Cellular Senescence as a Contributing Cause of Glaucoma
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With advancing age an ever greater number of cells in the body linger in a senescent state in which replication is halted rather than destroying themselves after reaching the Hayflick limit. This can be a reaction to cellular damage or potentially damaging tissue environments, and at least initially helps to lower the incidence of cancer by preventing cells that are potentially at risk from continuing to replicate. Unfortunately senescent cells secrete a range of proteins that degrade surrounding tissue and encourage nearby cells to also become senescent. Given large enough numbers of senescent cells this activity leads to meaningful loss of function in important organs and contributes to the development of age-related disease.

In recent years researchers have demonstrated benefits to health and healthy life span resulting from selective clearance of senescent cells in mice, and removing senescent cells is one of the targets of the SENS rejuvenation research program. Here scientists link cellular senescence to mechanisms known to contribute to glaucoma, a form of blindness caused by raised fluid pressure inside the eye and resulting nerve damage:

The most common form of glaucoma, primary open angle glaucoma, is an aging associated disease often characterized by elevated intraocular pressure induced by increased outflow resistance of the aqueous humor. The human trabecular meshwork (HTM), a complex three-dimensional structure comprised of cells, interwoven collagen beams and perforated sheets, is believed to provide the majority of outflow resistance in both normal and glaucomatous eyes. HTM cells, depending on the region of the HTM, either form sheets covering extracellular matrix (ECM) structures or are scattered throughout the ECM. What changes in the HTM resulting in increased resistance is poorly understood, but our recent study showed the HTM is ~20 fold stiffer in glaucoma, suggesting a prominent role of HTM mechanobiology. This tissue-scale stiffening is likely a result of biophysical changes to both the ECM and constituent cells, as structural changes to both the cytoskeleton and ECM have long been associated with glaucoma.

Building upon these findings, further research has led to a growing body of evidence that these biophysical changes are not epiphenomena, but upstream of factors important in the progression of the disease. A prime candidate for this process is cellular senescence, the irreversible arrest of cellular proliferation. Senescence is thought to contribute to many of the physiological changes associated with aging as well as aging associated disease. In this study, primary HTM cells were serially passaged until senescence and atomic force microscopy (AFM) was used to measure the intrinsic mechanical properties of senescent cells compared to normally proliferating controls. We found that stiffness was significantly increased in high passage HTM cells. In aggregate, these data demonstrate that senescence may be a causal factor in HTM stiffening and contribute towards disease progression. These findings provide insight into the etiology of glaucoma and, more broadly, suggest a causal link between senescence and altered tissue biomechanics in aging-associated diseases.

Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=3798&path%5B%5D=8094

A Role for the Epicardium in Heart Regeneration
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For some years now researchers have been investigating the biochemistry of species such as salamanders and zebrafish that are capable of regrowing limbs and internal organs. It is as yet unknown how hard it will be to improve human regenerative capacity using what is learned from this research, but definitive answers may emerge over the next decade:

While the human heart can't heal itself, the zebrafish heart can easily replace cells lost by damage or disease. Now, researchers have discovered properties of a mysterious outer layer of the heart known as the epicardium that could help explain the fish's remarkable ability to regrow cardiac tissue. After an injury, the cells in the zebrafish epicardium dive into action - generating new cells to cover the wound, secreting chemicals that prompt muscle cells to grow and divide, and supporting the production of blood vessels to carry oxygen to new tissues.

Researchers found that when this critical layer of the heart is damaged, the whole repair process is delayed as the epicardium undergoes a round of self-healing before tending to the rest of the heart. "The best way to understand how an organ regenerates is to deconstruct it. So for the heart, the muscle usually gets all the attention because it seems to do all the work. But we also need to look at the other components and study how they respond to injury. Clearly, there is something special about the epicardium in zebrafish that makes it possible for them to regenerate so easily. The epicardium is underappreciated, but we think it is important because similar tissues wrap up most of our organs and line our organ cavities. Some people think of it as a stem cell because it can make more of its own, and can contribute all different cell types and factors when there is an injury. The truth is we know surprisingly little about this single layer of cells or how it works. It is a mystery."

The new research showed that the process requires signaling through a protein called sonic hedgehog, and demonstrated that adding this molecule to the surface of the heart can drive the epicardial response to injury. Researchers also found that the epicardium produces a molecule called neuregulin1 that makes heart muscle cells divide in response to injury. When they artificially boosted levels of neuregulin1, even without injury, the heart started building more and more muscle cells. The finding further underscores the role of this tissue in heart health. The researchers now plan to perform larger screens for molecules that could enhance heart repair in zebrafish, and perhaps one day provide a new treatment for humans with heart conditions.

Link: http://today.duke.edu/2015/05/heartlayer

Is Calcification of Tissue a Primary Form of Damage in Aging?
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The SENS model of aging, and the resulting research programs aimed at producing rejuvenation treatments, are predicated on identifying the forms of cellular and tissue damage that are the initial, primary cause of aging. This means damage that occurs directly as a result of the normal operation of healthy metabolism, and excludes damage that occurs as a secondary consequence of other forms of damage. There is arguably a far greater variety of secondary damage than primary damage, which is only to be expected given the complexity of living organisms. Simple damage in a complex system produces complex results. This is why SENS can be viewed as a shortcut to meaningful results in treating aging: it is focused on a narrow, fairly well understood, and simpler region of our biology. The hope is that in repairing the primary forms of damage, most of the secondary forms of damage will then be repaired by our own maintenance mechanisms.

You don't have to dive too far into the research literature to find grey areas and unknowns, however. There are a number of forms of damage that could be either primary or secondary harms, and finding out which is the case still lies somewhere in the future. If funding for SENS research was far greater than it is now, then it would make sense to open repair programs for all of the ambiguous forms of damage: err on the side of caution and fix everything. Since funding is still minimal, however, the most cost-effective path is to work on fixing the definitive forms of primary damage and then see how that affects other forms of damage and change that occur in aging.

Q: A lot of tissues, including notably the arteries, develop calcium deposits with age. Isn't this also an important kind of aging damage? Don't you need to develop a new rejuvenation biotechnology to remove it from our tissues?

A: To answer the question, we first need to disaggregate (no pun intended) the general category of "calcification." There are quite a few tissues that calcify to some degree in most or all aging people, and the reasons why this occurs and the nature of the structural disruption it causes are quite distinct depending on the tissue. In fact, even looking at just the arteries, there are several different kinds of "arterial calcification," including calcification connected with atherosclerotic plaque and calcification of the fibrils of elastin protein that loan the arteries their elasticity.

It's unlikely that all of these are true aging damage, but it's quite plausible that at least some of them are. The key question is whether each of these calcified deposits are really an intrinsically more or less irreversible change, or if like many other things that go wrong in aging they're sufficiently dependent on other, primary age-related changes that they would revert to the healthy norm if the original insult were resolved. In the former case, we would indeed need to develop rejuvenation biotechnologies to remove them. But it seems likely that some forms of age-related tissue calcification occur and are sustained by the effects of other forms of aging damage or the body's responses to them - things like oxidative stress caused by accumulation of cells that have been taken over by mutant mitochondria, or the inflammatory secretions of senescent cells. If calcification is driven and perpetuated by the effects of other, primary kinds of aging damage, then all we will really have to do is remove or repair the original aging damage, and the downstream calcification will resolve itself "for free" (or the body's natural repair and maintenance machinery will do it for us).

The more well-understood form of arterial calcification, for instance, is pretty clearly a secondary effect of local atherosclerotic lesions, and driven by inflammation. Once we clear the oxidized cholesterol products from atherosclerotic foam cells and allow them to egress, the body's wound-healing response will cease to play its perverse role in perpetuating and complicating the lesion but will instead begin resolving and repairing the damage wrought in the artery wall. Under those conditions, the calcium deposits may well simply dissolve, or resolve as local cells are no longer being pushed (as they often are in atherosclerotic lesions) into adopting behaviors that closer resemble those of bone-forming cells.

Ultimately, barring strong evidence coming in one way or the other, the best policy is to remain agnostic about such cases, and focus precious research investments on those therapies that target the clearly-identified, recalcitrant cellular and molecular damage of aging. Like many types of secondary damage, other forms of tissue calcification may similarly become a non-issue once we've taken care of the core damage driving degenerative aging. If this turns out to be the case, calcification-specific rejuvenation biotechnologies will not be necessary.

Link: http://sens.org/research/research-blog/question-month-10-rejuvenation-calcification-amelioration

A Trial of Stem Cell Treatment for Macular Degeneration
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Researchers here report on another trial of embryonic stem cells, with a focus on demonstrating safety and absence of side-effects. The study size of four individuals, each given the treatment in one eye only, is too small to take the positive results as a sign that the treatment is effective enough to take to the clinic. The outcome is encouraging nonetheless:

Since their discovery and isolation in 1998, human embryonic stem cells (hESCs) have been considered a potentially valuable tool for generating replacement cells for therapeutic purposes. However, despite success in numerous animal models, fears over tumorigenicity and immunogenicity, coupled with ethical concerns, and inefficiencies in differentiation methods have all contributed to delays in carrying out human clinical trials. Only one group has reported the results of the safety and possible biological activity of embryonic stem cell progeny in individuals with any disease, but these investigators only enrolled patients who were mostly Caucasian. Here, we confirmed the potential safety and efficacy of hESC-derived cells in Asian patients.

Loss of the retinal pigment epithelium (RPE) is an important part of the disease process in several retinal disorders, including age-related macular degeneration (AMD) and Stargardt macular dystrophy (SMD). Animal studies have shown that hESC-derived RPE cell transplantation can rescue photoreceptors, resulting in the improvement of visual functions in RPE-oriented retinal degeneration models. Clinical trials of hESC-derived RPE cell transplantation have begun recently in the United States and Europe. Herein, we report on four Asian patients with macular degeneration (two with AMD and two with SMD) who underwent subretinal transplantation of hESC-derived RPE and were followed for 1 year to assess safety and tolerability.

In the two dry-AMD patients, visual acuity in the treated eyes improved by one letter (stable at counting fingers at 4 ft) and nine letters (a two-line improvement from 20/320 to 20/200) at 52 weeks, respectively. In contrast, the fellow (untreated) eyes decreased by 6 and 20 letters, respectively, during the same time period. In the two SMD patients, visual acuity improved in the treated eyes by 12 letters (counting fingers at 2 ft to 20/640) and 19 letters (a four-line improvement from 20/640 to 20/250), respectively, compared with nine letters of improvement in the fellow eyes at 52 weeks compared to baseline. The visual acuity improvement noted in the fellow eyes of SMD patients may be due to poorer baseline visual acuity than in the fellow eyes of the dry AMD patients. A 15-letter improvement (a doubling of the visual angle) is generally accepted as a clinically significant change.

Link: http://dx.doi.org/10.1016/j.stemcr.2015.04.005

Investigating Factors Relating to Survival After Age 50
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A fifty-year longitudinal study of human aging is wrapping up, and the results, as is usually the case, point to the importance of lifestyle choices in determining natural variations in human longevity. It also reinforces the point that you can't use good lifestyle choices to guarantee a path to an exceptional life span: the majority of people with the best lifestyles are still dead in their 80s, even though they on average do far better than their peers, with a lower level of pain and disease. The only way to reliably live far longer in good health is through progress in medical science, for the research community to produce rejuvenation therapies capable of repairing the cell and tissue damage that causes aging. The degree to which we all help to ensure those therapies are developed in time is the greatest determinant of our future health and longevity.

For the past 50 years, researchers have followed the health of 855 Gothenburg men born in 1913. Now that the study is being wrapped up, it turns out that ten of the subjects lived to 100 and conclusions can be drawn about the secrets of their longevity. Various surveys at the age of 54, 60, 65, 75, 80 and 100 permitted the researchers to consider the factors that appear to promote longevity. A total of 27% (232) of the original group lived to the age of 80 and 13% (111) to 90. All in all, 1.1% of the subjects made it to their 100th birthday. According to the study, 42% of deaths after the age of 80 were due to cardiovascular disease, 20% to infectious diseases, 8% to stroke, 8% to cancer, 6% to pneumonia and 16% to other causes. A total of 23% of the over-80 group were diagnosed with some type of dementia.

"The unique design has enabled us to identify the factors that influence survival after the age of 50. Our recommendation for people who aspire to centenarianism is to refrain from smoking, maintain healthy cholesterol levels and confine themselves to four cups of coffee a day." It also helps if you paid a high rent for a flat or owing a house at age 50 (indicating good socioeconomic standard), enjoy robust working capacity at a bicycle test when you are 54 and have a mother who lived for a long time. "Our findings that there is a correlation with maternal but not paternal longevity are fully consistent with a previous studies. Given that the same associations have been demonstrated in Hawaii, the genetic factor appears to be a strong one." But still we found that this "genetic factor" was weaker than the other factors. So factors that can be influenced are important for a long life.

Link: http://sahlgrenska.gu.se/english/research/news-article/lifestyle-advice-for-would-be-centenarians.cid1285361

The Dog Aging Project
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A group of researchers are advocating for clinical trials in household dogs to test methods of gently slowing aging that so far are largely studied in mice only. The high level goal here is to produce more rigorous data in longer-lived mammals, something that is presently lacking. If as a side-effect it helps to raise awareness of the potential to extend healthy human life spans through progress in medical science, then all to the good. At this point the researchers have turned in part to the public and philanthropy to raise funds for the project, and are going about it in a fairly organized way. It is good to see the scientific community developing these skills, as this form of fundraising coupled with greater involvement of donors will become increasingly important in the future:

For millions of people, pets are considered part of the family. Unfortunately, companion animals such as dogs age rapidly and have relatively short life expectancies. Scientists want to change this. Research in the biology of aging has made tremendous strides over the past several years, with a few interventions found capable of slowing aging and extending lifespan in small mammals such as mice and rats. These same interventions could provide dogs with two to five or even more years of additional healthy, youthful life.

The Dog Aging Project is a unique opportunity to advance scientific discovery while simultaneously providing enormous benefit for people and their pets. We believe that enhancing the longevity and healthspan - the healthy period of life - in peoples' pets will have a major impact on our lives. To accomplish this goal, we are creating a network of pet owners, veterinarians, and scientific partners that will facilitate enrolling and monitoring pets in the Project. The Dog Aging Project has two major aims: a longitudinal study of aging in dogs and an intervention trial to prevent disease and extend healthy longevity in middle-aged dogs.

The first phase of this study will enroll middle-aged dogs (6-9 years depending on breed) in a short-term (3-6 month), low-dose rapamycin regimen and follow age-related parameters such as heart function, immune function, activity, body weight, and cognitive measures. These animals will then be followed throughout life to determine whether there are significant improvements in healthy aging and lifespan. The next phase of the study will enroll a second cohort of middle-aged dogs into a longer-term, low-dose rapamycin regimen designed to optimize lifespan extension. As with phase one, several age-related parameters will be assessed before, during, and after the treatment period. Based on the mouse studies, we anticipate that rapamycin could increase healthy lifespan of middle-aged dogs by 2-5 years or more.

We believe that improving healthy lifespan in pet dogs is a worthy goal in and of itself. To be clear, our goal is to extend the period of life in which dogs are healthy, not prolong the already difficult older years. Imagine what you could do with an additional two to five years with your beloved pet in the prime of his or her life. This is within our reach today, with your help.

Link: http://dogagingproject.com/

Visceral Fat Correlates With Brain Tissue Damage
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Building and maintaining excess fat tissue, specifically the visceral fat clustered around internal organs, harms long-term health in numerous ways. It raises the risk of suffering from all of the most common age-related medical conditions, and raises lifetime medical expenditures even while lowering life expectancy. A primary mechanism here is thought to be greater levels of chronic inflammation spurred by this fat tissue, but visceral fat is metabolically active and prompts a wide range of changes throughout an individual's body. One of the end results is a greater level of physical damage to brain tissue over time, largely a result of breakage and failure in tiny blood vessels:

Obesity has been associated with microstructural brain tissue damage. Different fat compartments demonstrate different metabolic and endocrine behaviors. The aim was to investigate the individual associations between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) and microstructural integrity in the brain. This study comprised 243 subjects aged 65.4 ± 6.7 years. The associations between abdominal VAT and SAT, assessed by CT, and magnetization transfer imaging markers of brain microstructure for gray and white matter were analyzed and adjusted for confounding factors.

Our data indicate that increasing visceral adipose tissue rather than subcutaneous adipose tissue is associated with microstructural brain tissue damage in elderly individuals. This association cannot be accounted for by BMI, which is an easily obtainable clinical measure of obesity but does not discriminate different fat compartments. Awareness of differences in the underlying mechanisms between body fat patterns and brain damage may offer more focused individual advice or treatment than considering BMI only. Further research in a general population with a wider age range is necessary to study whether the relationship between visceral adiposity and microstructural brain tissue damage is merely a result of ageing, or exists independently of age. Furthermore, cognition tests could be of additional value for evaluating the clinical consequences of these findings.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1002/oby.21048/

Predicted Future Life Expectancy Continues to Increase
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Predicting human life expectancy in the decades ahead is a big business, as the vast pension and life insurance industries rely upon these forecasts. If the forecasts are dramatically wrong, and they will be just as soon as any significant advances in rejuvenation biotechnology reach the clinic, then financial upheaval lies ahead for all of the counterparties, insurers, and governments who bet against larger than expected increases in human life. The actuarial profession pays attention to the state of medical research aimed at intervention in the aging process, and the more mainstream treatment of age-related disease, and their estimates of life expectancy at a given future date have been rising in past years. This is the most recent example of this process at work:

A new study forecasting how life expectancy will change in England and Wales has predicted people will live longer than current estimates. The researchers say official forecasts underestimate how long people will live in the future, and therefore don't adequately anticipate the need for additional investments in health and social services and pensions for the elderly. Researchers developed statistical models using death records, including data on age, sex, and postcode, from 1981 to 2012 to forecast life expectancy at birth for 375 districts in England and Wales. They predict that life expectancy nationally will increase for men from 79.5 years in 2012 to 85.7 in 2030, and for women from 83.3 in 2012 to 87.6 in 2030. The longevity gap between men and women has been closing for nearly half a century and will continue to get narrower. The forecasts for 2030 are higher than those by the Office of National Statistics, by 2.4 years for men and 1.0 year for women.

People living in the longest-living areas in 2012 - found in southern England and well-off parts of London - are expected to live seven or eight years longer than those in parts of urban northern England, such as Blackpool, Liverpool and Manchester, and South Wales - equivalent to the difference in national life expectancy between the UK and Sri Lanka or Vietnam. By 2030, the gap is projected to grow to more than eight years. "The bigger gains in life expectancy we predict will mean pensions will have larger payouts, and health and social services will have to serve an older population than currently planned. We also forecast rising inequalities, with bigger increases in lifespan for people in affluent areas than those in disadvantaged areas. This means wealthy people will benefit more from health and social services than poor people, and therefore should be prepared to pay its costs through higher taxes."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=152147&CultureCode=en

Calico Life Sciences Partners with the Buck Institute for Research on Aging
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This sort of notice should be expected given that the leadership at Google's Calico venture shows all the signs of intending to set up a very broad research infrastructure for the development of drugs to modestly slow aging. Sooner or later they are going to partner with all of the major laboratories and research groups in the field that share the same interests. This latest news is missing any interesting details on which technologies they might be interested in, but that is par for the course. I point it out to play the connections game in this small research community, noting that the SENS Research Foundation also partners with the Buck Institute on, for example, senescent cell clearance research. Near everything else the Institute does is of little relevance to the SENS approach to development of rejuvenation biotechnology, however - it is more in line with the mainstream approach of manipulation of the operation of metabolism so as to slow aging. This is slowing the accumulation of damage, not trying to repair that damage, and will probably be more challenging and produce far less impressive results.

The future for SENS-like rejuvenation therapies such as senescent cell clearance is to step by step take over the mainstream by consistently producing much better results at much lower costs at each stage of the early development process. So far this is the way things are going for senescent cell clearance, but there are a lot of other technologies making up the rejuvenation toolkit of the future that remain far from that stage of progress.

The Buck Institute for Research on Aging in Novato announced Tuesday that it has entered into a partnership agreement with Calico Life Sciences, a Google-backed life extension company based in South San Francisco. Chris Stewart, chairman and CEO of the North Bay Life Science Alliance, an effort to develop the North Bay into an economic hub for life-science companies, said, "We're very excited. You're seeing for the first time a significant amount of private sector money going into research on aging. I think it is a good marriage between the two organizations."

In September 2014, Calico announced it had entered into a five-year joint venture with AbbVie, a Chicago-based pharmaceutical company, to develop treatments for cancer and Alzheimer's. Both Calico and AbbVie committed to investing $250 million initially with the option to each add another $500 million at an unspecified later date. Since then, Calico has entered into partnership agreements with five different research laboratories, including the Buck Institute, but it has kept the financial terms of those agreements and most other details secret. Stewart said more and more pharmaceutical companies are "outsourcing their research and development by going to universities or institutes like the Buck Institute and partnering with them. Rather than buying companies, Calico is doing some strategic partnerships."

Announcing the deal with the Buck Institute, Calico's president of research and development, Hal Barron, said in a press release, "Given the Buck's exclusive focus on aging, we believe that there's great potential to increase our understanding of the biology of aging and to accelerate the translation of emerging insights into therapies to help patients with age-related diseases." Aside from that, Calico declined all comment. The only details supplied in the press release were that Calico will have the option to obtain exclusive rights to discoveries made under research it supports at the Buck Institute and will establish and maintain "certain" science operations there. One possible reason for Calico's reticence is that it hasn't decided on what areas of age-related illness it wants to focus, and it doesn't want to tip its hand to competitors.

Link: http://www.marinij.com/general-news/20150428/buck-institute-in-novato-partners-with-google-entity-to-search-for-biotech-fountain-of-youth

Biocompatible Artificial Blood Vessels Guide Regrowth
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Researchers have demonstrated a new method of implanting artificial blood vessel structures to guide regrowth of tissue, leading to regeneration of a functional biological blood vessel:

Blocked blood vessels can quickly become dangerous. It is often necessary to replace a blood vessel - either by another vessel taken from the body or even by artificial vascular prostheses. Researchers have developed artificial blood vessels made from a special elastomer material, which has excellent mechanical properties. Over time, these artificial blood vessels are replaced by endogenous material. At the end of this restorative process, a natural, fully functional vessel is once again in place. The most important thing is to find a suitable material. The artificial materials that have been used so far are not ideally compatible with body tissue. The blood vessel can easily become blocked, especially if it is only small in diameter. Researchers have therefore developed new polymers. "These are so-called thermoplastic polyurethanes. By selecting very specific molecular building blocks we have succeeded in synthesizing a polymer with the desired properties."

To produce the vascular prostheses, polymer solutions were spun in an electrical field to form very fine threads and wound onto a spool. The wall of these artificial blood vessels is very similar to that of natural ones. The polymer fabric is slightly porous and so, initially, allows a small amount of blood to permeate through and this enriches the wall with growth factors. This encourages the migration of endogenous cells. The new method has already proved very successful in experiments with rats. "The rats' blood vessels were examined six months after insertion of the vascular prostheses. We did not find any aneurysms, thromboses or inflammation. Endogenous cells had colonized the vascular prostheses and turned the artificial constructs into natural body tissue." In fact, natural body tissue re-grew much faster than expected so that the degradation period of the plastic tubes can be made even shorter.

Link: http://www.meduniwien.ac.at/homepage/1/news-and-topstories/?tx_ttnews%5Btt_news%5D=5625