Fight Aging! Newsletter, August 18th 2014

August 18th 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • Chronic Inflammation Chews Up Your Blood Vessels
  • When You Are Damaged, You Break More Readily
  • Reminder: Rejuvenation Biotechnology 2014 is Next Week
  • A Cross-Section of Recent Results in the Study of Aging
  • LabCures: Crowdfunding by Laboratory Rather than by Project
  • Latest Headlines from Fight Aging!
    • Calico Website Launched
    • Genetic Studies of Longevity Leading to Drug Development
    • Studying Calorie Restriction and Rapamycin
    • Building Brain Tissue for Research and Testing
    • A Twist in the Progression of Atherosclerosis
    • Aging is the Cost of Species Adaption and Survival
    • Being Overweight or Obese Raises the Risk of Cancer
    • Working Towards a Way to Clear Cytomegalovirus
    • 12-Lipoxygenase is Critical in Type 2 Diabetes
    • Daumone as Calorie Restriction Mimetic


A number of the most serious age-related conditions involve the progressive structural and functional decay of your blood vessels. A number of different forms of cellular and molecular damage conspire to clog, weaken, and stiffen blood vessels until one of these small but vital pieces of the body's infrastructure fails catastrophically, and then a blockage or a bleed causes death or crippling injury in a matter of moments. The older you are the more extensive the damage and the worse the odds, but poor lifestyle choices will generally put you in a poorer position than would otherwise be the case.

Chronic inflammation is a noteworthy contribution to many issues associated with aging, and it is one of the contributing causes that most of us have a fair level of control over throughout most of our lives. By taking basic good care of health matters, exercising, and eating a diet low enough in calories to stay slim, the average individual will have a lower level of inflammation as a result. Inflammation is probably a primary mechanism in the link between excess fat tissue and raised risk of suffering from all of the common age-related disease. Visceral fat tissue is metabolically active in ways that promote inflammation, and the more of it you have the worse off you are. You can't escape chronic inflammation in aging entirely by staying thin and active, however, as significant raised inflammation levels also result from the characteristic age-related failure of the immune system. As a result of the damage of aging, the immune system becomes both ineffective and constantly overactive at the same time.

Why exactly is chronic inflammation bad? What does it do under the hood? There are many distinct mechanisms, but here are some papers to illustrate a couple that involve your blood vessels. In effect you might think of inflammatory processes as gnawing away at the structural integrity of these important tissues, at an insignificant pace in youth, but accelerating over the years. There is always repair taking place as well, of course, but ultimately the inflammation wins - or at least that will be the case until the research community is given enough support and funding to produce the means to reverse these mechanisms.

A Crucial Role for CDC42 in Senescence-Associated Inflammation and Atherosclerosis

Chronic inflammation is characterized by the long-term presence of immune cells in affected tissues and is associated with age-related diseases such as cancer, neurodegenerative disorders, and cardiovascular disease. Interestingly, levels of pro-inflammatory cytokines are elevated in the endothelial cells and serum of older persons in the absence of disease. Thus, inflammation that accompanies the natural aging process may contribute to the onset of age-related diseases, which are responsible for most of the mortality in modern societies.

Atherosclerosis is an age-related chronic inflammatory disease. In persons with atherosclerosis, chronic inflammation is mainly induced by sterile stimuli and it accelerates disease progression. The initial step of the atherosclerotic process involves recruitment of inflammatory monocytes to dysfunctional endothelial cells. Senescent endothelial cells have been suggested to represent "dysfunctional endothelial cells" since they are specifically localized in the atherosclerotic lesions of patients and share many common features, including the pro-inflammatory phenotype that can induce sterile inflammation related to atherosclerosis. Although senescence of endothelial cells has been implicated in the process of atherogenesis, a specific role of senescent endothelial cells in chronic inflammation associated with atherosclerosis remains uncertain due to the lack of in vivo models. The molecular mechanisms underlying the pro-inflammatory phenotype in senescent endothelial cells also remain unclear [but we] identified CDC42 signaling as a mediator of chronic inflammation associated with endothelial senescence.

Mesenchymal stem cells for treatment of aortic aneurysms

An aortic aneurysm (AA) is a silent but life-threatening disease that involves rupture. It occurs mainly in aging and severe atherosclerotic damage of the aortic wall. Even though surgical intervention is effective to prevent rupture, surgery for the thoracic and thoraco-abdominal aorta is an invasive procedure with high mortality. Therefore, an alternative strategy for treatment of AA is required. Recently, the molecular pathology of AA has been clarified. AA is caused by an imbalance between the synthesis and degradation of extracellular matrices in the aortic wall. Chronic inflammation enhances the degradation of matrices directly and indirectly, making control of the chronic inflammation crucial for aneurysmal development.

Meanwhile, mesenchymal stem cells (MSCs) are known to be obtained from an adult population and to differentiate into various types of cells. In addition, MSCs have not only the potential anti-inflammatory and immunosuppressive properties but also can be recruited into damaged tissue. MSCs have been widely used as a source for cell therapy to treat various diseases involving graft-versus-host disease, stroke, myocardial infarction, and chronic inflammatory disease such as Crohn's disease clinically. Therefore, administration of MSCs might be available to treat AA using anti-inflammatory and immnosuppressive properties.


It is about as proven as it gets in human studies that moderate exercise is good for you and a sedentary lifestyle is bad for you. The difference in life expectancy is probably somewhere in the low end of the five to ten year range, though it is very challenging to pin down how much of that is due to more direct mechanisms of exercise versus indirectly related items such as the amount of visceral fat tissue present in the body. Human studies turn out correlations only: it isn't as though you can structure your study population up front to determine cause and effect. That is possible in animal studies, however, and those robustly demonstrate that moderate exercise is good for you while lazing around being fat isn't. It is entirely reasonable, I believe, to live life under the assumption that the causation for exercise and health shown in animal studies is the reason for the correlation shown in human studies.

Things become somewhat more challenging when you move beyond moderate exercise in humans, however. Whether twice as much exercise is better and why it is that professional athletes live longer than the general population are harder questions to answer. The athlete correlation may well exist because people who are capable of success in that field of endeavor are simply more robust than the rest of us, and would have lived longer than their peers regardless of career. Similar issues exist with most past data on levels of exercise beyond merely moderate and the resulting benefits.

Here is another interesting question: is there such a thing as too much exercise? Is exercise like any drug in that the dose-response curve is most favorable in the middle, and going too far in either direction means losing the benefits? This becomes a more pressing issue in later life, when an individual is damaged by aging and suffering the consequences of a lifetime's accumulation of cellular and molecular defects. We are machines, and a damaged machine is more prone to breakage at any given level of activity. So when we learn that people who are old and damaged tend to have a raised rate of cardiovascular failure at greater levels of exercise, that is the lesson we should take away: damaged machines break. We shouldn't accept this fate for ourselves and restrict our activities, but rather eagerly support research into ways to repair the damage that so greatly impacts health and survival in later life.

Contrary to Popular Belief, More Exercise Is Not Always Better

There is strong epidemiological evidence of the importance of regular physical activity, such as brisk walking and jogging, in the management and rehabilitation of cardiovascular disease and in lowering the risk of death from other diseases such as hypertension, stroke, and type 2 diabetes. The Physical Activity Guidelines for Americans recommends about 150 minutes per week of moderate-intensity exercise or about 75 minutes of vigorous-intensity exercise. But there is clear evidence of an increase in cardiovascular deaths in heart attack survivors who exercise to excess, according to a new study.

[Researchers] studied the relationship between exercise and cardiovascular disease-related deaths in about 2,400 physically active heart attack survivors. They conducted a prospective long-term study using the National Walkers' and Runners' Health Studies databases. This study confirmed previous reports indicating that the cardiovascular benefits for walking and running were equivalent, as long as the energy expenditures were the same (although when walking, as compared to running, it will take about twice as long to burn the same number of calories). Remarkable dose-dependent reductions in deaths from cardiovascular events of up to 65% were seen among patients who were running less than 30 miles or walking less than 46 miles per week. Beyond this point however much of the benefit of exercise was lost, in what is described as a reverse J-curve pattern.

"These analyses provide what is to our knowledge the first data in humans demonstrating a statistically significant increase in cardiovascular risk with the highest levels of exercise. Results suggest that the benefits of running or walking do not accrue indefinitely and that above some level, perhaps 30 miles per week of running, there is a significant increase in risk. Competitive running events also appear to increase the risk of an acute event. However, our study population consisted of heart attack survivors and so the findings cannot be readily generalized to the entire population of heavy exercisers."

Increased Cardiovascular Disease Mortality Associated With Excessive Exercise in Heart Attack Survivors

Habitual physical activity and exercise have repetitively been shown to reduce the risk of sudden cardiac death and acute myocardial infarction. Several articles suggest that there is a U-shaped relationship between running dose and reduced all-cause mortality, but these studies lack the statistical power to formally test for a nonlinear dose-response relationship. We therefore used the National Walkers' and Runners' Health studies to examine the dose-response relationship between exercise energy expenditure and cardiovascular disease (CVD)-related mortality in heart attack survivors. The large number of highly active subjects, and the high risk for CVD mortality in persons having had a previous heart attack, provides the statistical power required for testing whether there is an increased CVD risk in the most active heart attack survivors.

Exercising for Health and Longevity vs Peak Performance: Different Regimens for Different Goals

Accumulating evidence suggests that exercise practices that are ideal for promoting health and longevity may differ from the high-volume, high-intensity endurance training programs used for developing peak cardiac performance and superb cardiorespiratory fitness (CRF). Studies consistently show that regular moderate-intensity physical activity (PA) is highly beneficial for long-term cardiovascular (CV) health. Improving the CRF from low to moderate to high will progressively improve CV prognosis and overall survival. However, the survival benefits from improvements in the CRF plateau at about 10 metabolic equivalents (with 1 metabolic equivalent equal to an oxygen consumption of 3.5 mL O2/kg body weight per minute), with no additional survival benefit accruing from higher CRF levels. Clearly, 30 minutes of regular vigorous PA enhances health and well-being, but performing 3-hour bouts of strenuous PA does not multiply the health benefits.


The SENS Research Foundation is hosting Rejuvenation Biotechnology 2014 on August 21st in Santa Clara, California. The theme for this conference is bringing together business and science to pave the way for later clinical applications of the results of research programs that are still in progress.

SENS Research Foundation is proud to present the Rejuvenation Biotechnology Conference: Emerging Regenerative Medicine Solutions for the Diseases of Aging. This conference will bring together leaders from the Alzheimer's, cardiovascular, cancer, and other age-related disease communities to discuss preventative and combinatorial strategies to address the diseases of old age.

The Rejuvenation Biotechnology Conference builds upon novel strategies being pioneered by the Alzheimer's and cancer communities. By convening the foremost leaders from academia, industry, investment, policy, and disease advocacy, SRF seeks to inspire consideration of the wider potential of these strategies and evaluate the feasibility of preventative and combinatorial medicine applications to treat all aging-related diseases. Through a series of presentations and panel discussions, Alzheimer's disease, cancer, cardiovascular disease, diabetes, macular degeneration, musculoskeletal disease and Parkinson's disease will be examined with scientific, economic, regulatory and other considerations in mind.

In the years ahead novel forms of medicine will emerge that are a long way removed from the sort of drugs that today's regulatory process is intended to handle: gene therapies to move mitochondrial DNA into the cell nucleus, for example. Moreover, this new medicine will target the causes of aging, and thus be intended for more than just the sick among the elderly. Patients will include everyone that present regulations declare to be healthy, even through they are old and damaged. If you are sixty years old and have no defined medical condition, then congratulations - but you are not healthy by any measure. Your risk of death and disease is much higher than it was three decades ago, and this is precisely because of the cellular and molecular damage that has gnawed away at every part of your biology. Present regulation and institutional views on aging and health are outmoded, an obstacle to a future in which the causes of aging can be treated. Much that is currently encoded as tradition or law in the medical research and development community must change.

Thus when considering a timeline of decades between today and the advent of functional rejuvenation biotechnologies, it is important to lay the groundwork. As public awareness and support grows, it helps to have influential individuals and organizations who are already willing to move forward and change. It always moves more slowly than we'd like it to, but the work has to be done: it is all a part of the broader spectrum of advocacy.

The list of speakers at the Rejuvenation Biotechnology conference is well worth a look, and there's a glossy PDF brochure as well. One portion of the conference agenda is a focus on how the existing obstructive regulatory system can be changed rather than how it can be worked around, which is what you'll get as a view from the community of those who must shape their careers within the bounds of what is permitted by the FDA. They can't talk about working around the system or (better) tearing it down as that has material consequences when it comes to the ability to lead research and development programs. Talking about change and expansion of regulation is permitted dissidence, while everything else is likely to cause issues for any program that a noteworthy dissident is involved in:

Escalating societal healthcare needs have driven an unprecedented era of biomedical innovation. However, the development of candidate technologies without consideration of a robust regulatory strategy is likely to contribute to stymied patient access and commercial viability. Therefore, this session will consider worldwide efforts to rapidly and proportionally develop international regulatory processes to accommodate increasingly heterogeneous and unfamiliar healthcare technologies and their swift translation from lab to bedside.

So everyone recognizes that there is a problem, in that regulation blocks progress and makes it far more expensive than it should be, but the usual reaction is some variant of "we need more and better regulation." Which is pretty much how we arrived at the ridiculous system of medical regulation that presently exists, in which it is illegal to treat aging, near everything that isn't explicitly permitted is forbidden, and it requires a decade of therapies widely available via medical tourism to embarrass politically sensitive regulators into allowing treatments to move forward. Absent that regional competition you can be certain that stem cell medicine would still be stuck in the labs, faced with ever-steeper demands for trials and data. At every step of the way people involved with medical regulation said "this isn't working," and yet the next regulatory iteration is always worse, more invasive, more costly, and more harmful than the last.


It is important to remember that much of the study of aging is just that - study of aging, no more. Most of the researchers involved in the field are not working on ways to enhance healthy longevity, or ways to treat aging as a medical condition. They are merely studying aging: collecting data and establishing theories about how aging proceeds. Aging science remains a strange field in that respect. If you look at cancer research, to pick one example, a much higher proportion of research is aimed at producing treatments or carried out in direct support of producing treatments, and you certainly won't find the same phenomenon of researchers quick to deny that any of their work would be used to actually treat the medical condition they focus on. While things have changed for the better in the aging research community, as illustrated by the fact that many noted researchers now advocate working towards greater human longevity, there remains a sizable contingent of researchers who do not talk about treating aging and who would avow that goal if asked in public.

Bear in mind that for every interesting item I point out here at Fight Aging! there are a dozen more papers that report on gathering data on aging and nothing more. The majority of funding goes towards a mix of epidemiological work that arguably has absolutely no impact whatsoever on the prospects for defeating age-related disease, and an endless cataloging of the changing biology of aging in ever-greater detail, which has only a minor impact. The small segment of research that might actually produce meaningful results, involving repair of the causes of aging, presently makes up a tiny fraction of a tiny fraction of the overall resources devoted to aging science. That whole field in and of itself is a small fraction of overall medical research, very much underfunded for its importance. Stepping up another level, medical research in general is a forgotten child in our culture, largely ignored and also poorly funded for its importance. People would rather have war, celebrity, and circuses. Much must change in the years ahead, and the past decade of growth and change in the culture of aging research has been but start. A good start, yes, but there is much to be done yet.

Here is a selection of papers that represent the sort of work that makes up much of aging research at the moment.

Declining intelligence in old age linked to visual processing

Age-related declines in intelligence are strongly related to declines on a very simple task of visual perception speed. The evidence comes from experiments in which researchers showed 600 healthy older people very brief flashes of one of two shapes on a screen and measured the time it took each of them to reliably tell one from the other. Participants repeated the test at ages 70, 73, and 76. The longitudinal study is among the first to test the hypothesis that the changes they observed in the measure known as "inspection time" might be related to changes in intelligence in old age. "The results suggest that the brain's ability to make correct decisions based on brief visual impressions limits the efficiency of more complex mental functions. As this basic ability declines with age, so too does intelligence. The typical person who has better-preserved complex thinking skills in older age tends to be someone who can accumulate information quickly from a fleeting glance."

Study examines midlife hypertension, cognitive change over 20-year period

Authors used the Atherosclerosis Risk in Communities (ARIC) study to examine the effects of hypertension by analyzing the results of three cognitive tests over time. Data from 13,476 participants were used and the maximum follow up was 23.5 years. The decline in global cognitive scores for participants with hypertension was 6.5 percent greater than for individuals with normal blood pressure. An average ARIC participant with normal blood pressure at baseline had a decline of 0.840 global cognitive z score points during the 20-year period compared with 0.880 points for participants with prehypertension and 0.896 points for patients with hypertension. Individuals with high blood pressure who used medication had less cognitive decline during the 20 period than participants with high blood pressure who were untreated.

Exercise, Sedentary Pastimes, and Cognitive Performance in Healthy Older Adults

Moderately vigorous physical activity (MVPA) provides a protective affect against cognitive decline and cardiovascular risk factors. Less is known about sedentary pastimes or non exercise physical activity (NEPA) and cognitive performance. 125 healthy adults 65 or older with no clinical evidence of cognitive impairment were enrolled. Sedentary pastimes were associated with executive dysfunction; MVPA with high memory scores and NEPA with improved working memory. Only sedentary pastimes and executive dysfunction retained significance after correction for multiple comparisons. Smoking and alcohol confounded the association of memory with sedentary pastimes and MVPA.

Incidence and Predictors of Multimorbidity in the Elderly: A Population-Based Longitudinal Study

We aimed to calculate 3-year incidence of multimorbidity, defined as the development of two or more chronic diseases in a population of older people free from multimorbidity at baseline. Data were gathered from 418 participants in the first follow up of the Kungsholmen Project (Stockholm, Sweden, 1991-1993, 78+ years old) who were not affected by multimorbidity (149 had none disease and 269 one disease). After 3 years, 33.6% of participants who were without disease and 66.4% of those with one disease at baseline, developed multimorbidity. After adjustments, worse cognitive function was associated with increased risk of multimorbidity among subjects with no disease at baseline. Higher age was the only predictor of multimorbidity in persons with one disease at baseline.

The contribution of personality to longevity: Findings from the Australian Centenarian Study

Centenarians were currently low in Openness and Extraversion and high in Neuroticism, but were low in Openness and high in Neuroticism, Conscientiousness and Extraversion when reflecting on past traits. Currently, centenarians in high care facilities reported higher levels of Neuroticism, as did centenarians who did not socialize. Cognitively intact centenarians reported higher levels of Agreeableness; and males reported lower Neuroticism compared to females when reflecting on past experiences. Centenarians were characterized by several personality traits, which facilitated positive health behaviors and thus contributed to their longevity. It is possible that personality may not be static across the lifespan, but instead, reflect advancing age, psychosocial factors and changes in life circumstances.


Current efforts to build a science crowdfunding community akin to the technology crowdfunding of KickStarter are largely a cut and paste of what works in for-profit space: similar presentation of projects, similar flow for donors and project managers, and so on. I remain dubious that this will work well, as the motivations for all parties are very different when comparing research funding to purchasing a new gizmo or comic, but I am nonetheless hopeful that among all of the experimentation someone will hit upon the magic recipe in the years ahead. Some fraction of people do meaningfully support science, after all, and this is demonstrated by the success of middle man organizations such as the big per-disease charities for various cancers, Parkinson's, Alzheimer's, and so on. These groups serve as intermediaries that process the incoherent desire to help and pipe money from donors to specific projects where it can do some good - or at least that is the way things work in the ideal world. This modern information age is all about disintermediation, however: making it so easy to find out how to donate to specific research projects within a donor's field of interest that much of the present function of the intermediary charities will ultimately fade away. The degree to which this will happen and the role played by present methods of crowdsourcing remain to be seen.

A recent post from Maria Konovalenko notes the existence of the very newly created venture LabCures. This is a research crowdfunding platform that focuses on the laboratory group as the fundamental unit to follow and fund rather than a per-project layout. This creates a very different dynamic to the fundraising process, and given what I've seen so far of online research crowdfunding I think that this is an approach well worth trying. The most success I have when fundraising is when doing so for a known organization, rather than for any specific project at that organization. People support teams, not games, and the level of knowledge needed jumps precipitously if you are asking someone to pick and choose research projects.

So you might consider this in the context of the potential for disintermediation noted above; after a certain point, people don't want to do the digging for information, but rather just donate and trust a reputable broker to direct the funds to where they can best be used. It is a big leap in and of itself to go from a general position of supporting research to cure a specific disease all the way to knowing enough to back specific laboratory groups: to know that you could be rooting for Wake Forest rather than just regenerative medicine in general. For most people that doesn't happen until they are suffering from the disease in question. Supporting teams in medical research might be all we should expect from busy, distracted people with access to the libraries of the internet, and thus the target that crowdfunding groups should aim for: building brand awareness for the competing teams, as it were. That goal intersects well with what the laboratories themselves are interested in achieving, as brand and public awareness have large impacts on all areas of their fundraising. So perhaps it should not be surprising to find that LabCures is a spin-off venture from one of these laboratories:

New Buck Institute spinoff will use Internet to solicit donations for medical research

LabCures, a new for-profit spinoff from the Buck Institute for Research on Aging in Novato, hopes to generate money for new research in the life sciences by using the Internet to attract lots of smaller donations. "The projects on our platform are not coming from the crowd, they are coming from a very unique, irreplaceable group of researchers. We're inviting all life science research labs in the United States, from institutes to universities to nonprofits, onto one platform and organizing the labs in ways that matter to the donor."

Why LabCures

Unique to LabCures, all labs on our platform come from verified University and Institute non-profit research facilities. Recognized scientists and open accountability means a new and direct method for contributing to medical research. Contributions made in the US are 100% tax deductible.

Researchers focus on science. LabCures is designed for individuals to find and support medical research that matters to them. By hosting labs in the life sciences we are able to focus on the unique characteristics of funding medical and biological research in ways that are meaningful. The reward is knowing, celebrating and empowering the research community.

LabCures does not set a time limit on lab profiles. Verified labs share current projects and associated budgets on an ongoing basis. Once a lab reaches its fundraising goal for a particular project it will update its followers on that project. This helps facilitate ongoing partnerships between contributors and researchers.

Labs keep what they raise. Research is not all or nothing and neither is LabCures. We understand contributions to research can be highly personal acts for which a lab will always benefit. We are worldwide. LabCures enables participation between the research community and any individual from anywhere in the world.

We make funding research easy. Users can reference their contributions made on LabCures and preference a debit or credit card to support a lab on a monthly basis. Users will also receive tax deductible receipts via email. Users will also stay current to research via update notifications from the lab.

You'll note that the initial groups populating the LabCures system are all aging research laboratories, which is understandable given the folk involved. This is a venture I'd like to see succeed in making it over the initial hurdle of attracting users and traffic, perhaps by engaging in an effort to present feeds of lab news, ranking labs, and providing review articles on what exactly these specific labs are up to. All of these are functions carried out by successful sites elsewhere, and there is no reason why they couldn't be mixed in with crowdfunding for philanthropic fundraising. At the very least, success here is measured in the degree to which other science crowdfunding sites such as Experiment grasp the point of the per-laboratory approach and work to adapt it into their systems.


Monday, August 11, 2014

Google's California Life Company has launched a stub website. The sparse information presented there is supportive of the view that Calico will be taking the Longevity Dividend path of focusing on genetics, metabolic manipulation, and standard issue drug discovery. This will look a lot like a continuation of sirtuin research, which is to say that they will spend a lot of money, generate a lot of data, and utterly fail to produce ways to meaningfully extend healthy human life. That is a fairly safe prediction for the outcome of any well-funded project that is not trying to build repair-based technologies to revert the causes of aging, but rather intends to alter the operation of metabolism to gently slow aging. Metabolism is immensely complex and poorly understood, and there is no well-defined course towards results that is analogous to the SENS plans for repair-based approach. A billion dollars and fifteen years has been spent on simply trying to reproduce a fraction of the most understood form of natural metabolic alteration that enhances longevity, the response to calorie restriction, with no good results. For that time and money we could have a demonstration of rejuvenation in mice via SENS therapies already.

Genetics is hot and drug discovery is safe and understood by investors. So as interest in treating aging is rising, we see funds raised and ventures started for groups trying to perform drug development based on genetic studies of aging and longevity. This is not because it has a hope of meaningful results, but because it is where funds can be raised, and where money can be made in the traditional Big Pharma fashion even without achieving any great extension of human longevity. In the Longevity Dividend viewpoint an ambitious goal is to add seven years of life expectancy over the next two decades through new drugs that alter metabolism - which is a miserable failure and a grand missed opportunity when compared to the indefinite extension of healthy life that might be attained by realizing comprehensive repair therapies for the damage that causes aging.

This is all disappointing, but that has been the signal all along as to where things were going with Calico: it is a project that may turn out to look a lot like a more highly publicized version of the Ellison Medical Foundation, in that it is simply adding more of the work already taking place at the NIA and elsewhere that is destined from the start to fail to advance human longevity. Its existence helps those elsewhere who are trying to raise funds to tackle aging, as it shifts conservative funding institutions in a direction of supporting such work, but that is about it.

To my eyes all of this reinforces the need to demonstrate beyond a doubt that repair approaches to reverse aging do in fact work, and work very much better and for far less cost of development than metabolic alteration. The way in which repair-based approaches will take over the mainstream of research is by showing that they produce compelling results at a time in which the other approaches are failing to do anything other than generate data and consume resources. The nearest approach to that point for the purposes of convincing people who support slowing aging but are not on board with aiming for rejuvenation is probably the targeted destruction of senescent cells, but even there it has been hard to raise funding for continued work and the reliance is on philanthropy to run the present study in normal rather than accelerated aging mice.

We're tackling aging, one of life's greatest mysteries.

Calico is a research and development company whose mission is to harness advanced technologies to increase our understanding of the biology that controls lifespan. We will use that knowledge to devise interventions that enable people to lead longer and healthier lives. Executing on this mission will require an unprecedented level of interdisciplinary effort and a long-term focus for which funding is already in place.

We are scientists from the fields of medicine, drug development, molecular biology, and genetics. Through our research we're aiming to devise interventions that slow aging and counteract age‑related diseases. Understanding the fundamental science underlying aging and finding cures for the intractable diseases associated with aging require time, deep technical expertise, research and partnerships. We're just getting started and will post career opportunities here when they become available.

Monday, August 11, 2014

The research linked below is an example of work in the Longevity Dividend model: study the comparative genetics of longevity in humans to find epigenetic patterns and genetic variants that correlate with membership of long-lived families. From there proceed to identify underlying mechanisms and undertake drug development to find ways to recreate those differences. This mainstream, well-supported research is absolutely the wrong path to take if the aim is to producing meaningful extension of healthy life, however. Aging occurs because we accumulate damage as a side-effect of metabolism within and around our cells. Outside of a few rare and devastating genetic mutations, we all suffer exactly the same types of damage for exactly the same reasons. Genetic and epigenetic variants have a limited effect on our interaction with this growing damage until very old age, so we should ignore them: researchers should focus instead on repairing and reverting these known forms of damage that cause aging. The resulting treatments built for this purpose will be applicable to everyone, and thus can be mass produced cheaply.

Given a choice between spending vast sums on building age-slowing drugs that help maintain people for longer in a state of being old and damaged, or building repair biotechnologies that help maintain people in a youthful, undamaged state, I know in which direction my money is heading. Drugs to slow aging will never be particularly helpful for those already old and damaged, while repair biotechnologies will aid those in greatest need of repair. It seems fairly self-evident to me where the focus should be. Yet the vast majority of research funding for the comparatively young field of longevity science is aimed at the inferior goal of slowing aging. This must change.

Frailty is a common condition associated with old age, characterized by weight loss, weakness, decreased activity level and reduced mobility, which together increase the risk of injury and death. Yet, not all elderly people become frail; some remain vigorous and robust well into old-age. The question remains: why? "People who are frail are more vulnerable to serious complications from falls or surgery and more susceptible to infection. Understanding why some elderly people do not experience a loss of balance or strength and do not suffer from abnormal gait may help us prevent and treat such physical decline."

The new project taps into the resources of [the] LonGenity Research Study, which builds upon the Longevity Genes Project, an ongoing 15-year study with more than 500 Ashkenazi Jews over the age of 95. LonGenity compares the genetics of the centenarians and their children with those with usual survival. Over the past 10 years, [researchers have] identified several biological markers that may explain their extreme longevity. "We have shown that our centenarian participants have a significant genetic advantage over the general population. Their rare genetic variants have allowed them to live longer, healthier lives and avoid or significantly delay age-related diseases, such as Alzheimer's and type 2 diabetes. We now want to know if a family history of those same 'longevity genes' reduces the risk for frailty."

The researchers will build on a pilot study funded by the American Federation for Aging Research that linked exceptional longevity to improved physical function and reduced risk of frailty. [The] team plans to further those initial efforts to identify gene variants that keep frailty at bay, explore biological pathways that may lead to frailty, and develop drugs that mimic the effect of those frailty-preventing genes.

Tuesday, August 12, 2014

Here is an example of the sort of work presently taking place in many of the labs interested in aging and longevity, consisting of exploration of existing drugs shown to have some effect on life span in animal studies, alongside continued research into the details of the calorie restriction response:

"Research has shown that consuming fewer calories, while maintaining sufficient nutrients, extends lifespan, and there are ongoing clinical studies in humans. However, aging also is associated with increased susceptibility to diseases. Remarkable extension of lifespan has been achieved in organisms by lowering calorie intake or tricking cells into thinking that there is not enough food. These manipulations are being considered for potentially increasing lifespan in humans. It is critical to understand the effects of these interventions upon physiological function of older organisms, as any increase in longevity must be accompanied by improved quality of life."

Rapamycin, or Rapa, a drug used to keep the body from rejecting organ and bone marrow transplants, blocks an enzyme that controls cellular division. Rapa has been shown to extend lifespan in mice; however, the effects of chronic low-dose Rapa-mediated treatment on resistance to infection remain unknown.

"Our study will test whether life-extending dietary interventions may improve or impair survival from, and immunity to, infection, allowing us to evaluate whether manipulations of nutrient pathways may be safe and desirable to achieve optimal healthy longevity. While calorie restriction appears to improve immune function and homeostasis in old animals, the few infectious challenge experiments suggest increased susceptibility to infection. Our exploratory proposal aims to test the hypothesis that calorie restriction and drugs that trick the cells into thinking that there is not enough food, such as Rapa, could be deleterious for protective immunity, because they may curtail full development of immune responses. We aim to dissect possible defects and discover whether we may use Rapa as is or whether we may need to seek for similar compounds with beneficial effects in healthy aging across different tissues."

Tuesday, August 12, 2014

A lot of the early applications of tissue engineering are focused on aiding research: the small amounts of tissue created are using for testing and investigation. That is a stepping stone for the various companies and labs involved, a way to generate revenue and interest while steadily improving their capabilities. It is worth keeping an eye on these efforts, because it is from here that later applications in clinical medicine will arise.

Currently, scientists grow neurons in petri dishes to study their behavior in a controllable environment. Yet neurons grown in two dimensions are unable to replicate the complex structural organization of brain tissue, which consists of segregated regions of grey and white matter. Recently, tissue engineers have attempted to grow neurons in 3D gel environments, where they can freely establish connections in all directions. Yet these gel-based tissue models don't live long and fail to yield robust, tissue-level function.

Now [a] group of bioengineers report that they have successfully created functional 3D brain-like tissue that exhibits grey-white matter compartmentalization and can survive in the lab for more than two months. As a first demonstration of its potential, researchers used the brain-like tissue to study chemical and electrical changes that occur immediately following traumatic brain injury and, in a separate experiment, changes that occur in response to a drug. The tissue could provide a superior model for studying normal brain function as well as injury and disease, and could assist in the development of new treatments for brain dysfunction.

The key to generating the brain-like tissue was the creation of a novel composite structure that consisted of two biomaterials with different physical properties: a spongy scaffold made out of silk protein and a softer, collagen-based gel. The scaffold served as a structure onto which neurons could anchor themselves, and the gel encouraged axons to grow through it. To achieve grey-white matter compartmentalization, the researchers cut the spongy scaffold into a donut shape and populated it with rat neurons. They then filled the middle of the donut with the collagen-based gel, which subsequently permeated the scaffold. In just a few days, the neurons formed functional networks around the pores of the scaffold, and sent longer axon projections through the center gel to connect with neurons on the opposite side of the donut. The result was a distinct white matter region (containing mostly cellular projections, the axons) formed in the center of the donut that was separate from the surrounding grey matter (where the cell bodies were concentrated).

Wednesday, August 13, 2014

Atherosclerosis is a dangerous condition caused by molecular damage to certain proteins circulating in the blood and then spurred on by growing chronic inflammation in aging. Where it takes root, the walls of your arteries corrode, malform, and expand inward into soft plaques of degenerative material. This is largely formed of macrophage cells attracted to the area by dysfunctional signaling and then choked by the debris. Ultimately this leads to serious vascular dysfunction, but more importantly if a large enough chunk of plaque material breaks away it will cause a heart attack or stroke.

Here researchers suggest that the immune system is not the dominant origin for the macrophages that make up plaque debris, and a more important and unusual source is actually closer at hand:

Scientists [have identified] a long-overlooked function of vascular smooth muscle cells in atherosclerosis. Atherosclerosis [is] a chronic inflammatory disease of the arteries arising from interactions of modified lipoproteins and various cell types including monocyte-derived macrophages from the blood and smooth muscle cells (SMCs) in the vessel wall. "It is unclear, however, how each particular cell type contributes to the development of an atherosclerotic lesion. One highly controversial issue is the contribution of vascular SMCs to plaque growth."

[The] researchers performed lineage tracing experiments in mice, in which they have genetically labeled mature SMCs in the vessel wall of young mice before the onset of the disease and then monitored their fate in older atherosclerotic animals. "Surprisingly, we found that SMCs in the arterial wall can undergo clonal expansion during disease progression and convert into macrophage-like cells that have lost the classical SMC marker, α-smooth muscle actin. It seems that certain atherosclerotic lesions contain even more SMC-derived macrophages than traditional monocyte-derived macrophages."

These findings indicate that previous studies based on immunostaining of plaque cells for smooth muscle and macrophage markers have vastly underestimated the role of SMCs and overestimated the role of monocyte-derived macrophages in atherosclerosis. "Targeting SMC-to-macrophage transdifferentiation could be a novel therapeutic strategy to treat atherosclerotic heart disease and perhaps many other diseases with a smooth muscle component."

Wednesday, August 13, 2014

A small number of species have exceedingly long life spans and show few signs of degenerative aging, so clearly biology is up to the task of continual repair and vigor. Yet the vast majority of species consist of individuals who age, and who will die because of aging should they survive the many other causes of mortality in the wild. Why do we age to death? The present consensus is that the prevalence of aging is the result of an evolutionary arms race to the bottom. Species that age better adapt to changing conditions and thus will take over most evolutionary niches. In effect we age because the world changes. Some thoughts here from a researcher in the field:

In the long run, the ability of a species to evolve is more important than anything else in determining its competitive success. This is true almost by definition: given enough time, the ability to adapt and improve will overtake any initial disadvantage. But evolutionary theory these last 50 years has been quite skeptical of "in the long run". If it is driven to extinction because of a competitive disadvantage in the short run, then what matters if it has the potential to improve, eventually?

This has everything to do with aging. A population with aging has more diversity and a faster turnover compared to a similar population in which death is only due to famine, predators, disease, etc. So - in theory - a population with aging evolves more rapidly than a population that doesn't age. But "the long run" can be thousands of lifetimes, and in the meantime those individuals that die early (of aging) are at a competitive disadvantage compared to those who continue to live, and have that much more time in which to produce offspring.

Can an aging population resist invasion (by longer-lived competitors) and cohere long enough that its superior rate of adaptation turns into a decisive advantage? This is the question that has been at the center of my research the last dozen years. On the one hand, there is abundant evidence that aging is no accident, that it has evolved via natural selection that explicitly favors aging. On the other hand, the theoretical argument casts doubt on the scenario where aging is selected on this basis.

The best resolution I have been able to find for this paradox is that aging has been able to evolve on this basis, and it is because the short-term advantage of unrestrained reproduction has been held in check by a different, faster-acting evolutionary principle than evolvability. Unrestrained reproduction leads to population overshoot, population crash, and extinction. This is a powerful, fast-acting evolutionary force, and populations have had to adapt by tempering individual competitiveness. This has created an environment in which the long-term advantage of aging is relevant, and aging as a population-level adaptation can thrive on this basis.

Thursday, August 14, 2014

This recent study provides yet another reason to make lifestyle choices that better manage your weight. If nothing else cancers thrive in an inflammatory environment, and metabolically active visceral fat tissue generates chronic inflammation. More of it is definitely worse for your long-term health in a range of ways:

Using data from general practitioner records in the UK's Clinical Practice Research Datalink (CPRD), the researchers identified 5.24 million individuals aged 16 and older who were cancer-free and had been followed for an average of 7.5 years. The risk of developing 22 of the most common cancers, which represent 90% of the cancers diagnosed in the UK, was measured according to BMI after adjusting for individual factors such as age, sex, smoking status, and socioeconomic status. A total of 166,955 people developed one of the 22 cancers studied over the follow-up period. BMI was associated with 17 out of the 22 specific types of cancer examined.

Each 5 kg/m² increase in BMI was clearly linked with higher risk of cancers of the uterus (62% increase), gallbladder (31%), kidney (25%), cervix (10%), thyroid (9%), and leukaemia (9%). Higher BMI also increased the overall risk of liver (19% increase), colon (10%), ovarian (9%), and breast cancers (5%), but the effects on these cancers varied by underlying BMI and by individual-level factors such as sex and menopausal status. Even within normal BMI ranges, higher BMI was associated with increased risk of some cancers.

Based on the results, the researchers estimate that excess weight could account for 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers in the UK. They also estimate that a population-wide 1 kg/m² increase in average BMI (roughly an extra 3 to 4 kg, or 8 to 10 pounds, per adult), which would occur every 12 years or so based on recent trends, would result in an additional 3790 cases of these 10 cancers in the UK each year.

Thursday, August 14, 2014

Like other herpesviruses, cytomegalovirus (CMV) cannot be effectively naturally cleared from the body as it has evolved the means to hide from the immune system. It is harmless for most people in the short term, but over the long term it causes ever more of the limited supply of immune cells to become uselessly devoted to fighting it. Since near everyone is exposed to CMV by the time they are old, this appears to be an important contribution to the age-related decline of the immune system.

One possible approach to dealing with this issue is to selectively destroy CMV-specialized immune cells. They will be replaced naturally and fairly quickly, or that replacement can be hurried along with an infusion of immune cells grown from a sample of the patient's tissues. The cancer research community is a fair way along in the development of highly selective cell destruction technologies that identify targets based on their distinctive surface chemistry, and this work can be adapted for use in winnowing the immune system.

Another approach is to find ways to clear out CMV, but that isn't so helpful for people who have lived with it for a long time and are therefore already suffering the consequences in the form of a distorted balance of immune cells. Nonetheless, here is a look at research into how CMV hides from the immune system. This is a starting point on the path towards disabling these molecular mechanisms to enable immune cells to clear CMV from the body:

Human cytomegalovirus (HCMV) is a herpesvirus that infects most people in the world, usually without producing symptoms. However, infection is life-long and must be kept in check by the immune system. When the immune system is weakened, the outcome of HCMV infection can be very serious. Thus, HCMV is the major cause of birth defects resulting from infection of the fetus during pregnancy, and it can cause severe disease in people with a weakened immune system, especially transplant recipients and HIV/AIDS patients. One type of immune cell, the natural killer (NK) cell, is crucial in controlling cells in the body that are abnormal. They do this by recognizing cells, which have special stress proteins on their surface, and killing them. When cells are infected with HCMV, they start to make these stress proteins. However, the virus has evolved ways to stop NK cells from killing infected cells by quickly stopping the stress proteins from reaching the surface. We have now identified two HCMV genes that target a major stress protein (called MICA) and cause its rapid destruction. Removing these two genes from HCMV renders infected cells very susceptible to killing by NK cells. This discovery might help the development of new ways to fight HCMV.

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells. Despite [activation], HCMV effectively suppressed cell surface expression of NKG2D ligands through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2D ligands. While infection with a UL16 deletion mutant caused the expected increase [in NKG2D ligand] cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert.

Friday, August 15, 2014

For the overwhelming majority of sufferers, type 2 diabetes is a lifestyle disease. It is something that they did to themselves, and which could be turned back at near any point with a suitable (albeit increasingly drastic) change in diet and lifestyle. Giving yourself the highest chance of avoiding type 2 diabetes is easy: stay active and stay thin. Nonetheless, the medical research community spends a lot of time and effort on finding ways for people to remain fat and indolent while still avoiding diabetes - though of course these efforts also apply to the much smaller population unfortunate enough suffer the condition regardless.

Here researchers find a way to protect the small population of insulin generating beta cells impacted by the mechanisms of type 2 diabetes, but by the sounds of it this will not affect any of the numerous other consequences of becoming fat, such as a raised risk of suffering all of the other common age-related conditions.

An enzyme called 12-LO promotes the obesity-induced oxidative stress in the pancreatic cells that leads to pre-diabetes, and diabetes. 12-LO's enzymatic action is the last step in the production of certain small molecules that harm the cell. The findings will enable the development of drugs that can interfere with this enzyme, preventing or even reversing diabetes. In earlier studies, these [researchers] showed that 12-LO (which stands for 12-lipoxygenase) is present in these cells only in people who become overweight.

The harmful small molecules resulting from 12-LO's enzymatic action are known as HETEs, short for hydroxyeicosatetraenoic acid. HETEs harm the mitochondria, which then fail to produce sufficient energy to enable the pancreatic cells to manufacture the necessary quantities of insulin.

For the study, the investigators genetically engineered mice that lacked the gene for 12-LO exclusively in their pancreas cells. Mice were either fed a low-fat or high-fat diet. Both the control mice and the knockout mice on the high fat diet developed obesity and insulin resistance. The investigators also examined the pancreatic beta cells of both knockout and control mice, using both microscopic studies and molecular analysis. Those from the knockout mice were intact and healthy, while those from the control mice showed oxidative damage, demonstrating that 12-LO and the resulting HETEs caused the beta cell failure. "Our research is the first to show that 12-LO in the beta cell is the culprit in the development of pre-diabetes, following high fat diets. Our work also lends important credence to the notion that the beta cell is the primary defective cell in virtually all forms of diabetes and pre-diabetes."

Friday, August 15, 2014

In this open access paper researchers present the evidence for daumone to be a calorie restriction mimetic in mammals:

The liver is one of the most susceptible organs to aging, and hepatic inflammation and fibrosis increase with age. Chronic inflammation has been proposed as the major molecular mechanism underlying aging and age-related diseases, whereas calorie restriction has been shown to be the most effective in extending mammalian lifespan and to have anti-aging effects through its anti-inflammatory action. Thus, it is necessary to develop effective calorie restriction mimetics.

Daumone, a pheromone secreted by Caenorhabditis elegans, forces them to enter the dauer stage when facing inadequate conditions. Because Caenorhabditis elegans live longer during the dauer stage under energy deprivation, it was hypothesized that daumone may improve survival i


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