3D) integumentary organ system, including appendage organs such as hair follicles and sebaceous glands, from induced pluripotent stem cells. This bioengineered 3D integumentary organ system was fully functional following transplantation into nude mice and could be properly connected to surrounding host tissues, such as the epidermis, arrector pili muscles, and nerve fibers, without tumorigenesis. The bioengineered hair follicles in the 3D integumentary organ system also showed proper hair eruption and hair cycles, including the rearrangement of follicular stem cells and their niches.

It is already possible to design and computationally model nanomedical devices, complex molecular machines intended to operate in large numbers in our tissues for extended periods of time, even if it is not yet possible to manufacture and use them in the large numbers needed. This design and modeling has been going on for quite some time in some portions of the research community, in fact. You might recall the respirocyte as an early design, a device to multiply the oxygen carrying capacity of blood a hundredfold or more. This is only one of a growing stable of designs, many of which are intended to carry out repair of the damage of aging since there has long been an overlap between advocates for life extension and advocates for molecular nanotechnology. This is groundwork for the medical technology of the 2030s and beyond, as constructing and using such machines in large enough numbers to matter will require, at the very least, precision molecular manufacturing - which is the large hurdle - and a range of incremental advances in wireless command and control systems.

Futurists have long speculated that nanotechnology - the engineering of materials and devices at the molecular scale - will revolutionise virtually every field it touches, medicine being no exception. Here's what to expect when you have fleets of molecule-sized robots coursing through your veins. To learn more about the potential for medical nanotech, I contacted Frank Boehm, author of the recently released book, Nanomedical Device and Systems Design: Challenges, Possibilities, Visions.

Let me tell you about one conceptual nanomedical diagnostic concept to give you an idea. It's what I call the Vascular Cartographic Scanning Nanodevice (VCSN) - a sophisticated and autonomous one micron wide nanomedical device for imaging living organisms. I envisage that thousands of VCSN devices would work in massively parallel fashion to scan and image the entire human vasculature, down to the capillary level (3 microns). The acquired spatial data would then enable physicians and surgeons to "fly through" the entire circulatory system using a joystick and computer display. These ultrahigh resolution medical images would allow for the detailed inspection of every portion of the system to discover plaque deposits and to precisely determine arterial/venous wall thicknesses, and hence, whether the patient might be at risk for a potential aneurysm, particularly within the brain.

We could use these devices to significantly enhance the human immune system. I describe one such class of conceptual nanodevice, which I have dubbed the "sentinel." Once nanomedicine matures, the human immune system might be augmented with the capacity to rapidly identify and eradicate threats, like chemical toxins or pathogenic micoorganisms. Autonomous micron-scale "sentinel" class nanodevices, imbued with comprehensive data on all known toxins and pathogens, might continually "patrol" the human vasculature and lymphatic system for the presence of invasive species. They could also penetrate into tissues. And if an unknown intrusive agent is discovered, a default protocol would be spontaneously launched to ensure their complete destruction via chemical, oxidative, hyperthermic, or highly localised nanomechanical disassembly. These Sentinels could operate in conjunction with the innate human immune system, serving as exceptionally sensitive "first responders" to rapidly identify, engage, disable, and degrade all manner of foreign entities.

Extension of the human lifespan could be facilitated through the removal of a substance called lipofuscin from certain types of non-dividing cells, including the brain, heart, liver, kidneys and eyes. Lipofuscin is a metabolic end product that accumulates primarily within lysosomes (the garbage disposal organelles within cells). It's thought that when lipofuscin accumulates to certain levels, it begins to negatively impact cell function, which eventually manifests in many age related conditions. I imagine a procedure in which dedicated "Defuscin" type nanodevices are deployed - they would enter cells and then the lysosomes to bind with and remove lipofuscin through an enzymatic or nanomechanical digest and discharge protocol, a fundamental concept that was originally proposed by Robert Freitas.

Link: http://www.gizmodo.com.au/2016/04/how-medical-nanotech-will-change-humanity-forever/

I have criticized the Longevity Dividend view on extending healthy life for a lack of ambition, for focusing on expensive and slow ways to obtain tiny gains in life expectancy through the manipulation of metabolism. Calorie restriction mimetic development and the forthcoming metformin clinical trial are representative of this school of thought. Here, however, is a view of what to do about aging that makes the Longevity Dividend seem radical. It is focused entirely on policy, provision of existing medical technology, and non-medical prevention strategies such as lifestyle choices to modestly reduce risk of age-related disease - as for the World Health Organization reports it derives from, it is a bureaucratic vision of doing something about aging without doing anything about aging. In this era of tremendous and transformative progress in biotechnology, it seems like burying one's head in the sand to talk at length about improving the state of aging without making medical research and development the primary focus.

Most countries of the world are emerging from the first or are in various stages of the second demographic transition. The first transition is from an agrarian society with high mortality and fertility rates to one where mortality, starting with child mortality, falls; this is followed by declines in fertility. As the "bulge" of children surviving ages into employability, the labor supply becomes greater than the dependent population of children, potentially creating economic growth. This results in what is called a first demographic dividend. This period is time limited. The stage that follows is one in which persisting declines in mortality lead to a population that is living longer. Combined with low fertility, the age structure changes with higher proportions of the population at older ages. Evidence indicates that longevity induces the accumulation of capital, including individual savings in anticipation of retirement. A country's wealth rises. This is termed the second demographic dividend. If policies are constructive and effective, the second dividend can lead to sustained positive economic outcomes.

Mounting evidence suggests that the second demographic dividend does not encompass, by itself, the full potential benefit that society could derive from a larger population of older and aging adults. Additional and sustainable benefits could arise if people arrive at old age healthy and if the large, unrealized social capital of older adults can be activated, conferring benefits both economically and in other measures of societal well-being.

To accomplish this would require a new frame of goal setting for successfully aging societies with investments needed in (a) education, (b) disease prevention and health promotion so that the people arrive at older age healthier and stay healthier longer, and (c) new social institutions and roles to enable paid work by older adults or new high impact generative roles, bringing new social capital to solve major unmet societal needs, while enhancing well-being for the older adults who are accomplishing this. Proposed here is the idea that such investments could lead to a third demographic dividend for aging societies, in addition to the increased wealth of the second demographic dividend.

Link: http://gerontologist.oxfordjournals.org/content/56/Suppl_2/S167.full