A Scanning Approach to Detect Transthyretin Amyloid Buildup in the Heart

Accumulation of transthyretin amyloid is one of the root causes of aging. This is a form of protein misfolding that products harmful deposits, amyloids, in tissues. In recent years this type of amyloid has been identified as the major cause of death in supercentenarians, but it was not until very recently understood to also be a significant cause of heart failure in the earlier stages of old age. Researchers here demonstrate a scanning methodology to detect transthyretin amyloid in heart tissue, which should hopefully lead to more resources directed towards finalizing the development of an existing therapeutic approach to breaking down and clearing this amyloid. That approach has been trialed successfully in a few patients, but is currently languishing in the endless regulatory pipeline somewhere prior to clinical availability. It is madness that so little funding and urgency is given to this sort of development, especially given the existence of an approach that appears to work: transthryretin amyloid clearance should be undertaken every few years by pretty much every adult over the age of 40, and the outcome would be significantly less heart disease.

A type of heart failure caused by a build-up of amyloid can be accurately diagnosed and prognosticated with an imaging technique, eliminating the need for a biopsy. The technique may also detect the condition - called transthyretin-related cardiac amyloidosis (ATTR-CA) - before it progresses to advanced heart failure. "This is a huge advance for patients with ATTR-CA, which is under recognized and often misdiagnosed. This test will spare certain patients from having to undergo a biopsy in order to get a definitive diagnosis. Many people with ATTR-CA are frail and elderly, so being able to avoid a biopsy, even when it can be done with a less-invasive catheter-based procedure, is a significant step forward."

ATTR-CA is one of many types of amyloidosis, a condition in which a protein breaks down and forms fibrils that deposit in organs and tissues, eventually causing the organs to fail. In ATTR-CA, the transthyretin protein breaks down and forms amyloid fibrils, which mainly accumulate in the heart, disrupting its function. Different types of amyloidosis require different treatments, so obtaining an accurate diagnosis is critical. ATTR-CA was once thought to be rare, but it's now known that ATTR-CA resulting from a normal variant of the transthyretin protein has a prevalence of about 32 percent in patients with heart failure over age 75 years at autopsy. The prevalence in hospitalized patients with heart failure is about 13 percent.

The diagnostic tool evaluated in the study is derived from bone scintigraphy, a form of single-photon emission computed tomography, or SPECT, that is conventionally used to detect bone cancer. In bone scintigraphy, patients are injected with a radioactive isotope with a particular affinity for bone that has remodeled due to bone cancer. Early on, researchers noticed that the isotope, technetium 99m pyrophosphate (Tc 99m PYP), also gravitates to amyloid deposits in the heart, a defining characteristic of ATTR-CA. In this study, the researchers examined the diagnostic accuracy of the Tc 99m PYP test for ATTR-CA in a retrospective study of 179 amyloidosis patients (121 with ATTR and 50 with other types). The researchers found that the imaging test was able to correctly identify ATTR in 91 percent of those diagnosed with the disease, and was able to rule out ATTR-CA in 92 percent of those with other forms of amyloidosis or no amyloidosis.

Link: http://newsroom.cumc.columbia.edu/blog/2016/08/24/amyloid-related-heart-failure-now-detectable-with-imaging-test/

Marmosets in Aging Research

The use of animals in the study of aging has always meant striking a balance between species life span and distance from humans in the evolutionary tree of life. Very short-lived species such as worms and flies allow for much cheaper, faster studies, but the biochemistry of these species is more distant from ours, meaning fewer of the results are relevant to human medicine. Fortunately many of the fundamental processes of aging are near universal in animal life, all the way down to yeast colonies, so it is possible to perform useful exploratory research at a reasonable price. Still, researchers are ever in search of a better class of animal, one that has a much greater similarity to humans without the very lengthy life span. Even using short-lived mammals such as mice, that live for a few years, results in studies that are expensive and long-running when considered as a fraction of the length of a career, or placed against the size of most grants. Further, even mice have sometimes meaningful differences when compared with humans, such as their telomere dynamics. If large amounts of time and money are to be spent, then researchers would ideally want to run studies of aging in primates, and this has happened for decades-long studies of calorie restriction in rhesus macaques. Such studies are highly unlikely to happen again in the foreseeable future, however, given a broad dissatisfaction with the planning and outcomes of these examples. Researchers have started to look at the small selection of comparatively short-lived primates instead, and currently there is a faction advocating the use of marmosets:

Great leaps forward in our understanding of the basic biology of aging, including interventions that extend longevity, have come about from using common laboratory animal models. As we now strive to apply these findings for human benefit, a serious concern arises in how much of this research will directly translate to normal, largely healthy, and genetically varied populations of people. Laboratory animals, including rodents, are only distantly related to humans and have undergone different evolutionary pressures that likely have driven species-specific idiosyncrasies of aging. Due to our long lifespans, any outcomes of longevity interventions in human studies are unlikely to be discovered even during the research careers of current graduate students. There is then strong rationale for testing whether the interventions discovered that slow aging in laboratory rodents, such as dietary restriction, mTOR (mechanistic target of rapamycin) inhibition, or acarbose, will also extend the lifespan of species more closely related to humans. In this context, the calorie restriction studies utilizing non-human primates are prime examples of this approach. However, the rhesus macaques used in these studies also have relatively long lifespans which required time commitment in the order of decades to accomplish the recently published final results.

Most non-human primates that can be kept in healthy laboratory populations have relatively long lifespans, but the small South American common marmoset (Callithrix jacchus) may offer a number of advantages over other non-human primate species, particularly for researchers interested in aging. The normal lifespan of the common marmoset is the shortest of any anthropoid primate, with an average lifespan in captivity of approximately 7-8 years and maximum lifespans reported between 16 and 21 years. While much longer-lived than rodents, the average age of marmosets is more manageable for a designed longevity study than the 25-year average lifespan of rhesus macaques or the 70-plus average lifespan of humans. In addition, marmosets in a closed colony have a natural adult mortality that drives a decline in their cumulative survival rate from about 85 to 35% that occurs between 5 and 10 years of age. In other words, a carefully designed intervention study could occur over the time course of a single NIH RO1 granting period using this non-human primate.

Similar to other non-human primates, the sequenced marmoset genome has high homology (more than 93%) with that of humans. Many of the common molecular biology tools, including antibodies, have relatively good cross-species recognition. Marmosets have a growing track record as a non-human primate model used for a number of diseases and pathologies that are generally considered as age-related, including Parkinson's disease, respiratory diseases, and infectious diseases. Moreover, marmosets display age-related changes in pathologies associated with diabetes, cardiac disease, cancer, and renal disease similar to those seen in humans. Marmosets thus represent a complement to the existing non-human primate models used to study aging and, in particular, a model in which effects on longevity might be assessed in a relatively timely manner. Despite this promising outlook, there are some potential challenges to using the common marmoset as a non-human primate model to study aging. Like other non-human primates, there is much less genetic tractability in this species relative to the mouse, which must be taken into account when designing studies on the biology of aging. However, transgenic marmosets have been previously generated and new technologies including CRISPR/Cas systems may lead the way in developing new, genetically modified marmoset models for the study of age-related diseases or the basic biology of aging.

Link: http://dx.doi.org/10.3402/pba.v6.32758

Criticizing Programmed Theories of Aging

Today I'll point out an open access critique of programmed aging theories by the originator of the disposable soma theory of aging, one of the modern views of aging as accumulated damage rather than programming. The question of how and why we age is wrapped in a lot of competing theory, but of great practical importance. Our biochemistry is enormously complex and incompletely mapped, and thus the processes of aging, which is to how exactly our biochemistry changes over time, and all of the relationships that drive that change, are also enormously complex and incompletely mapped. Nonetheless, there are shortcuts that can be taken in the face of ignorance: the fundamental differences between young and old tissue are in fact well cataloged, and thus we can attempt to reverse aging by treating these changes as damage and repairing them. If you've read through the SENS rejuvenation research proposals, well, that is the list. The research community may not yet be able to explain and model how exactly this damage progresses, interacts, and spreads from moment to moment, but that effort isn't necessary to build repair therapies capable of rejuvenation. You don't need to build a full model of the way in which paint cracks and peels in order to scrub down and repaint a wall, and building that model is a lot most costly than just forging ahead with the painting equipment.

The engineering point of view described above, simply getting on with the job when there is a good expectation of success, is somewhat antithetical to the ethos and culture of the sciences, which instead guides researchers to the primary goal of obtaining full understanding of the systems they study. In practice, of course, every practical application of the life sciences is created in a state of partial ignorance, but the majority of research groups are nonetheless oriented towards improving the grand map of the biochemistry of metabolism and aging rather than doing what can be done today to create rejuvenation therapies. Knowledge over action. If we had all the time in the world this would be a fine and golden ideal. Unfortunately we do not, which places somewhat more weight on making material progress towards the effective treatment of aging as a medical condition - ideally by repairing its causes.

But what are the causes of aging? The majority view in the research community is that aging is a process of damage accumulation. The normal operation of metabolism produces forms of molecular damage in cells and tissues, a sort of biological wear and tear - though of course the concept of wear and tear is somewhat more nuanced and complex in a self-repairing system. This damage includes such things as resilient cross-links that alter the structural properties of the extracellular matrix and toxic metabolic waste that clutters and harms long-lived cells. As damage accumulates, our cells respond in ways that are a mix of helpful and harmful, secondary and later changes that grow into a long chain of consequences and a dysfunctional metabolism that is a long way removed from the well-cataloged fundamental differences between old and young tissues. An old body is a complicated mess of interacting downstream problems. In recent years, however, a growing minority have suggested and theorized that aging is not caused by damage, but is rather a programmed phenomenon - that some portion of the what I just described as the chain of consequences, in particular epigenetic changes, are in fact the root cause of aging. In the programmed view of aging, epigenetic change causes dysfunction and damage, not the other way around. That these two entirely opposite views can exist is only possible because there is no good map of the detailed progression of aging - only disconnected snapshots and puzzle pieces. There is a lot of room to arrange the pieces in any way that can't be immediately refuted on the basis of well-known past studies.

There are two ways to settle the debate of aging as damage versus aging as evolved program. The first is to produce that grand map of metabolism and aging, something that I suspect is at the least decades and major advances in life science automation removed from where we stand now. The other is to build therapies that produce large degrees of rejuvenation, enough of a difference to put it far beyond argument that the approach taken is the right one. That is not so far away, I believe, as the first SENS rejuvenation therapies are presently in the early stages of commercial development. I think that, even with the comparative lack of funding for this line of development, ten to twenty years from now the question will be settled beyond reasonable doubt. Meanwhile, the programmed aging faction has become large enough and their positions coherent enough that the mainstream is beginning to respond substantially to their positions; I expect that this sort of debate will continue all the way up to and well past the advent of the first meaningful rejuvenation therapies, which at this point look to be some form of senescent cell clearance.

Can aging be programmed? A critical literature review

Many people, coming new to the question of why and how aging occurs, are attracted naturally to the idea of a genetic programme. Aging is necessary, it is suggested, either as a means to prevent overcrowding of the species' environment or to promote evolutionary change by accelerating the turnover of generations. Instead of programmed aging, however, the explanation for why aging occurs is thought to be found among three ideas all based on the principle that within iteroparous species (those that reproduce repeatedly, as opposed to semelparous species, where reproduction occurs in a single bout soon followed by death), the force of natural selection declines throughout the adult lifespan. This decline occurs because at progressively older ages, the fraction of the total expected reproductive output that remains in future, on which selection can act to discriminate between fitter and less-fit genotypes, becomes progressively smaller. Natural selection generally favours the elimination of deleterious genes, but if its force is weakened by age, and because fresh mutations are continuously generated, a mutation-selection balance results. The antagonistic pleiotropy theory suggests that a gene that has a benefit early in life, but is detrimental at later stages of the lifespan, can overall have a net positive effect and will be actively selected. The disposable soma theory is concerned with optimizing the allocation of resources between maintenance on the one hand and other processes such as growth and reproduction on the other hand. An organism that invests a larger fraction of its energy budget in preventing accumulation of damage to its proteins, cells and organs will have a slower rate of aging, but it will also have fewer resources available for growth and reproduction, and vice versa. Mathematical models of this concept show that the optimal investment in maintenance (which maximizes fitness) is always below the fraction that is necessary to prevent aging.

In recent years, there have been a number of publications claiming that the aging process is a genetically programmed trait that has some form of benefit in its own right. If this view were correct, it would be possible experimentally to identify the responsible genes and inhibit or block their action. This idea is, however, diametrically opposed to the mainstream view that aging has no benefit by its own and is therefore not genetically programmed. Because experimental strategies to understand and manipulate the aging process are strongly influenced by which of the two opinions is correct, we have undertaken here a comprehensive analysis of the specific proposals of programmed aging. On the principle that any challenge to the current orthodoxy should be taken seriously, our intention has been to see just how far the various hypotheses could go in building a convincing case for programmed aging.

This debate is not only of theoretical interest but has practical implications for the types of experiments that are performed to examine the mechanistic basis of aging. If there is a genetic programme for aging, there would be genes with the specific function to impair the functioning of the organism, that is to make it old. Under those circumstances, experiments could be designed to identify and inhibit these genes, and hence to modify or even abolish the aging process. However, if aging is nonprogrammed, the situation would be different; the search for genes that actively cause aging would be a waste of effort and it would be too easy to misinterpret the changes in gene expression that occur with aging as primary drivers of the senescent phenotype rather than secondary responses (e.g. responses to molecular and cellular defects). It is evident, of course, that genes influence longevity, but the nature of the relevant genes will be very different according to whether aging is itself programmed or not.

For various programmed theories of aging, we re-implemented computational models, developed new computational models, and analysed mathematical equations. The results fall into three classes. Either the ideas did not work because they are mathematically or conceptually wrong, or programmed death did evolve in the models but only because it granted individuals the ability to move, or programmed death did evolve because it shortened the generation time and thus accelerated the spread of beneficial mutations. The last case is the most interesting, but it is, nevertheless, flawed. It only works if an unrealistically fast-changing environment or an unrealistically high number of beneficial mutations are assumed. Furthermore and most importantly, it only works for an asexual mode of reproduction. If sexual reproduction is introduced into the models, the idea that programmed aging speeds up the spread of advantageous mutations by shortening the generation time does not work at all. The reason is that sexual reproduction enables the generation of offspring that combine the nonaging genotype of one parent with the beneficial mutation(s) found in the other parent. The presence of such 'cheater' offspring does not allow the evolution of agents with programmed aging.

In summary, all of the studied proposals for the evolution of programmed aging are flawed. Indeed, an even stronger objection to the idea that aging is driven by a genetic programme is the empirical fact that among the many thousands of individual animals that have been subjected to mutational screens in the search for genes that confer increased lifespan, none has yet been found that abolishes aging altogether. If such aging genes existed as would be implied by programmed aging, they would be susceptible to inactivation by mutation. This strengthens the case to put the emphasis firmly on the logically valid explanations for the evolution of aging based on the declining force of natural selection with chronological age, as recognized more than 60 years ago. The three nonprogrammed theories that are based on this insight (mutation accumulation, antagonistic pleiotropy, and disposable soma) are not mutually exclusive. There is much yet to be understood about the details of why and how the diverse life histories of extant species have evolved, and there are plenty of theoretical and experimental challenges to be met. As we observed earlier, there is a natural attraction to the idea that aging is programmed, because developmental programming underpins so much else in life. Yet aging truly is different from development, even though developmental factors can influence the trajectory of events that play out during the aging process. To interpret the full complexity of the molecular regulation of aging via the nonprogrammed theories of its evolution may be difficult, but to do it using demonstrably flawed concepts of programmed aging will be impossible.

Given that the author here has in the past been among those who dismissed the SENS initiative as an approach to treating aging by repairing damage, it is perhaps a little amusing to see him putting forward points such as this one: "despite the cogent arguments that aging is not programmed, efforts continue to be made to establish the case for programmed aging, with apparent backing from quantitative models. It is important to take such claims seriously, because challenge to the existing orthodoxy is the path by which science often makes progress." Where was this version of the fellow ten years ago?

Ghrelin Receptor and Inflammaging

Ghrelin is related to the hunger response, but has a very broad range of influences on many tissues and systems, including immune system activities. Inflammaging is the name given to the inflammation-focused view of the characteristic decline and dysfunction of the immune system with aging. While increased levels of inflammation occur for everyone due to immune system aging, those people who allow themselves to become overweight suffer a greater level of chronic inflammation, driven by the way in which metabolically active visceral fat tissue provokes immune activation. The research here joins all of these dots, and the scientists involved demonstrate that removing the ghrelin receptor in mice can suppress the influence of fat tissue on chronic inflammation:

"To date, ghrelin is the only known appetite-stimulating hormone. The pharmaceutical industry has been calling ghrelin 'the key to obesity' since its discovery. We investigated the impact of ghrelin signaling on adipose tissue macrophages, in order to understand the role of ghrelin signaling in obesity." Hunger stimulates ghrelin in the gut, which activates brain regions where the ghrelin receptor, growth hormone secretagogue receptor, or GHS-R, is highly expressed, triggering the hunger sensation. Ghrelin enhances appetite and increases weight gain, promoting obesity and consequent insulin resistance.

Obesity, in essence, is a condition characterized by low-grade chronic inflammation in adipose tissues. Adipose tissue serves as a major endocrine organ, secreting various hormones and cytokines which play crucial roles in normal metabolism and obesity-associated dysfunctions. Adipose tissue macrophages, or ATMs, are a major mediator of inflammation in adipose tissues, which are closely linked to insulin resistance. Macrophages are a type of white blood cells that surround and digest microbes, pathogens and other foreign substances. "Macrophages are a major mediator of inflammation in the body. Increased macrophage infiltration in adipose tissues has been shown to positively correlate with age-associated metabolic complications, neurodegenerative diseases and cardiovascular diseases."

ATMs consist of two subsets - pro-inflammatory M1 and anti-inflammatory M2. M1-like macrophages are associated with an obese and insulin-resistant state, while M2-like macrophages are associated with a lean and insulin-sensitive state. M1-like macrophages release pro-inflammatory cytokines to inhibit insulin action in the tissues. On the other hand, M2-like macrophages release anti-inflammatory cytokines. "We have found that the GHS-R functions as a key regulator of age-associated adipose tissue inflammation. The removal of GHS-R shifts macrophages toward an anti-inflammatory state." Aging is commonly accompanied by increased fat mass and chronic low-grade inflammation, so concurrences of obesity and insulin resistance become significantly greater as people get older.

GHS-R global null mice - with the GHS-R removed in all cell types - showed a macrophage profile shifted toward the anti-inflammatory M2, exhibiting a healthier lean and insulin-sensitive phenotype. "Old mice with GHS-R deletion showed a reduction in macrophage infiltration, M1/M2 ratio and pro-inflammatory cytokine production in adipose tissues." The new findings suggest suppressing the ghrelin receptor may serve as a new therapeutic strategy for inflammation and obesity in aging. The study indicates the ghrelin receptor plays an important role in macrophages, which can have profound implications on obesity and insulin resistance. Current research using global null mice cannot determine whether the phenotype is resulted in by the effect of GHS-R in macrophages alone, however. Scientists must determine the macrophage-specific effects of GHS-R, and understand precisely how ghrelin signaling works, in order to avoid unintended side effects. The researchers are now developing new mouse models which would enable them to delete GHS-R selectively in macrophages.

Link: http://today.agrilife.org/2016/08/22/agrilife-researcher-takes-close-look-inflamm-aging/

Shorter Period of Rapamycin Treatment in Mice Produces Greater Slowing of Aging

Rapamycin, an immunosuppressant and MTOR inhibitor, is known to slow aging in mice - though it has been debated whether this extension of life span is actually a slowing of aging versus a lower rate of cancer. Researchers here try a variety of different treatment regimens and find that a comparatively short period of rapamycin treatment in mouse middle age produces better effects than the longer term dosage that has been standard in studies. The publicity materials emphasize the high points and the outliers in the mouse data; I'd recommend reading the paper for a more responsible and overall view of the outcomes.

Even with improved results and possibly a new longevity record for this mouse species, I don't think the improved outcomes much alter the overall picture for trying to slow the processes of aging in this way, by altering metabolism towards the sort of changes known to occur in response to calorie restriction. It is, however, interesting to consider what must be going on in mouse biochemistry to allow a shorter intervention to have a larger effect than a longer intervention. One possibility is that the longer intervention does in fact have all of the beneficial effects, but that the unpleasant side-effects of rapamycin begin to outweigh those benefits greatly as the mice get older. Regardless, keep in mind that mice have very plastic life spans - interventions such as calorie restriction and growth hormone receptor knockout that extend life in mice by 40-70% are known not to have large effects on longevity in humans, and we should expect that to be the case for the beneficial side of rapamycin as well.

Rapamycin, approved by the FDA for certain organ transplant recipients, is already known to extend life in mice and delay some age-related problems in rodents and humans. Still, many questions prevail about when, how much and how long to administer rapamycin, what its mechanisms of action are in promoting healthy aging, and ways to avoid serious side effects. Researchers showed that a transient dose of rapamycin in middle age was enough to increase life expectancy and improve measures of healthy aging. The scientists treated mice with rapamycin for 90 days starting at 20 months of age, approximately the mouse equivalent of a 60 year old person. The control and rapamycin-treated mice were maintained identically both before and after the treatment period. Remarkably, the rapamycin treated mice lived up to 60 percent longer after the treatment was stopped, compared to the animals that received a mock control treatment.

This, the researchers said, seems to be the biggest increase in life expectancy ever reported in normal mice from a medication. "It's quite striking that short-term rapamycin treatment had such a lasting impact on health and survival after the treatment was stopped." The reasons behind this outcome aren't completely clear, according to the researchers, but one interpretation might be that the animals were, to some degree, rejuvenated by the treatment and became biologically younger than their actual age. The most-senior mouse in the study was Ike, the namesake of a relative of one of the researchers. The mouse Ike lived 1400 days. For a person, that would be like hailing a 140th year birthday. "To our amazement, considering the relatively small size of the group of mice we studied, Ike might have been one of the longest lived mice of his kind." Ike was a wild-type C57BL/6, a designation for the one of the most common sub-strains of mice.

On the other hand, some of the side effects observed during the study were less than celebratory. The cautionary findings, the researchers noted, illustrate the need to better understanding the relationship between the dose of rapamycin and its beneficial as well as detrimental effects. The researchers saw a gender difference when higher doses of rapamycin were given: males outlived the females. At lower doses, both male and female mice had longer lives, compared to untreated mice. Higher doses can make female mice more susceptible to aggressive cancers of blood-forming cells and tissue. At the same time, middle-aged female mice receiving high-doses of rapamycin were less likely to develop other types of cancer. The transient rapamycin treatment also changed the composition of the microbiome - the collection of bacteria and other microbes - in the guts of the mice. They had more segmented, filamentous bacteria of a type not usually present in high numbers in aged mice. While these bacteria are not invasive, they adhere tightly to the cells of the intestinal wall and may encourage the formation of immune cells in the mouse. Otherwise, the influence of this gut microbiome change from rapamycin on the health of an animal, for good or bad, and whether the same thing happens in humans, has not been determined.

Link: http://hsnewsbeat.uw.edu/story/brief-rapamycin-therapy-middle-aged-mice-extends-lives

An Interview with Kelsey Moody of Ichor Therapeutics, Bringing a SENS Therapy for Macular Degeneration to the Clinic

As I mentioned last week, earlier this year Fight Aging! invested a modest amount in the Ichor Therapeutics initiative to develop a treatment for macular degeneration, joining a number of other amateur and professional investors in helping to get this venture started. The approach taken here is based on the results of research carried out at the Methuselah Foundation and SENS Research Foundation over much of the past decade, funded by philanthropists and the support of our community of longevity science enthusiasts. This is how we succeed in building the future: medical science in the laboratory leads to medical development in startup companies, each new stage bringing treatments capable of repairing specific forms of age-related molecular damage that much closer to the clinic.

Ichor Therapeutics is one of a growing number of success stories to emerge from the SENS rejuvenation research community. Young scientists, advocates, and donors involved in earlier projects - years ago now - have gone on to build their own ventures, while retaining an interest in stepping up to do something meaningful to help bring an end to aging. Back in 2010, Kelsey Moody worked on the LysoSENS project to find ways to break down damaging metabolic waste in old tissues; fast-forward six years, and he is the now the CEO of a successful small biotechnology company with a great team, taking that very same technology and putting it to good use. I recently had the chance to ask Kelsey a few questions about the future of SENS rejuvenation research, as well as how the Ichor scientists intend to construct a new class of therapy for macular degeneration, one based on removing one of the root causes of the condition.

Who are the people behind Ichor Therapeutics? How did you meet and decide that this was the thing to do? Why macular degeneration as a target?

People have always been the focus of Ichor. Since day one we have worked to create a positive environment that cultivates a product-oriented research focus and emphasizes autonomy and personal accountability for work. As a result, ambitious self-starters tend to find their way to Ichor and remain here. However, we recognized early on that just filling a lab with a bunch of blue-eyed bushy tailed young up-and-comers is not sufficient to develop a robust, mature, translational pipeline. We have augmented our team with a number of critical staff members who are seasoned pharma operators, including our Quality Assurance Director and General Counsel.

Age-related macular degeneration (AMD) was chosen as a target because we believe it is the closest SENS therapy to the clinic. While we obviously have an interest in providing cures for the patients suffering from AMD and are attracted to the large market opportunities such a treatment could bring, our broader interest is in validating the entire SENS paradigm. We believe that Aubrey de Grey continues to receive excessive criticism because nothing spun out of SENS has ever made it into a legitimate pre-clinical pipeline, much less to the bedside. However, this does not mean he is wrong. Our goal is to be the first group to bring a SENS inspired therapy into the clinic and in doing so, silence critics and generate new energy and capital for this cause.

I understand there's a lengthy origin story for the approach you are taking to treat AMD; it'd be great to hear some of it.

Our approach to treating AMD is based on the hypothesis that cellular junk that accumulates over the lifespan significantly contributes to the onset and progression of AMD. Our goal is to periodically reduce the burden of the junk so it never accumulates to levels sufficient to induce pathology. The strategy to accomplish this calls for the identification of enzymes that can break down the junk in a physiological setting, and the engineering of these enzymes such that they can break down the target in the correct organelle of the correct cell without appreciable collateral damage to healthy cells or tissue.

Methuselah Foundation and SENS Research Foundation did excellent work in establishing this program nearly a decade ago. They successfully identified a number of candidate enzymes that could break down the molecular junk, but reported that the targeting systems evaluated failed to deliver these enzymes to the appropriate organelles and cells. My group reevaluated these findings, and discovered that these findings were flawed. The delivery failure could be entirely attributed to a subtle, yet highly significant difference between how the target cells behave outside of the body as compared to inside the body. It turned out that the approach was in fact valid, it was the cell based assay that had been used that was flawed. This discovery was striking enough that SENS Research Foundation provided Ichor with funding and a material and technology transfer agreement to reassess the technology, and over $700,000 in directed program investments and grants have been received in the last year or two.

You recently completed a round of funding for the AMD work; what is the plan for the next year or so?

The new funds will allow us to develop a portfolio of enzyme therapy candidates to treat AMD. We will obtain critical data necessary to secure follow-on investment including in vitro studies (cell culture studies to confirm mechanism of action and cytotoxicity) and pivotal proof-of-concept in vivo studies, such as toxicity, PK/PD (how long the enzyme stays in the body and where), and efficacy. We will also be restructuring the company (reincorporating an IP holding company in Delaware, ensuring all contracts are up to date and audited) and ensuring our IP position is on solid footing (licensing in several related patents from existing collaborators, and filing several provisional patents from our intramural work). Collectively, we believe these efforts will position us to obtain series A for investigational new drug (IND) enabling pre-clinical studies.

You've been involved in the rejuvenation research community for quite some time now. What is your take on the bigger picture of SENS and the goal of ending aging?

This is a loaded question. What I can say is that the medical establishment has made great progress in the treatment of infectious disease through the development of antibiotics, vaccines, and hygiene programs. However, similar progress has not been realized for the diseases of old age, despite exorbitant expenditures. I have chosen to work in this space because I think a different approach is necessary, and it is here that I believe my companies and I can be the most impactful. I think SENS provides a good framework within which to ask and answer questions.

What do you see as the best approach to getting nascent SENS technologies like this one out of the laboratory and into the clinic?

We need more people who fully understand, in a highly detailed way, what a real translational path looks like. To take on projects like this, being a good scientist is not enough. We need people who can speak business, science, medicine, and legal, and apply these diverse disciplines to a well articulated, focused product or problem. There is no shortage of people who partially understand some of these, but the details are not somewhat important - they are all that matter for success in this space.

Another area is for investors. Some of the projects that come across my desk for review are truly abysmal, yet I have seen projects that are clearly elaborate hoaxes or outright scams (to anyone who has stepped foot in a laboratory) get funded to the tune of hundreds of thousands of dollars or more. While it is perfectly reasonable for high net worth individuals to gamble on moon shots in the anti-aging space (and I am ever grateful for the investors who have taken such a gamble on us) even aggressive development strategies should have some basis in reality. This is especially true as more and more high tech and internet investors move into the space.

If this works stupendously well, what comes next for Ichor Therapeutics?

I really want to get back into stem cell research, but I basically need a blank check and a strong knowledge of the regulatory path to clinic before I feel comfortable moving into the space. A successful AMD exit would accomplish both of these goals, and position us to pivot to cell-based therapies.

Cells can Transfer Lysosomes, Spreading Damaging Age-Related Waste Materials

It is known that cells can transfer mitochondria from one to another under some circumstances, and here researchers demonstrate that they can transfer lysosomes as well. The lysosomes in a cell play the role of recycling units, breaking down damaged structures and waste proteins. Unfortunately there are some forms of waste that our biochemistry cannot manage, and these compounds accumulate over time into a harmful mix called lipofuscin. In old tissues, long-lived cells have clogged and malfunctioning lysosomes, unable to perform the task of recycling waste. This spirals downwards into a garbage catastrophe and the cells either die or become highly dysfunctional themselves. This process of resilient waste accumulation in lysosomes is one of the root causes of aging and age-related disease.

The research here focuses on just one form of damaged protein and one class of conditions caused by the accumulation of that protein, but the transfer of lysosomes noted by the researchers has broad implications for the more general process of lysosomal dsyfunction in aging. If cells are transferring lysosomes in all tissues then this will act to dilute damage for the worst affected cells at the cost of spreading the damage more widely within important cell populations - it will be an important determinant of the way in which damage and decline progresses. That said, this is of interest but not importance given a class of therapy that can break down the waste that makes up lipofuscin. With such a tool, capable of delivering suitable enzymes to the lysosome, it doesn't matter how the waste material spreads. The SENS Research Foundation has been working on this for a while now, mining the bacterial world for suitable enzymes. Some of these have been licensed to Human Rejuvenation Technologies, and others to Ichor Therapeutics for further development for specific therapies.

Synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, are characterized by the pathological deposition of aggregates of the misfolded α-synuclein protein into inclusions throughout the central and peripheral nervous system. Intercellular propagation (from one neuron to the next) of α-synuclein aggregates contributes to the progression of the neuropathology, but little was known about the mechanism by which spread occurs. In this study researchers used fluorescence microscopy to demonstrate that pathogenic α-synuclein fibrils travel between neurons in culture, inside lysosomal vesicles through tunneling nanotubes (TNTs), a new mechanism of intercellular communication.

After being transferred via TNTs, α-synuclein fibrils are able to recruit and induce aggregation of the soluble α-synuclein protein in the cytosol of cells receiving the fibrils, thus explaining the propagation of the disease. The scientists propose that cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. However, this results in the disease being spread to naive neurons. This study demonstrates that TNTs play a significant part in the intercellular transfer of α-synuclein fibrils and reveals the specific role of lysosomes in this process. This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies. These compelling findings, together with previous reports from the same team, point to the general role of TNTs in the propagation of prion-like proteins in neurodegenerative diseases and identify TNTs as a new therapeutic target to combat the progression of these incurable diseases.

Link: http://www.pasteur.fr/en/institut-pasteur/news-institut-pasteur/tunneling-nanotubes-between-neurons-enable-spread-parkinson-s-disease-lysosomes

Enhancing Cell Therapy to Enable Greater Recovery Following Stroke

Researchers here demonstrate a method of improving the effectiveness of a stem cell therapy targeted to brain tissues, enabling the treatment to repair more of the damage caused by a stroke:

A team of researchers has developed a therapeutic technique that dramatically increases the production of nerve cells in mice with stroke-induced brain damage. The therapy relies on the combination of two methods that show promise as treatments for stroke-induced neurological injury. The first consists of surgically grafting human neural stem cells into the damaged area, where they mature into neurons and other brain cells. The second involves administering a compound called 3K3A-APC, which the scientists have shown helps neural stem cells grown in a petri dish develop into neurons. However, it was unclear what effect the molecule, derived from a human protein called activated protein-C (APC), would have in live animals.

A month after their strokes, mice that had received both the stem cells and 3K3A-APC performed significantly better on tests of motor and sensory functions compared to mice that received neither or only one of the treatments. In addition, many more of the stem cells survived and matured into neurons in the mice given 3K3A-APC. "This animal study could pave the way for a potential breakthrough in how we treat people who have experienced a stroke. If the therapy works in humans, it could markedly accelerate the recovery of these patients."

To confirm that the stem cells were responsible for the animals' improved function, the researchers used a targeted toxin to kill the neurons that had developed from them in another group of mice given the combination therapy. These mice showed the same improved performance on the tests of sensory and motor functions prior to being given the toxin but lost these gains afterwards, suggesting that the neurons that grew from the implanted cells were necessary for the improvements. In a separate experiment, the team examined the connections between the neurons that developed from the stem cells in the damaged brain region and nerve cells in a nearby region called the primary motor cortex. The mice given the stem cells and 3K3A-APC had many more neuronal connections, called synapses, linking these areas than mice given the placebo. In addition, when the team stimulated the mice's paws with a mechanical vibration, the neurons that grew from the stem cells responded much more strongly in the treated animals. "That means the transplanted cells are being functionally integrated into the host's brain after treatment with 3K3A-APC. No one in the stroke field has ever shown this, so I believe this is going to be the gold standard for future studies."

Link: https://www.nih.gov/news-events/news-releases/stem-cell-therapy-heals-injured-mouse-brain

Mapping the Role of Foxn1 in Thymic Function

Researchers have of late been mapping the activities and relationships of Forkhead box protein N1 (Foxn1) in the thymus, and the paper I'll point out today outlines some of the most recent findings. Sadly it isn't open access, but I'm sure that won't stop the determined reader in this day and age. This work is of interest to our community of longevity science supporters because increased levels of Foxn1 have been shown to restore a more youthful level of thymic activity in older animals and human cell lines, and have been used to regrow thymic tissue when used in conjunction with cell therapies.

Why is thymic activity important? To simplify greatly, the thymus is where new T cells of the adaptive immune system mature after they are created. Its comparatively low level of activity in adults is one of the gating factors limiting the supply of new immune cells across most of the life span. Children have a very active thymus, and as a result a comparatively large supply of new immune cells, but the organ atrophies quite early in adulthood in a process known as thymic involution. Fat tissue replaces most of the structures that once nurtured immune cells and going forward an adult must get by with far fewer new immune cells. This low level of supply is one of the factors that effectively limits the size of the immune cell population in adults, and the fact that this population is limited eventually gives rise to a form of harmful resource misallocation. After a lifetime of exposure to pathogens, by the time old age arrives too many immune cells become focused on threats that cannot be cleared from the body, such as cytomegalovirus. When a large fraction of the limited population of cells become uselessly specialized in that way, too few cells are left to perform all of the other needed tasks: destroying cancerous and senescent cells, tackling unfamiliar pathogens, and so on.

The decline of the immune system is an important component of the frailty of aging, but this isn't just because old people become very vulnerable to infection. A failing immune system accelerates many of the other causes of aging. It produces greater chronic inflammation, as it is more active even as it is less able to do its job, contributing to a faster progression of near all of the common age-related diseases. The immune system is responsible for destroying senescent cells, which in larger numbers cause harm through the creation of inflammation and destruction of tissue structures. Fewer of these cells destroyed means more left to produce damage and dysfunction. Then there are potentially and actually cancerous cells, which have a greater chance of survival as the immune system becomes ever less effective. This is not to mention that the immune system plays a role in wound healing, as well as many other important processes. Given all of this, the goal of a restored immune system is a very important one, and even partially restoration should produce clear benefits.

One approach to this problem is to destroy the unwanted cells that are taking up space. Another approach is to deliver a much larger supply of new immune cells, such as directly via regular cell therapies, or alternatively through restoration of the thymus. There are a few different possible ways to restore the thymus. Transplantation has been shown to work in mice, producing improved immune function and extension of life, but that isn't going to work in human medicine since we'd want everyone to get a new thymus in old age. Tissue engineering is a strong possibility: researchers have made promising inroads towards the creation of thymic tissue. Then there is the use of Foxn1 to spur regrowth of the thymus, and this can even be mixed in with forms of cell therapy to grow thymic tissue within the patient rather than build outside the body and then transplant. Given the demonstrated importance of Foxn1, it is worth paying attention to research such the results noted here.

Study suggests routes to improved immunity in older people

Humans, like all higher animals, use T cells as part of the immune system, to fight off infections and cancer. T cells are generated in an organ called the thymus, where they closely interact with thymic epithelial cells (TEC) as they mature. People without TEC cannot generate T cells, severely compromising the immune system and consequently increasing the risk for life threatening infections and cancer. More than 20 years ago the transcription factor Foxn1 was identified as an essential molecule for the normal development of TEC. However, the genes directly controlled by Foxn1 - and thus responsible for the various TEC functions - have remained unidentified.

The researchers used new experimental models and analytical tools to investigate which genes were regulated by Foxn1 and how it affected them. Transcription factors bind to particular sections of our DNA and the team is the first to identify the DNA sequence bound by Foxn1. From there, they identified the hundreds of genes whose expression is regulated by this master regulator. These include genes that are essential to attract precursor cells in the blood, which are destined to become T-cells, to the thymus, genes that commit these precursor cells to become T cells and genes that provide the molecular machinery which allows the selection of those T cells that best serve an individual. Experiments in which Foxn1 expression by TEC was inhibited, confirmed that the transcription factor needs to be continuously present for TEC to function normally.

"The thymus is the organ in humans that first displays an age-dependent, physiological decline in function. It grows until puberty and then shrinks throughout the rest of our lives. This is thought to contribute to the decline in immunity in older people, which makes them more susceptible to opportunistic infections and cancers. The findings from these studies therefore provide important insight into the genetic control of regular TEC function and identify new potential strategies to preserve thymus function for longer, raising the prospect of a healthier old age."

Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells

Thymic epithelial cell differentiation, growth and function depend on the expression of the transcription factor Foxn1; however, its target genes have never been physically identified. Using static and inducible genetic model systems and chromatin studies, we developed a genome-wide map of direct Foxn1 target genes for the postnatal thymic epithelium and defined the Foxn1 binding motif. We determined the function of Foxn1 in these cells and found that, in addition to the transcriptional control of genes involved in the attraction and lineage commitment of T cell precursors, Foxn1 regulates the expression of genes involved in antigen processing and thymocyte selection. Thus, critical events in thymic lympho-stromal cross-talk and T cell selection are indispensably choreographed by Foxn1.

Development of a Cell Therapy to Increase Remyelination in the Brain

In this open access paper, results are presented for an animal study of an approach to increasing the pace of remyelination in the brain. Myelin acts as sheathing for the axons that connect nerve cells; when it is degraded, insufficiently maintained, or damaged, the result is dysfunction in the nervous system. A range of demyelinating diseases result from the loss of myelin in specific locations, many of which are life-threatening. To a lesser degree, loss of myelin occurs over the course of aging for all of us. It is unclear as to the degree that this process contributes to age-related decline in cognitive and physical function, but given what is known from the observation of demyelinating diseases it is unlikely that the losses are harmless. Thus it is well worth paying attention to progress towards therapies that can increase the rate of remyelination, as it is likely that a robust and effective approach would be useful for all older individuals:

Microglia play critical but incompletely understood roles in propagation and resolution of central nervous system (CNS) injuries. These cells modulate neuroinflammation, produce factors that regulate activities of astrocytes, oligodendrocytes, and neurons, and clear debris to provide an environment for oligodendrocytes to begin to remyelinate neurons. Separately, limited information is available concerning the role of human blood monocytes in the dynamics of repair of brain injury. Circulating human monocytes include subpopulations that differ in their ability to migrate to tissues, proliferate, and form inflammatory or reparative macrophages at sites of injury. Based on experiments in rodents, several groups have proposed that cell products composed of human monocytes could be considered as candidates for the treatment of injury-induced CNS demyelination. CD14+ monocytes present in human umbilical cord blood (CB) are among these candidates.

We have recently developed DUOC-01, a cell therapy product composed of cells with characteristics of macrophages and microglia that is intended for use in the treatment of demyelinating CNS diseases. DUOC-01 is manufactured by culturing banked CB-derived mononuclear cells (MNCs). The studies described in this report were designed to provide proof of concept for the use of DUOC-01 in treatment of demyelinating diseases that do not arise from enzyme deficiency. To accomplish this, we assessed the ability of DUOC-01 to promote remyelination of mouse brain after cuprizone-induced (CPZ-induced) demyelination, a model that has been widely used to study the mechanisms and cellular dynamics of remyelination in the corpus callosum (CC) region, and also to test the effects of various interventions, including cell therapy agents.

We showed, to the best of our knowledge for the first time, that CPZ feeding in immunodeficient mice results in reversible demyelination in the CC with a time course similar to the process in immune-competent mouse strains, and that this model can be used to assess the activity of human cell therapy products in promoting brain remyelination. Using this model, we demonstrate that the DUOC-01 cell product accelerates brain remyelination following CPZ feeding. We also show that uncultured CD14+ CB cells that give rise to DUOC-01 also accelerate remyelination, but significantly less actively than DUOC-01 cells. A comparison of whole-genome expression arrays of CB CD14+ monocytes and DUOC-01 revealed large differences in gene expression, and helped identify candidate molecules that may participate in remyelination. We subsequently confirmed that cells in the DUOC-01 product express and secrete several factors that promote myelination by several mechanisms.

Link: http://insight.jci.org/articles/view/86667

Towards a Regenerative Therapy for the Lacrimal Gland and Dry Eyes

The lacrimal gland provides moisture for the eyes, and like all parts of our physiology is prone to decline and failure in old age. Dry eye conditions, some of which are painful and debilitating, are common in old people. Researchers here demonstrate a cell therapy to spur regeneration of the lacrimal gland in an animal study, a step along the road to achieving the same thing in humans:

The eye's lacrimal gland is small but mighty. This gland produces moisture needed to heal eye injuries and clear out harmful dust, bacteria and other invaders. If the lacrimal gland is injured or damaged by aging, pollution or even certain pharmaceutical drugs, a person can experience a debilitating condition called aqueous deficiency dry eye (ADDE) - sometimes called "painful blindness." If injured, a healthy lacrimal gland naturally regenerates itself in about seven days. When diseased and chronically inflamed, however, regeneration stops - and scientists are not sure why.

Researchers looked at whether they could kick start regeneration by injecting progenitor cells into the lobes that make up the lacrimal gland. Progenitor cells are similar to stem cells in their ability to differentiate into different kinds of tissue. In this study, the researchers used progenitor cells that were poised to become epithelial tissue, a key component of the lacrimal gland. The researchers knew they faced a major challenge: sorting and separating "sticky" epithelial cell progenitors without destroying them. "We had to figure out how to dissociate the tissue into single cells without completely obliterating everything." The researchers solved this problem by developing markers to label the cells of interest and then testing different enzymes and other reagents to draw them out of tissues.

With these cells in hand, the researchers injected them into the lacrimal glands of mouse models of Sjogren's syndrome, an autoimmune disease that results in ADDE, dry mouth and other symptoms. The team used only older, female mice because ADDE most commonly strikes that demographic in humans. The treated mice showed a significant increase in tear production, indicating - for the first time - that epithelial cell progenitors could repair the lacrimal gland. Further tests suggested that epithelial cell progenitors helped by restoring the connection between cells called myoepithelial contractile cells and the lacrimal gland's secretory cells, which produce tears. The next step in this research will be to study how long the improvement in the lacrimal gland lasts after progenitor cell injections.

Link: http://www.scripps.edu/news/press/2016/20160818makarenkova.html

The Geroscience Network: Determined to Slow Aging through Medical Science

Across the last twenty years or so two very important, slow-moving battles over ideas and strategy have been fought within and around the aging research community. The first was to gain acknowledgement that the treatment of aging as a medical condition is a viable goal, and thus obtain the necessary support to make progress towards that goal. Even as recently as fifteen years ago ago, after years of extending the lifespan of laboratory animals in various ways, treating aging was still more or less a forbidden topic in the research community. Thankfully we have a long way since then in the matter of ideas, and it was a tough and long-running uphill process of advocacy and persuasion - a great deal of work was required to create change. Today we can say that this first battle is near done and finished, with only the mopping up remaining to be accomplished within the scientific community. Those who a decade ago dismissed the goal of treating aging or simply remained silent are now ready to talk in public and provide support. The public at large is unfortunately still behind the times, much less informed or convinced on the matter of aging, but that will change too.

It is the second battle within the scientific community that is now more of a concern for advocates - certainly more of a concern for this advocate. That battle is to shape the research strategies that are funded and pursued: in short whether to try to modestly slow aging or to aim to build rejuvenation therapies capable of reversing aging. When it comes to the future of our health and longevity, this is just as important as the efforts needed to move the research community to support the treatment of aging at all, and at this point has much further to go to a satisfactory conclusion. Sadly we live in a world in which, for various historical and regulatory reasons, the research community is almost entirely set on trying to modestly slow aging. Research groups follow the traditional approach of drug development, searching for compounds that can alter the operation of metabolism so as to slow down some of the changes that accompany aging. This is enormously expensive and has a low rate of success - you can look at the failed efforts to produce calorie restriction mimetics, for example, such as the hundreds of millions of dollars and a decade put into sirtuin research with nothing to show for it at the end. Current efforts to repurpose the drug metformin are likely to end up in the same place: enormous sums and a great deal of effort are spent chasing effects that are tiny.

Aging is all about damage accumulation. Slowing aging means a slower pace at which damage accrues. Reversing aging means repairing that damage - and thus there are ways to do much better than merely tinkering metabolism to somewhat slow down the arrival of new damage. Since the research community has a very good catalog of the damage that causes aging, researchers are in a position to build treatments to repair it, therapies that can in principle produce rejuvenation. Those treatments have been planned and visualized in great detail for years now, and in a sparse few cases are under early clinical development in startups. Yet repairing the damage of aging to produce rejuvenation is a minority concern in the broader field, with little support despite its far greater potential. This, then, is the battle fought now, to direct the research community to the far better option rather than continuing in their status quo of working towards the far worse option.

The Geroscience Network is an example of what has come from victory in the first battle of ideas, to generate much greater support for treating aging within the research community. In the past few years things have blossomed to the point at which many influential figures openly advocate for the goal of treating aging, the root cause of all age-related disease, rather than treating age-related diseases one by one. The Geroscience Network was established among those US research groups and institutions whose principals have the greatest interest in treating aging as a medical condition. To quote the pertinent part of their brief:

We hypothesize that by targeting fundamental mechanisms of aging, clinical interventions can be envisaged that could delay or prevent age-related diseases and disabilities as a group, rather than one at a time. By planning and working in a coordinated way through the Geroscience Network, we intend to accelerate development and translation of effective treatments to delay or prevent age-related disabilities and diseases.

Some of the Geroscience Network researchers recently published a selection of open access position papers in the Journals of Gerontology. The papers frame their determination to treat aging, and are focused on aspects of the strategy: how to move forward within the regulatory system, how to undertake clinical translation of potential therapies, how to build clinical trials for this new world of treating aging rather than age-related disease. Notably where specific technologies are mentioned there is little of anything that SENS rejuvenation research supporters would recognize as an effective approach to treat aging, however. The Geroscience Network is the product of researchers who have a slightly overlapping but overall quite different view of aging, which you can find described in the noted Hallmarks of Aging paper, or the later pillars of aging materials. Much of what is seen in those publications as a cause of aging, such as epigenetic changes, looks to my eyes to be a later consequence of the forms of molecular damage described in the SENS proposals. The overlapping areas where the Hallmarks of Aging and SENS agree, such as senescent cell clearance, are to be welcomed where they lead to efforts like UNITY Biotechnology, but it is still the case that more representative examples of Geroscience Network participant projects include the clinical trial of metformin and efforts to develop calorie restriction mimetic drugs, such as the failed sirtuin projects. So while on the one hand it is great to see that the treatment of aging is now well supported as a goal for the research community, it remains unfortunate that the chosen approaches are so very marginal.

Still, there is a clear path ahead for the spread of SENS technologies into the mainstream. That is to demonstrate effectiveness, the old story of bootstrapping enough success on a shoestring budget to obtain greater support from those who were originally skeptical or had their own favored but less effective approach. Senescent cell clearance is the pioneering example here: advocated in the SENS vision for fifteen years, but ignored by the vast majority of researchers. Only in the last five years, since a 2011 demonstration of effectiveness, has more of the research community started to work in this area - and now two startups are working on bringing therapies to the clinic. This example puts the future of SENS rejuvenation therapies squarely on us, the donors, the philanthropists, the supporters. We determine the degree to which SENS succeeds in spreading to the mainstream by our efforts to pull in enough funding and attention to get the research done and the prototypes built. So look at the message of the Geroscience Network researchers with some optimism: yes it is frustrating that they are headed down the wrong road, but they will adopt SENS approaches just as soon as those approaches can be proven in animal studies. Yes, it will be a hard work all the way to the finish line, but when was anything in life easy? In any case, take a look at the papers and see what you think.

Moving Geroscience Into Uncharted Waters

Research into the basic biology of aging has undergone a seismic shift in the last 10-20 years, moving rapidly from the very descriptive approach focused on the aged that was the predominant focus by the end of the last century, to a more mechanistic (and primarily genetics-driven) phase, focused less on describing the aging phenotype in different models, and more on a definition of the molecular and cellular drivers of the process. This progression was accompanied by an evolution in the concepts and ideas that have dominated the field in the past, namely free radicals, cell senescence, and caloric restriction, each of which became the seed upon which the modern foci of research now stands. Progress in a variety of research areas has crystallized into the beginnings of a conceptualization of the process, including seminal publications that described the major hallmarks or pillars of aging.

Aging research is not simply an academic pursuit, it actually holds more promise in terms of helping mankind than most or all other biomedical fields. In terms of health and human suffering, it is well known that four out of five older Americans suffer from at least one chronic disease, and more than half suffer from multiple comorbidities. Aging being the major risk factor for all those diseases, it follows that research into aging could be pivotal in our efforts to reduce the suffering associated with the ravages of old age. In addition to the direct health issues, it has been calculated that care for the elderly currently accounts for 43% of the total health care spending in the United States. By delaying aging even by a lesser degree than currently achieved in animal models, there will be significant gains both in terms of health and wealth. The enormous advances in basic aging research, coupled with the promises described in the previous paragraphs, led to the concept of geroscience, a field that aims to understand the molecular and cellular mechanisms responsible for aging being the major risk factor and driver of common chronic conditions and diseases of the elderly. Of course, there is considerable work to be done in order to bring the field forward and move aging biology towards translation. Major areas in need of further development include, in the preclinical space, the development of better, reliable, and predictive biomarkers, as well as development of metrics for health, including resilience.

Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms

An effective preclinical pipeline for developing interventions that target fundamental aging processes could one day transform medicine. However, at the Geroscience Network retreat, it was evident that the best potential strategies for drug discovery and development were not perceived as uniform among those working in the field. In some sense this is not surprising, as researchers have yet to define what is needed to develop a mechanism-based aging therapeutic with clinical utility. Still, the discordance among leaders in the field was enlightening-revealing many unanswered questions and unmet challenges in the discovery and preclinical development of drugs that target mechanisms of aging.

Recent, fundamental advances in our understanding of aging biology have brought the prospects of therapeutic interventions to extend health span and treat age-related diseases and disabilities as a group closer to reality. Despite the growing numbers of promising genetic and pharmaceutical interventions, significant work and financial investment are still needed in order to translate these basic science discoveries into the clinic. To this end, clinical trial strategies relevant to human frailty and resilience must first be established in validated invertebrate and vertebrate models. In addition, standardized preclinical drug development pathways are desperately needed. Some barriers to the clinical translation of therapies that target fundamental aging processes can be overcome by developing new preclinical testing approaches and clinical trials strategies, as well as and funding impediments unique to aging interventions. Together, we must engage in dialog and establish a framework to facilitate the translation of candidate compounds into effective drugs that promote health span and target age-related disorders in humans.

Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes

The successful translation of therapies that target fundamental aging processes into routine clinical interventions could transform the practice of medicine and human health. A number of candidate drugs (many already FDA-approved for other indications) have shown promise in preclinical studies. This Geroscience Network retreat developed ideas for proof-of-concept clinical trials that could be the next step in translating interventions that target fundamental aging processes into clinical practice. We described three frameworks for proof-of-concept trials, targeted at age-related diseases, geriatric syndromes, and resilience to acute stressors. Some aspects of clinical trial design are common to all three, whereas some require unique consideration in each framework. Importantly, proof-of-concept clinical trials would serve to test and advance the "geroscience hypothesis" that targeting the fundamental biology of aging will affect a range of age-related outcomes. Trial outcomes would be multidimensional and include outcomes related to the mechanism of action of the intervention; specific to the disease, syndrome, or stress under study; related to off-target effects of the intervention; and broadly relevant to the mechanisms and physiology of aging. Finally, several concrete steps could greatly accelerate the progress of clinical trials of interventions that target basic aging processes, including the development of standardized templates for trial design, toolkits for standardized outcome measurements, the establishment of a national geroscience biobank, and the development of specialist trial and training centers in the Geroscience Network.

Strategies and Challenges in Clinical Trials Targeting Human Aging

Clinical trials that target fundamental aging processes in humans are a novel concept that presents unique challenges and enormous opportunities. Challenges include selection of appropriate study populations, study designs, interventions, and outcomes. We presented two models that conceptualize trial designs for interventions that target fundamental aging processes in long-term and acute settings, defined by extension of health span and resilience to acute stressors, respectively. However, in order to gain the full support of federal and private sectors for development of therapeutics that target aging in humans, it is important to have "aging" or aging-associated outcomes such as frailty, functional decline, and multimorbidity designated as conditions eligible for registration by the FDA. Evidence from human studies is emerging that indicates certain interventions can target multiple age-related conditions simultaneously, potentially by interfering with the aging process itself. With the aging population projected to grow exponentially in the near future, clinical studies that can demonstrate the protective effect of these therapeutics during acute and chronic perturbations in aging humans are more timely than ever. Thus, delaying or preventing the disabilities that occur as a consequence of the aging process would result not only in tremendous cost savings for the healthcare system but also in gains for society on the whole from the increase in productive contributions from older members of society.

Resilience in Aging Mice

Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance healthspan and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects.

At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context. The preliminary set of tests ranked by the participants is discussed here, recognizing that this is a first attempt.

Investigating the Role of Hsp70 in Clearing out Damaged Proteins

Heat shock proteins such as the Hsp70 family are involved in the housekeeping processes that keep cells functioning well by destroying damaged proteins. They become active in response to stresses that cause a higher rate of damage to the protein machinery within cells, such as toxicity or heat - and hence the name. Many of the genetic alterations and other interventions shown to modestly slow aging in short-lived laboratory animals involve increased cellular maintenance in one way or another, so there is some interest in the research community in building therapies to artificially increase such maintenance activities. So far this hasn't resulted in useful approaches, however, and thus the only reliable way to improve these matters in your own life is still to exercise and practice calorie restriction - increased cellular maintenance is one of the ways in which these lifestyle choices make a difference to long-term health. There is no doubt value in going beyond this to seek much greater increases in cellular maintenance through medical science, but the large sunk costs and lack of results so far suggests that other, more direct means of repairing important forms of cell and tissue damage will be cheaper and more effective. Here I'm thinking of the SENS research proposals; the present state of natural repair processes would be sufficient given the existence of rejuvenation therapies capable of as-needed damage repair of the more critical issues.

One hallmark of aging is the accumulation of protein aggregates, promoted by the unfolding of oxidized proteins. Unraveling the mechanism by which oxidized proteins are degraded may provide a basis to delay the early onset of features, such as protein aggregate formation, that contribute to the aging phenotype. Members of the 70 kDa-heat shock protein (Hsp70) family are, in their function as molecular chaperones, involved in folding of newly synthesized proteins and refolding of damaged or misfolded proteins, as well as in assembly and disassembly of protein complexes. The role of Hsp70 in protection against oxidative stress-related damage has been widely accepted. However, to our knowledge, a possible function of Hsp70 in promoting the removal of oxidized proteins has not been investigated. In the current study, we are able to demonstrate not only the involvement of Hsp70 in protection against the oxidative stress-related accumulation of oxidized proteins, but also in their proteasomal degradation.

Hsp70 knockdown and prevention of Hsp70 induction during stress resulted in significantly increased levels of protein carbonyls after hydrogen peroxide treatment. Although heat shock proteins can refold mildly disordered proteins, it is clear that heat shock proteins are not able to repair covalently-modified oxidized proteins nor to reverse oxidative protein modifications. Thus, we suggested that Hsp70 must somehow be implicated in the removal of oxidized proteins. Moreover, Hsc70 deficiency did not lead to changes in protein carbonyl levels and, therefore, Hsc70 seems not to have a major role in this process. Albeit, Hsp70 and Hsc70 have a quite similar structure, it appears that their participation in (oxidative)-stress induced protein degradation is different. It is postulated that both proteins differ in their C-terminal regions, which may result in different cellular functions. Hsc70 is an important housekeeping protein, mostly responsible for the folding of newly synthesized proteins and involved in maintaining protein homeostasis in non-stressed conditions. In contrast, Hsp70 is mainly responsible for a rapidly inducible cell protection following stress situations. Relating to this, we have shown that Hsc70 expression is not affected by oxidative stress, while Hsp70 expression is induced about two-fold in our cellular model, which is comparable to results obtained in other cell lines. Since oxidative damage to proteins leads to their unfolding, the 'heat shock response' is activated and the expression of molecular chaperones is increased.

We demonstrated the ability of Hsp70 to bind oxidized proteins in vitro, as well as in our cell model and in vivo. Interestingly, these oxidized proteins bound to Hsp70 did not show a higher polyubiquitination, which further supports the widely accepted assumption that oxidized proteins are degraded by the 20S proteasome in an ubiquitin-independent way. It has been demonstrated that oxidized proteins are not preferentially ubiquitinated and that an intact ubiquitination system is not required for their degradation. Using various techniques, we demonstrated that Hsp70 interacts additionally with the 20S proteasome, confirming our hypothesis that Hsp70 seems to mediate the interaction between oxidized proteins and the 20S proteasome.

Taken together, the results presented in our current study demonstrate the involvement of the stress-inducible molecular chaperone Hsp70 in the 20S proteasomal degradation of oxidized proteins. We suggest that in the early phase after oxidative stress, Hsp70 binds to partially unfolded oxidized proteins and keeps them in a soluble, degradable form. Oxidized proteins bound to Hsp70 can then migrate to 20S proteasomes where they can be efficiently degraded. Thus, besides the direct recognition of oxidized protein substrates by the 20S proteasome, there seems to be another, Hsp70-mediated, way to catalyze the efficient degradation of oxidized proteins. Future studies should investigate the involvement of co-chaperones/interacting proteins and co-factors which may be involved in this process and which modulate the ability of Hsp70 to mediate shuttling of oxidized proteins to the 20S proteasome. Moreover possible interaction sites of Hsp70 on 20S proteasome subunits remain to be identified. Furthermore, there is increasing evidence that the stress-related inducibility of Hsp70 expression declines in aged cell models and organisms and that the chaperones are overloaded in aged cells due to increasing formation and accumulation of oxidized proteins and. Thus, modulating Hsp70 levels may be a possible pharmaceutical goal to maintain protein homeostasis and prevent the formation of toxic protein aggregates that can disrupt cellular function.

Link: http://dx.doi.org/10.1016/j.freeradbiomed.2016.08.002

Twins Exhibit Slightly Lower Mortality Rates than Non-Twins

Researchers here report on an interesting finding emerging from epidemiological data on twins, in that twins exhibit modestly lower mortality rates than the rest of the population. The paper focuses on the support and relationship angle, referencing the marriage effect on life expectancy, but I think that one could just as well field arguments based on effects in the womb, statistical differences in physical robustness, or a number of other items linked to longevity in human or animal studies that have shown up in the literature over the past few decades. Ultimately this is all interesting but irrelevant to the future of human longevity: small natural differences will be overwhelmed by the results of progress in medicine if things go well. A few years either way won't much matter when rejuvenation therapies can add decades of healthy life, something that may well happen within our lifetime if enough support goes to the right lines of research.

While studies of extreme longevity clustered within human families have indicated at least some genetic role in determining lifespan at very advanced ages, twin studies, which offer the opportunity to disentangle the genetic and environmental factors for a given trait, indicate genetic factors are responsible for only a modest amount of the variation (20-30%) in human lifespan and that the role of genetic factors is minimal before age 60, but increases thereafter. Although twin studies that focus on the correlation in age-at-death have yielded important insights into the role of genetics in human lifespan, the determinants of human survival patterns are immensely complex and change with age - i.e. while genetic factors play an increasingly larger role at advanced ages, environmental, social, and behavioral factors influence survival patterns much more heavily at younger ages. Perhaps owing to this complexity and the traditional structure of twin survival studies, less is known about differences in survival across age by zygosity, the underlying mortality processes that produce these differences, or the role of zygosity itself in shaping age patterns of survival.

Using data from the Danish Twin Registry and the Human Mortality Database, we show that monozygotic (MZ) twins have greater cumulative survival proportions at nearly every age compared to dizygotic (DZ) twins and the Danish general population. We examine this survival advantage by fitting these data with a two-process mortality model that partitions survivorship patterns into extrinsic and intrinsic mortality processes roughly corresponding to acute, environmental and chronic, biological origins. Overall, we find a survival advantage for MZ twins over DZ twins of both sexes at nearly every age and of DZ twins over the general population, but that different processes confer these advantages at different ages. For females, the survival advantage at all ages can be attributed to lower extrinsic mortality rates. Among males, extrinsic advantages account for the survival advantage up to about age 65 where the overall survival advantage begins to narrow and MZ males show better intrinsic survival than DZ males and DZ males show better intrinsic survival compared to the general population.

This research has documented a 'twin protection effect' akin to a marriage protection effect where a socially close relationship contributes to better survival outcomes throughout most of life. Notably, while we find evidence for a health protection effect arising from zygosity, the use of twin data allows us to avoid the confounding issue of self-selection that studies of marriage and health often encounter. Research on marriage protection effects as well as the findings presented in this paper are part of a larger body of literature that documents the importance of social support and cohesion for mortality and longevity outcomes. In this case greater survival for MZ twins over DZ twins and DZ twins over the general population is driven by lower extrinsic mortality at most ages, which is a likely consequence of the social bond between twins buffering against risky behaviors, providing emotional or material assistance during times of stress exposure, and promoting health-enhancing behaviors.

Link: http://dx.doi.org/10.1371/journal.pone.0154774

Aubrey de Grey at the Launching Longevity Panel, and Announcing Acceptance of the First Paper to be Published on MitoSENS Research

Today I'll direct your attention to a couple of videos, thematically linked by the presence of Aubrey de Grey, cofounder of the SENS Research Foundation and tireless advocate for progress towards working rejuvenation therapies. For the first of the videos, de Grey recently took part in a panel discussion involving representatives of the biotechnology industry, the research establishment, and venture capital community, with the topic being the coming development of a new industry that will develop therapies to extend healthy life and turn back aging. That industry has barely started to form its earliest and smallest stage today, as the first lines of rejuvenation research reach the point of commercial viability. There are a few startups and a lot of deep pockets yet to be convinced that this is going somewhere - though the commentary in the panel is encouraged, considering those involved.

The recent Rejuvenation Biotechnology 2016 conference hosted by the SENS Research Foundation was more along the same lines, focused on creating a foundation for the near future industry that will build and provide rejuvenation therapies. The purpose of the conference series is to help smooth the way for these treatments to move rapidly from the laboratory to the clinic, to build the necessary relationships, manage expectations, and pull in the additional support needed to make best possible progress. The conference was livestreamed over the past couple of days, and at one point Aubrey de Grey announced the just-then-and-there acceptance of the first scientific publication for the MitoSENS team at the SENS Research Foundation. They are presently in the lead, at the cutting edge, among the few groups working on the project of copying mitochondrial genes into the cell nucleus to protect them from the damage of aging. Ultimately, copying all thirteen genes should completely remove the contribution of mitochondrial damage to degenerative aging, as mitochondria will no longer become dysfunctional as their local DNA is damaged. They will get the proteins they need from the cell nucleus instead. It is a worthy project, and it is always welcome to see progress on this front.

Launching Longevity: Funding the Fountain of Youth

Can technology make human longevity a reality? As the pace of discovery accelerates, scientists and entrepreneurs are closing in on the Fountain of Youth. Disrupting the aging process by hacking the code of life, promises better health and longer maximum lifespans. With many layers of complexity from science to ethics, there are still skeptics placing odds against human longevity. Venture capitalists are betting on success; putting big money on the table to fund longevity startups. Google/Alphabet and drugmaker AbbVie have invested $1.5 billion on Calico, while Human Longevity Inc. recently raised $220 million from their Series B funding round. Complementing traditional venture investment, VCs like Peter Thiel and Joon Yun have established foundations and prizes to accelerate the end of aging. Why are VCs suddenly investing heavily in longevity startups? Will extended lifespan be a privilege of the wealthy or will the benefits be accessible to all? How long before these well-funded startups bring viable products to market?

Aubrey de Grey Announces Progress in MitoSENS

Ok everybody, before I introduce the next session I just wanted to make a very small, brief, but very welcome announcement. Literally half an hour ago we received some extremely good scientific news. Those of you who have been following SENS research since before the SENS Research Foundation itself even existed will know that, about a decade ago, the very first project, the very first research program that we were able to initiate - with the help of, especially, the initial donation of Peter Thiel - was to make mitochondrial mutations harmless by essentially putting backup copies of the mitochondrial DNA into the nuclear genome, modified in such way of course that the encoded proteins would be colocated back into the mitochondria to do their job. This is an idea that was first put forward more than 30 years ago, but it is an idea that despite quite a bit of initial effort, nobody was able to make work. When I first came across this concept, in fact I'd thought of it myself, it's a pretty obvious idea really, I came to the conclusion that a lot of the despair and despondency and pessimism about this approach was premature, and that it was worth having another go, and so that was the very first project we decided to fund.

Suffice to say that it has not been quite as easy as I was hoping to make progress in that space, but progress has now been made, step by step, over the past several years, with the help especially of the absolutely amazing team we have at the research center, who work on this, headed by Matthew O'Connor. Amutha Boominathan is the number two on the team, and is absolutely indispensable, I've no idea where we'd be without her. So, what's happened half an hour ago is that for the very first time in the entire history of this project, we have got far enough to have a paper accepted in a very nice journal, Nucleic Acids Research, which reports on our progress in this area. The headline result in this paper is that we are the first team ever to get two of the proteins encoded by genes in the mitochondrial DNA simultaneously functioning in the same cell line, and of course - two is equivalent to infinity for mathematicians, you know that, right? - this is extremely heartening news, and I just wanted to let you all know, thank you.

Exposing Old Nerve Cells to Young Cerebrospinal Fluid

In recent years a growing number of researchers have investigated the effects of putting old tissue into a young supporting environment. Typically this involves parabiosis: joining the circulatory systems of an old mouse and a young mouse. Given a knowledge what exactly is different between old and young environments, work also be carried out in cell cultures, however. Researchers have been using these methodologies to search for and evaluate potentially important signaling changes that occur with aging. Of particular interest are changes that impact stem cell populations, causing them to become less active, as the decline in stem cell activity with age is an important contribution to frailty and loss of function. In the research noted here, scientists are focused on cerebrospinal fluid and neural tissues rather than blood and the cardiovascular system, but find similar signs of an ability to spur greater stem cell activity in old tissue:

Researchers have discovered that the choroid plexus, a largely ignored structure in the brain that produces the cerebrospinal fluid, is an important regulator of adult neural stem cells. The study also shows that signals secreted by the choroid plexus dynamically change during aging which affects aged stem cell behavior. Stem cells are non-specialized cells found in different organs. They have the capacity to generate specialized cells in the body. In the adult brain, neural stem cells give rise to neurons throughout life. The stem cells reside in unique micro-environments, so-called niches which provide key signals that regulate stem cell self-renewal and differentiation. Stem cells in the adult brain contact the ventricles, cavities filled with cerebrospinal fluid (CSF) that bathes and protects the brain. The research team has now shown that the choroid plexus is a key component of the stem cell niche, whose properties change throughout life and affect stem cell behavior.

The researchers uncovered that the choroid plexus secretes a wide variety of important signaling factors in the CSF, which are important for stem cell regulation throughout life. During aging, the levels of stem cell division and formation of new neurons decrease. The research team showed that although stem cells are still present in the aged brain, and have the capacity to divide, they do so less. "One reason is that signals in the old choroid plexus are different. As a consequence stem cells receive different messages and are less capable to form new neurons during aging. In other words, compromising the fitness of stem cells in this brain region. But what is really amazing is that when you cultivate old stem cells with signals from young fluid, they can still be stimulated to divide - behaving like the young stem cells. We can imagine the choroid plexus as a watering can that provides signals to the stem cells. Our investigations also open a new route for understanding how different physiological states of the body influence stem cells in the brain during health and disease, and opens new ways for thinking about therapy."

Link: https://www.unibas.ch/en/News-Events/News/Uni-Research/Cerebrospinal-fluid-signals-control-the-behavior-of-stem-cells-in-the-brain-.html

New Understanding of why ApoE4 is Associated with Alzheimer's Disease

It is by now well known that the ApoE4 variant of Apolipoprotein E is associated with a higher risk of Alzheimer's disease in many populations. This is thought to be the case because this variant is less effective in roles that influence the breakdown of amyloid-β, a form of metabolic waste that accumulates in Alzheimer's patients. Researchers here provide evidence that ApoE4 is also relevant to the harmful accumulation of damaged tau protein, another form of waste that is associated with Alzheimer's disease. This should probably be taken as an indication that greater attention should be given to the development of ways to clear tau aggregates as well as amyloid aggregates:

For decades, scientists have known that people with two copies of a gene called apolipoprotein E4 (ApoE4) are much more likely to have Alzheimer's disease at age 65 than the rest of the population. Now, researchers have identified a new connection between ApoE4 and protein build-up associated with Alzheimer's that provides a possible biochemical explanation for how extra ApoE4 causes the disease. Apolipoprotein E comes in three versions, or variants, called ApoE2, ApoE3 and ApoE4. All the ApoE proteins have the same normal function: carrying fats, cholesterols and vitamins throughout the body, including into the brain. While ApoE2 is protective and ApoE3 appears to have no effect, a mutation in ApoE4 is a well-established genetic risk factor for late-onset Alzheimer's disease. Previous reports have suggested that ApoE4 may affect how the brain clears out amyloid-β, but what was happening at the molecular level wasn't clear.

Scientists had previously uncovered hints that ApoE4 might degrade differently than the other variants, but the protein that carried out this breakdown of ApoE4 was unknown. To find the protein responsible for degrading ApoE4, researchers screened tissues for potential suspects and homed in on one enzyme called high-temperature requirement serine peptidase A1 (HtrA1). When they compared how HtrA1 degraded ApoE4 with ApoE3, they found that the enzyme processed more ApoE4 than ApoE3, chewing ApoE4 into smaller, less stable fragments. The researchers confirmed the observation in both isolated proteins and human cells. The finding suggests that people with ApoE4 could have less ApoE overall in their brain cells - and more of the breakdown products of the protein. "There's been an idea tossed around that ApoE4 breakdown products could be toxic. Now, knowing the enzyme that breaks it down, we have a way to actually test this idea." But it's not just a lack of full-length ApoE or an increase in its fragments that may be causing Alzheimer's in people with ApoE4. Researchers also found that ApoE4 - because it binds so well to HtrA1 - keeps the enzyme from breaking down the tau protein, responsible for tau tangles associated with Alzheimer's.

Link: http://www.salk.edu/news-release/new-mechanism-discovered-alzheimers-risk-gene/

A New $15,000 Challenge Grant Announced for SENS Cancer Research Crowdfunding

Earlier today at the Rejuvenation Biotechnology 2016 conference, the SENS Research Foundation folk announced a $15,000 challenge grant for the present OncoSENS cancer research crowdfunding effort. All donations from here forward will be matched dollar for dollar from the grant, and the deadline for the fundraiser has been extended for another thirty days to give this a chance to run. The funds raised from the community through this initiative will be used to carry out the first high-throughput screening of drug candidates for cancers that use the alternative lengthening of telomeres (ALT) mechanism to maintain their growth. Finding ways to block ALT is a necessary part of any future universal cancer therapy based on preventing telomere extension in cancer cells: all cancers must do this to grow, and without it they will wither away. The matching fund is provided by the generosity of an anonymous donor and Christophe and Dominique Cornuejols, who you will recall have helped to build the matching funds for the past few years of Fight Aging! SENS fundraisers. Their efforts are very much appreciated! You can find the announcement at 5:18 in the conference livestream from earlier today:

Rejuvenation Biotechnology Conference, Wednesday Morning Lifestream, 5:18

Cancer will be controlled, the only question is how long it takes to achieve that goal. The next generation of immunotherapies and other very targeted approaches to kill cancer cells with few side-effects will greatly improve patient outcomes for all of the most common cancers. These therapies will still, however, have the disadvantage of being very tailored to specific cancers and attributes of cancer cells. It takes a lot of time and money to produce a new treatment for cancer, and if that treatment is specific to only one or only a few of the hundred of subtypes of cancer ... well, that isn't very efficient. There is only so much funding and only so many researchers. Tackling cancer one type at a time is just not the way to win on a short timeframe.

The strategy and economics of the situation are why it is so very important that work on a universal cancer therapy prospers. The most targetable mechanism that is known to be necessary for all cancers is telomere lengthening. Telomeres are sequences of repeated DNA that cap the ends of chromosomes, and a little of that length is lost with each cell division. This is a part of the limiting mechanism that prevents the overwhelming majority of ordinary somatic cells in our bodies from running amok to divide and replicate endlessly: cells with short telomeres self-destruct or become senescent, in either case dividing no more. Cancers can grow destructively because the mutated state of their cells has unlocked one of the few possible ways to lengthen telomeres. A range of research groups are working on the production of therapies to block telomere extension that occurs through telomerase activity, but next to no-one is working with ALT. Because individual tumors evolve rapidly, blocking both telomerase and ALT will be necessary: blocking only telomerase has already been demonstrated in animal studies to cause a cancer to switch over to ALT. Thus the SENS Research Foundation, supported by philanthropic donations from people like you and I, has stepped in to pick up the slack and get this job done. Do you want a future free from cancer? Then here is a chance to help make that happen: donate to the OncoSENS fundraiser.

Measuring Small Differences in Aging Between Populations

The advent of tools capable of accurately assessing the state of biological aging, such as measurement of changes in DNA methylation patterns, means that researchers can now produce additional and more robust data on quite small differences in longevity that exist when comparing various human populations. Measurement doesn't say much about why these differences exist: there we are back to discussing the degree to which it is genetics versus lifestyle and culture. Nonetheless, this particular study provides good evidence for the utility of DNA methylation as a biomarker of aging, given that the results match up fairly well with those obtained from statistical population data. Having a reasonably accurate measure of biological age is very important for the future development of rejuvenation therapies, as it will make it much faster and cheaper to determine what works and what doesn't work. The cost of research and development will be greatly reduced if researchers can immediately test the results of a potential rejuvenation therapy rather than having to wait and see what it does to health and life span.

"Latinos live longer than Caucasians, despite experiencing higher rates of diabetes and other diseases. Scientists refer to this as the 'Hispanic paradox.' Our study helps explain this by demonstrating that Latinos age more slowly at the molecular level." Latinos in the U.S. live an average of three years longer than Caucasians, with a life expectancy of 82 versus 79. At any age, healthy Latino adults face a 30% lower risk of death than other racial groups. Researchers used several biomarkers, including an "epigenetic clock", to track an epigenetic shift linked to aging in the genome. Epigenetics is the study of changes to the DNA molecule that influence which genes are active but don't alter the DNA sequence itself. The team analyzed 18 sets of data on DNA samples from nearly 6,000 people. The participants represented seven different ethnicities: two African groups, African-Americans, Caucasians, East Asians, Latinos and an indigenous people who are genetically related to Latinos. Called the Tsimane, the latter group lives in Bolivia.

When the scientists examined the DNA from blood - which reveals the health of a person's immune system - they were struck by differences linked to ethnicity. In particular, the scientists noticed that, after accounting for differences in cell composition, the blood of Latinos and the Tsimane aged more slowly than other groups. The research points to an epigenetic explanation for Latinos' longer life spans. For example, the biological clock measured Latino women's age as 2.4 years younger than non-Latino women of the same age after menopause. "We suspect that Latinos' slower aging rate helps neutralize their higher health risks, particularly those related to obesity and inflammation. Our findings strongly suggest that genetic or environmental factors linked to ethnicity may influence how quickly a person ages and how long they live."

The Tsimane aged even more slowly than Latinos. The biological clock calculated the age of their blood as two years younger than Latinos and four years younger than Caucasians. The finding reflects the group's minimal signs of heart disease, diabetes, hypertension, obesity or clogged arteries. "Despite frequent infections, the Tsimane people show very little evidence of the chronic diseases that commonly afflict modern society. Our findings provide an interesting molecular explanation for their robust health." In another finding, the researchers learned that men's blood and brain tissue ages faster than women's from the same ethnic groups. The discovery could explain why women have a higher life expectancy than men.

Link: http://www.newswise.com/articles/it-s-true-latinos-age-slower-than-other-ethnicities

A Look at the Mechanisms of Arterial Stiffening

This open access paper provides a perspective on some of the mechanisms of stiffening of blood vessels, though curiously without talking much about cross-linking of important structural molecules in the extracellular matrix. This stiffening is one of the most dangerous and damaging immediate consequences of the cell and tissue damage that lies at the root of aging. It causes hypertension, a condition of chronic high blood pressure, and a consequent detrimental remodeling of heart tissue. This leads to many of the varieties of cardiovascular disease, including an increased rate of breakage of tiny blood vessels in the brain, each destroying a tiny amount of tissue, but collectively causing a deterioration of cognitive function. Ultimately this results in vascular dementia, heart failure, and other fatal conditions. But it all starts with a loss of elasticity in blood vessels driven by mechanisms such as senescent cell accumulation, cross-link formation, and calcification in blood vessel walls.

Stiffening of the aorta and large elastic arteries is a hallmark of vascular aging. It has a number of adverse haemodynamic consequences, including a major contribution to isolated systolic hypertension. When measured by aortic pulse wave velocity (aPWV), it is highly predictive of clinical cardiovascular disease events independent of blood pressure, both in the general population and in groups with additional risk factors. Formerly thought to be simply a marker of atherosclerosis, the pathology of aortic stiffening may differ, at least in part, from that of atherosclerosis. Thus, in primate models of atherosclerosis, aPWV is reduced compared to non-atherosclerotic controls, at least in the early stages of atherosclerosis. In humans, aPWV is largely independent of risk factors other than age and blood pressure and is not elevated in the presence of non-calcified atheromatous plaque. The prognostic importance of arterial stiffening and the fact that it may be driven by a specific pathology distinct from atherosclerosis makes it an appealing target to prevent cardiovascular disease events.

In older subjects, calcification occurs in the media of the arterial wall around elastin fibres ('elastocalcinosis') and within atherosclerotic plaque in the intima. Although often regarded as distinct entities, intimal and medial calcifications often coexist. Arterial stiffening is closely associated with calcification, an association that could be explained by coexistent atherosclerosis. However, animal models show that medial calcification (in the absence of atherosclerosis) increases arterial stiffness, suggesting a direct causal relation between calcification and stiffening. Using combined computed tomography and magnetic resonance imaging to measure calcification and atheroma in the Twins UK population, we have shown that even though calcification often colocalises with atherosclerotic plaque, the association of stiffness with calcification is not explained by coexistent atheromatous plaque. Furthermore, the correlation between calcification and stiffness is explained by shared genetic factors distinct from those responsible for atherosclerosis. Arterial calcification is now known to be an active process resembling osteogenesis in which vascular smooth muscle cells undergo osteoblastic differentiation, expressing many of the proteins associated with bone formation and releasing vesicles into the extracellular matrix which serve as nucleation sites for the accumulation of hydroxyapatite crystals.

Whilst calcification may represent the later stages of a degenerative arteriosclerotic process that can be detected macroscopically, it is likely to be initiated by elastin degradation and a change in the type of collagen, which may also contribute to arterial stiffening independent of calcification. Such a degenerative process may relate to repetitive mechanical stress. It is thought to promote calcification through elastin-derived soluble peptides (matrikines or elastokines) which activate smooth muscle cell osteogenic differentiation and increase matrix affinity for nucleating mineral deposition. Matrix metalloproteinases (MMPs) degrade components of the extracellular matrix including elastin, and in vivo, MMP-mediated elastin degradation is closely associated with both medial calcification and increased arterial stiffness. MMPs are also implicated in cutaneous elastin degradation that may parallel changes in the arterial wall. MMP9 expression in the skin, for example, has been shown to relate to arterial stiffness.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949363/

More Evidence for the Inheritance of Longevity

There is plenty of evidence to show that comparative longevity for individuals within a species is to some degree inherited, running in families. Humans are no different in this regard. We might compare that with present thinking on the degree to which life expectancy in our species is genetic versus environmental, however: it is thought that genetic differences only become significant in old age, during the struggle of damaged systems to maintain some level of function. A commonly quoted assessment is that 75% of life expectancy variation is due to choice and environment, and only 25% is due to genetics. So what is the important inheritance here, genes or culture? I use the term culture in the very narrow sense of your upbringing, the habits, values, and knowledge you acquire or choose due to the influence of those around you. In the wealthier parts of the world the most important cultural outcomes for recent generations are whether or not you smoke, whether or not you become overweight, and whether or not you keep up with regular moderate exercise. Arguably formal education and a disposition towards personal wealth are important too, but the true nature of these relationships is very hard to disentangle from other associated factors when examining population statistics.

In the years ahead this will all change, and natural variations in life expectancy will become unimportant in comparison to whether or not people have access to rejuvenation therapies that can repair the molecular damage that causes aging. A class of therapy capable of adding ten healthy years to life would swamp all of the existing common lifestyle effects on human life span. After the advent of several of these types of therapy, long-term health will become almost entirely determined by medical technology. This is the goal to aim for, to lift up everyone into a future in which there is no more ill health or age-related disease, no more short straw in the genetic lottery, and life in good health is a choice for as long as desired. Freedoms of this sort must be built; they cannot simply be declared.

The paper here, like most assessments of the data for inheritance of longevity, doesn't have much to add on the contribution of genes versus environment. Genetic associations are known to exist, and they are found here as they are in other studies. I suspect that accurate assessments of the individual contributions to human longevity for all of these various factors, genes and lifestyle choices, will not be completed by the research community before they become moot. Medical progress will ultimately make natural variations in longevity just as irrelevant as natural variations in resistance to smallpox - an interesting historical question, but not one studied by any great number of people.

Long-lived parents could mean a healthier heart into your seventies

The longer our parents lived, the longer we are likely to live ourselves, and the more likely we are to stay healthy in our sixties and seventies. Having longer-lived parents means we have with much lower rates of a range of heart conditions and some cancers. A major study found that our chances of survival increased by 17 per cent for each decade that at least one parent lives beyond the age of 70. The researchers used data on the health of 186,000 middle-aged offspring, aged 55 to 73 years, followed over a period of up to eight years. The team found that those with longer lived parents had lower incidence of multiple circulatory conditions including heart disease, heart failure, stroke, high blood pressure, high cholesterol levels and atrial fibrillation. For example, the risk of death from heart disease was 20% lower for each decade that at least one parent lived beyond the age of 70 years. In addition, those with longer lived parents also had reduced risk of cancer; 7% reduced likelihood of cancer in the follow-up per longer-lived parent.

Although factors such as smoking, high alcohol consumption, low physical activity and obesity were important, the lifespan of our parents was still predictive of disease onset after accounting for these risks. The study built on previous findings which established a genetic link between parents' longevity and heart disease risk. That paper studied 75,000 participants in the UK Biobank, and found that offspring of longer-lived parents were more likely to have protective variants of genes linked to coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type 1 diabetes, inflammatory bowel disease and Alzheimer's disease.

"This work helps us identify genetic variations explaining the better health of people with longer-lived parents. We prominently found genetic factors linked to blood pressure, cholesterol levels and smoking, which underlines how important these avoidable and treatable risks are. However, we also found novel genetic factors, which could provide new clues to help us understand why having longer-lived parents has health benefits. This study provides additional fuel to really bolster research efforts by us and others in geroscience, a field that seeks to understand relationships between the biology of aging and age-related diseases. Aging is the most important risk factor for common chronic conditions such as heart disease, Alzheimer's and cancer, which are likely to share pathways with aging and therefore interventions designed to slow biological aging processes may also delay the onset of disease and disability, thus expanding years of healthy and independent lives for our seniors."

Longer-Lived Parents and Cardiovascular Outcomes

Cardiovascular risk assessment currently identifies higher risk individuals through parental histories of early onset myocardial infarction. However, having relatively long-lived parents is associated with markedly lower coronary heart disease (CHD) risks and longer survival. Parental longevity associations with other common cardiovascular outcomes are little studied. We estimated associations between parents' age at death and common incident conditions plus mortality in a large middle-aged cohort.