Fight Aging! Newsletter, November 9th 2015

November 9th 2015

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in 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 medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Fight Aging! Matching Fundraiser Update: A Third of the Way
  • An Approach to Solving the Blood Vessel Problem in the Tissue Engineering of Organs
  • Considering Longevity Annuities
  • Changes in Regeneration Across a Lifespan in Various Species
  • The Relevance of SEC Changes to Crowdfunding Rules
  • Latest Headlines from Fight Aging!
    • Investigating the Role of GDF-10 in Brain Regeneration
    • An Attempt to Quantify the Degree to Which Alzheimer's is a Lifestyle Disease
    • Janus Kinases as a Target to Reduce Chronic Inflammation
    • On the Role of α-synuclein in Parkinson's Disease
    • Arterial Stiffening Correlates with Raised Calcium Levels
    • Proposing Alzheimer's to be Several Distinct Conditions
    • A Caution on Muscle Stem Cells
    • Raised SIGIRR Levels May Mediate Reduced Chronic Inflammation via Calorie Restriction
    • New Sterols Clear Amyloid Protein Aggregates in Cataracts
    • Brain Connectivity and Fitness in Older Adults


The Fight Aging! matching fundraiser launched a month ago, and is now a third of the way to success: more than 57,000 of the 125,000 goal has been donated, and until the end of the year every further donation is matched from the matching fund provided by a few generous philanthropists. All of these charitable donations go towards supporting and expanding the ongoing rejuvenation research programs coordinated by the SENS Research Foundation. This work, carried out collaboration with renowned laboratories in the US and Europe, aims to bring aging under medical control by repairing its root causes, the forms of cell and tissue damage that occur as a side-effect of the normal operation of metabolism, and which accumulate with age to cause disease and dysfunction.

The SENS Research Foundation has had a banner year in terms of progress towards the goal of bringing the causes of aging under medical control, as noted in the 2015 annual report: seed funding the US startup Oisin Biotechnology to work on senescent cell clearance; transferring lysosomal aggregate clearance technology to Human Rejuvenation Technologies for development; the French company Gensight is now devoting significant funding to to clinical development of the mitochondrial repair technologies whose early stage research was supported under the SENS banner; progress towards the toolkit needed for glucosepane cross-link clearance was published in the prestigious journal Science; a second Rejuvenation Biotechnology conference continued the work of bringing industry and academia together to smooth the path for future development in this field; a crowdfunding initiative brought in hundreds of donors and tens of thousands in donations for mitochondrial repair research. The efforts of past years, funded in part by everyday philanthropists just like you and I, alongside people like Peter Thiel, Jason Hope, and Aubrey de Grey, are bearing fruit. Everyone who donated in the past should be feeling pretty good about the foundations of new medicine that they have helped to build right around now. The wheel is turning, the avalanche begun.

The future is still to be constructed, however. Science is a slow business, and the breakthrough progress towards therapies for aging that will occur in the first years of the 2020s must be funded in its earliest stages today if it is ever to see the light of day. The SENS programs, and the staff and allies of the SENS Research Foundation, are collectively a proven vehicle for getting this job done; they are picking the right laboratories, programs, and lines of research to back in order to produce meaningful results. We have 68,000 left to raise in the 2015 Fight Aging! fundraiser, every donation matched by philanthropists who put up the Fight Aging! fund, and all donations used well to create progress in this vital field of medicine. We have two months to do it in, the deadline being the end of the year. Help us to hit this target!


Blood vessels are very important, and so it is always worth paying attention to progress such as that noted below, research that inches closer to the goal of being able to grow suitable blood vessel networks to supply large sections of engineered tissue. It is no great exaggeration to say that the shape and progress of the field of tissue engineering is determined by the thorny issue of building blood vessels - or rather the inability to build blood vessels. Cells must be continually supplied with nutrients and oxygen, and in anything larger than a thin slice of tissue this must be accomplished by an intricate web of tiny blood vessels, in turn joined to larger blood vessels, and which would be connected into the circulatory system if transplanted into a living individual.

Unfortunately it is still a little beyond the present state of the art to construct a blood vessel network that is up to the job of supplying a complete organ - though things are certainly moving closer to that goal in some labs. Larger individual blood vessels can be made in a variety of ways, such as by bioprinting a layered sheet and rolling it up, but building a spreading tree of hundreds or thousands of branching tiny vessels is still a problem in search of a robust solution. This is perhaps the biggest reason why the development of decellularization has seen such support among organ engineers: it bypasses the issue by using a donor organ with the cells stripped from it to provide the extracellular matrix scaffold complete with blood vessel structures. Its chemical cues can guide new, patient-matched cells to repopulate the organ and recreate all of its necessary blood vessels. Other applications of tissue engineering carried out so far have largely been limited to thin structures that can be nurtured without blood vessels, and which are quickly populated by new blood vessels when grafted.

Now that researchers are at the point of actually constructing complex, functional organ tissues from a small sample of patient-derived cells, it is becoming even more pressing to find a practical solution to the blood vessel network issue. If you have wondered why cutting edge tissue engineering has focused on the production of small tissue sections for use in research and testing, the creation of what are called organoids, accomplished for neural tissue, kidneys, livers, the thymus, and so forth, then let me tell you that the challenge of blood vessel network creation is a big part of the answer.

So here we have an interesting approach, which should probably be considered in the context that not all engineered organs don't actually have to look like their corresponding evolved organs. They just have to work. In some cases form follows function, so researchers are very constrained, but for chemical factories and filters like kidneys, livers, the pancreas, and so forth, the situation is different. If the engineered organ is a strange and unsightly collection of lumps assembled specifically to make the blood vessel problem more tractable, but still carries out its necessary jobs because it has all the right cells doing all the right things, then it is a viable candidate for transplantation.

Researchers create implant with network of blood vessels

Using sugar, silicone and a 3-D printer, a team of bioengineers and surgeons have created an implant with an intricate network of blood vessels that points toward a future of growing replacement tissues and organs for transplantation. The research may provide a method to overcome one of the biggest challenges in regenerative medicine: How to deliver oxygen and nutrients to all cells in an artificial organ or tissue implant that takes days or weeks to grow in the lab prior to surgery. The study showed that blood flowed normally through test constructs that were surgically connected to native blood vessels.

One of the hurdles of engineering large artificial tissues, such as livers or kidneys, is keeping the cells inside them alive. Tissue engineers have typically relied on the body's own ability to grow blood vessels - for example, by implanting engineered tissue scaffolds inside the body and waiting for blood vessels from nearby tissues to spread to the engineered constructs. That process can take weeks, and cells deep inside the constructs often starve or die from lack of oxygen before they're reached by the slow-approaching blood vessels.

Using an open-source 3-D printer that lays down individual filaments of sugar glass one layer at a time, the researchers printed a lattice of would-be blood vessels. Once the sugar hardened, they placed it in a mold and poured in silicone gel. After the gel cured, the team dissolved the sugar, leaving behind a network of small channels in the silicone. Collaborating surgeons connected the inlet and outlet of the engineered gel to a major artery in a small animal model. The team observed and measured blood flow through the construct and found that it withstood physiologic pressures and remained open and unobstructed for up to three hours. "This study provides a first step toward developing a transplant model for tissue engineering where the surgeon can directly connect arteries to an engineered tissue. In the future we aim to utilize a biodegradable material that also contains live cells next to these perfusable vessels for direct transplantation and monitoring long term."

In vivo anastomosis and perfusion of a 3D printed construct containing microchannel networks

The field of tissue engineering has advanced the development of increasingly biocompatible materials to mimic the extracellular matrix of vascularized tissue. However, a majority of studies instead rely on a multi-day inosculation between engineered vessels and host vasculature, rather than the direct connection of engineered microvascular networks with host vasculature. We have previously demonstrated that the rapid casting of 3D printed sacrificial carbohydrate glass is an expeditious and reliable method of creating scaffolds with 3D microvessel networks. Here, we describe a new surgical technique to directly connect host femoral arteries to patterned microvessel networks. Vessel networks were connected in vivo in a rat femoral artery graft model. We utilized laser Doppler imaging to monitor hind limb ischemia for several hours after implantation and thus measured the vascular patency of implants that were anastomosed to the femoral artery. This study may provide a method to overcome the challenge of rapid oxygen and nutrient delivery to engineered vascularized tissues implanted in vivo.


Conservative models for the next few decades of human life spans in the wealthier regions of the world, those used by insurance industry giants to create their products, predict only a gentle continuation of present trends towards greater life expectancy. These gains clock in at the moment at 2.5 years every decade for life expectancy at birth and one year every decade for adult life expectancy. The actuarial community has for the past decade increasingly hedged its models with pronouncements of uncertainty, which is eminently sensible in an age of accelerating progress in biotechnology. Still, despite this, the financial industry is comfortable offering a class of products varying called longevity insurance, longevity annuities, deferred income annuities, life annuities, or a variety of other terms: pay the company a lump sum now, and starting at some point in the future you are paid a regular income until you die. As for any such transactions, the company makes money on this proposition by correctly predicting demographics such that, on average, it pays out less than it can make with the lump sum.

A secure retirement, no matter how long you live

Longevity annuities have actually been around in various forms for a decade or more. They've been getting a lot more attention lately, however, because the U.S. Treasury Department issued rules last year that make it easier and more attractive to buy a certain type of longevity annuity within retirement accounts such as 401(k)s and IRAs.

Essentially, a longevity annuity is a twist on a somewhat more familiar type of annuity, the immediate annuity. With an immediate annuity, you hand over a sum of money to an insurer in return for guaranteed monthly payments that start at once and continue for the rest of your life. (You can also opt for payments to continue as long as either you or your spouse or partner is alive.)

Like an immediate annuity, a longevity annuity provides guaranteed income for life, except that while you invest your money now, the payments don't begin until later, typically much later, say, 10 to 20 years in the future. In effect, buying a longevity annuity is a bit like buying a life insurance policy, but instead of making a payment to your heirs when you die, a longevity annuity makes monthly payouts to you for the rest of your life, assuming you're still alive when those payments are scheduled to begin.

Now in the world of yesterday, in which there was only a little uncertainty in the possibly unexpected upside of life expectancy, this is all fine and well. Some people want the assurance that they will not run out of money in later retirement, and judge the direct and opportunity costs of setting up a longevity insurance policy to be worth it for the end result of peace of mind. Fortunately we no longer live in that world. We live in a world in which there is a good chance that a range of rejuvenation therapies after the SENS model will start arriving for early adopters - people willing to dive into medical tourism - from five to twenty years from now, depending on circumstances. Interestingly, however, those of us reading this now are in a small minority in buying into this vision of the future. Very few people follow medical research closely, and comparatively few people think that the future of aging will be radically different from aging today.

This arguably presents an opportunity to profit from being in the know. As I put it some years ago, take the money and run: sign a longevity insurance policy with a large company, making sure that the fine print doesn't sabotage the plan, and then strive not to die from any accidental cause as we enter the age in which medical control over the causes of aging becomes possible. In making use of future rejuvenation therapies, your healthy longevity will likely prove to be significantly greater than that predicted by the current actuarial consensus. However, it is worth remembering that adherence to contracts over the long term is for people who can't afford to buy the political process:

It would seem to be the case that either:

a) enough people die at younger ages than you that the offering company makes money and stays in business. In other words, healthy life extension research did not succeed rapidly enough to help you either - you will age, suffer and die.

b) healthy life extension takes off and the insurer is left with a huge liability, which may or may not actually be paid. That depends on how well the insurer handled the funds, the level of economic growth across the years, and the level of interest in the original product, amongst other items. Bribing politicians to write new law to remove obligations is a very predictable out, however.

c) the product is of poor enough value that the company can offer it even though healthy life extension research succeeds - in which case you would likely have been better off placing your funds elsewhere.

So in addition to betting that the company you sign with remains solvent for long enough to make it worthwhile, you are also betting that the losses from longevity insurance caused by large gains in life expectancy across most of the population will not otherwise sink the industry. There is no free lunch, and it seems likely that creating an exceptionally good deal for yourself that lasts decades or longer is only possible when few other people also think they can get a free lunch from longevity insurance and act accordingly.


Here I'll point out an open access review paper that looks over what is known of regenerative capacity and aging in a variety of species in which individuals have quite different trajectories of health and degeneration over a life span. A whole section of the research community is very interested in cataloging the processes of aging as they occur in other species: the comparative biology of aging. Near all species age in the sense of suffering growing damage, degeneration, and frailty as we do, but life spans can be wildly different even in very similar species. A factor of ten difference in life span between near relatives is not unknown; consider the three years of ordinary laboratory rats versus the thirty years of naked mole rats, for example.

Within the context of a given life span, the panoply of well-known species exhibit enormous differences in susceptibility to specific forms of disease and dysfunction. Some species of whale can live for centuries, have many times as many cells as we humans, and yet experience similar or lower rates of cancer than we do over our shorter life spans. Rats and mice are little cancer factories, but naked mole rats seem entirely immune to cancer. They are further considered one of the negligibly senescent species, a list that includes rockfish, turtles, possibly lobsters, and a number of lower organisms such as hydra that might even be entirely ageless in a suitably forgiving environment. Individuals of these negligibly senescent species typically show next to none of the familiar progressive decline of aging until the very end of their lives.

Moving on to consider the matter of regeneration from injury alone, a number of species with the capacity to regrow organs without scarring, such as salamanders and zebrafish, also exhibit little or no reduction in regenerative capabilities over the course of a lifetime. Hydra feature here again as paragons of always-on regeneration, capable of regrowing and replacing any part of their structure if given the chance to do it. It is fair to say that there is a suspiciously good correlation between negligible senescence and greater regeneration when surveying the animal kingdom.

Some research groups aim to go beyond observation in order to mine the biology of these unusually regenerative, long-lived, and cancer-resistant species. They are in search of the basis for potential therapies, ways to port over these varied benefits to the less capable and more vulnerable human biology. It is an open question as to whether or not it will be practical to do this in the near future in any particular case. It depends absolutely on the details, and those have yet to be fully deciphered, even for salamander regeneration, which has been studied with the tools of modern biotechnology for many years now.

Changes in Regenerative Capacity through Lifespan

From the onset of development until the end of their lifespan, most organisms experience a progressive decline in their regenerative abilities. From a biological perspective, regeneration can be subdivided into the ability to replace lost or damaged cells, which includes tissue turnover and limited injury responses found in the majority of organisms including mammals, and the ability to regenerate complex structures, which is mostly absent in mammals but finds expression in a number of other animals. During aging, mammals exhibit changes in their ability to regenerate vital biological structures such as the vascular, nervous, muscular, haematopoietic and skeletal systems as well as many organs and cell types, which correlate with the overall organismal decay.

Although metazoan species exhibit a diverse range of lifespans, it is notable that in most organisms studied so far there is a strong association between the decline in regenerative capacity and the aging process. Indeed, it has been proposed that aging results from the inability to maintain proper tissue structure and function due to insufficiencies in regenerative capacity. Hence, regeneration and aging could represent two sides of the same coin. This idea is supported by the existence of organisms with extreme regenerative capacities, such as planarians and salamanders, which exhibit negligible signs of aging, as indicated by the lack of measurable functional declines with age.

The principles that underlie the decline in regenerative abilities through lifespan are currently being unravelled. However, it is already clear that both cell-intrinsic (such as cellular senescence) as well as cell-extrinsic factors (such as alterations in the regenerative environment) play significant roles. Notably, these factors show extensive overlap with those known to underlie the aging process, highlighting the interconnection between aging and regeneration and stressing that therapeutic approaches designed towards enhancement of regenerative abilities could also result in considerable health/lifespan improvements.

This review discusses the nature of the changes in regenerative abilities that take place through lifespan and across phylogeny, the factors which underpin such changes and the avenues for therapeutic interventions which leverage off this body of research. A particular emphasis is placed on knowledge derived from the classic regeneration models, organisms capable of extensive regeneration of complex structures in which age related declines in regenerative abilities are not observed, as this can shed light on important mechanisms with potential therapeutic application. It is becoming increasingly clear that certain factors, such as cellular senescence, constitute common denominators which impact on various regenerative systems and thus hold great promise for clinical intervention. However, despite the progress made so far, it is also evident that we are far from reaching a full understanding of the interplay between regenerative capacity and aging. Further research will benefit from studies in both vertebrate and invertebrate models of age-related regenerative decline, as well as from work in organisms where these capacities are not affected by aging, such as salamanders. Together, these approaches will deliver important insights into the variations of regenerative capacity through lifespan.


Crowdfunding of scientific research is a matter of great interest to our community. We want to see more rapid funding of the foundation technologies needed for rejuvenation therapies, treatments capable of repairing the causes of degenerative aging, a field in which most of the early stage nuts and bolts are clearly envisaged but still have to be built. Here at Fight Aging!, we're raising funds for SENS rejuvenation research programs right now, in fact, matching charitable donations until the end of the year.

This sort of comparatively cheap, early stage, high risk science is normally funded by some combination of philanthropy and outright creative accounting when it comes to tracking grant expenditures. Donors are pitched on a regular basis, and a little kept back from every grant to fund unrelated explorations. For the most part what the average fellow in the street would call scientific funding, of the sort provided by large companies and government agencies, is in fact development funding. The real scientific discovery and the greatest risk of failure happens prior to the arrival of funds granted by these institutional sources: they have little interest in underwriting that initial stage of the process, and want to see proven mechanisms, complete understanding, and a clear plan on how to proceed before becoming involved. So it isn't unfair to suggest that the pace of progress in our modern society is actually governed by how much philanthropic support there is for true early stage research.

Back to crowdfunding. That is how people like you and I, who have woken up and realized that rejuvenation therapies are a near-future possibility provided that the necessary early stage work is supported, can collaborate to raise the profile and speed the progress of this work. We lead the pack, we hold up a lantern, we start things moving, and all of this effort is a way to draw in much larger dononations from a few institutions or individuals who ultimately donate a majority of the funding. Behind every successful scientific project there is a power law distribution of funds, but those high net worth individuals who can donate large sums of money to charitable causes such as research are typically highly conservative and risk averse. They are only willing to reinforce success, they only step in when they see strong and growing grassroots support, and the larger the donation the more this is the case.

There are other ways in which this process of growing a crowd to draw in large-scale funding can play out, and we've seen the makings of some of them in for-profit Kickstarter-style crowdfunding. Here crowdfunding can act somewhat like a voting and preorder infrastructure, and when conducted well it allows startup companies to quickly show proof of viability, making it much easier obtain venture funding and move ahead on that basis. These transactions from the crowd are not investments, however: they are still just purchases. The shape of this situation is changing right now, however. The SEC, the US body that claims regulatory jurisdiction over investment in startups, is moving to allow crowdfunding of investment in young companies. This is probably a thing that you were not aware was forbidden to you, not being a member of that modestly privileged set of people having both the money and the interest in becoming an angel investor. Shortly, however, there will be an ecosystem in which tens of thousands of people buy tiny slices of young companies, most of which will evaporate, in the same way as they presently vote with their wallets at Kickstarter.

A majority of the resulting fun and games will be irrelevant to the goals of this community vis a vis funding scientific research and clinical applications of that research. Certainly there will be all sorts of adverse selection effects and gnashing of teeth on the part of the venture community interested in keeping more of a hold over funding opportunities. It does, however, open some doors for us, creating a few new possibilities for collaborative fundraising. As you'll know if you've been following Fight Aging! for a while, the Methuselah Foundation has used charitable donations to seed fund startups here and there for some years; one of them was Organovo, and another, Oisin Biotech, is presently working on senescent cell clearance, one of the most likely SENS therapies to come to fruition in the near future. Good opportunities for seed stage investment in clinical development of first generation rejuvenation therapies, to my eyes meaning SENS technologies and some cancer and regenerative medicine projects, are still pretty thin on the ground at this point. You have to know a lot of the right people and know the field very well to even know that these opportunities exist. That will change in the next few years.

It is important to note that early stage research in the laboratory, of the sort we're funding with charitable donations today, overlaps with early stage clinical development of the sort carried out by Oisin Biotech. There is no clear dividing line between the two, and in many cases whether the work takes place in a non-profit or for-profit environment is simple happenstance, a matter of the inclinations and connections of those involved. So were there an opportunity to crowdfund work that takes place in a startup company, where participants were treated as seed investors, I'd support that goal if the science and development looked like an opportunity to move closer to rejuvenation therapies. I see little practical difference between this and charitable funding: one has a small shot at a profit some years ahead, the other has a present tax deduction. But in both cases, these are ways for people of modest means to collaborate and speak out in large numbers, to make the case to wealthier investors or donors to participate, to vote the opinion that a cause or a company or a line of research is viable and worthy of support. At the moment we are only talking to the donors, the philanthropists interested in funding research. The much larger community of wealthy investors are focused elsewhere, but gaining their attention as described above seems a very viable project.

In the years ahead, this will happen, I think. We'll see the arrangement of crowdfunded investment as a way to raise the profile of specific startups, and to pull in seed funding for their initial scientific development. We will support such ventures when we think they can carry out important steps forward in the finalization and clinical translation of research if all goes well. The need for networking and transparency and connections and insider advisers who can tell good from bad will never go away, but the door is opening for greater community participation and coordination in more of the development process. We will be able to reach out to and persuade new sources of for-profit funding, which are generally much larger than those provided by the non-profit philanthropic community. But ultimately the crowdfunding of rejuvenation research startups will not look all that different from the crowdfunding of rejuvenation research laboratory programs when it comes to the basics of persuasion, fundraising, and the end goals of getting things done. I am looking forward to seeing how it all shakes out.


Monday, November 2, 2015

Following a stroke, the survivors exhibit varying degrees of limited regeneration in the brain. Researchers are interested in finding reliable ways to enhance that process. Beyond the context of recovering from such injuries, it is important in the development of treatments for aging to be able to spur greater ongoing growth and regeneration in the aging brain:

Looking at brain tissue from mice, monkeys and humans, scientists have found that a molecule known as growth and differentiation factor 10 (GDF10) is a key player in repair mechanisms, such as axonal sprouting, that are activated following stroke. During axonal sprouting, healthy neurons send out new projections ("sprouts") that re-establish some of the connections lost or damaged during the stroke and form new ones, resulting in partial recovery. Before this study, it was unknown what triggered axonal sprouting. Previous studies suggested that GDF10 was involved in the early stages of axonal sprouting, but its exact role in the process was unclear. Examining animal models of stroke as well as human autopsy tissue, researchers found that GDF10 was activated very early after stroke. Then, using rodent and human neurons in a dish, the researchers tested the effect of GDF10 on the length of axons, the neuronal projections that carry messages between brain cells. They discovered that GDF10 stimulated axonal growth and increased the length of the axons.

Researchers treated mouse models of stroke with GDF10 and had the animals perform various motor tasks to test recovery. The results suggested that increasing levels of GDF10 were associated with significantly faster recovery after stroke. When the researchers blocked GDF10, the animals did not perform as well on the motor tasks, suggesting the repair mechanisms were impaired - and that the natural levels of GDF10 in the brain represent a signal for recovery. It has been widely believed that mechanisms of brain repair are similar to those that occur during development. The team conducted comprehensive analyses to compare the effects of GDF10 on genes related to stroke repair with genes involved in development and learning and memory, processes that result in connections forming between neurons. Surprisingly, there was little similarity. The findings revealed that GDF10 affected entirely different genes following stroke than those involved in development or learning and memory. "We found that regeneration is a unique program in the brain that occurs after injury. It is not simply Development 2.0, using the same mechanisms that take place when the nervous system is forming."

Monday, November 2, 2015

To what degree is Alzheimer's disease a consequence of poor lifestyle choices such as being sedentary and overweight, as is largely the case for type 2 diabetes, versus a consequence of the unavoidable accumulation of cell and tissue damage that causes degenerative aging? Researchers here run the numbers to obtain a partial answer. You'll note a couple of interesting associations such as with low body mass index (BMI) in later life, as considerable loss of weight in old age is usually a sign of systematic health issues, and the fact that people with cancer tend not to get Alzheimer's, an phenomenon noted in recent years, but which as of yet has no full explanation.

Age-standardized prevalence of Alzheimer's disease (AD) for those aged ≥60 years varied in a narrow band, 5-7% in most world regions. AD accounts for approximately 60% of dementia incidence. Over the past 100+ years, researchers have never stopped to investigate the pathogenic mechanisms, prevention and therapy for AD. However, we had currently no effective drugs for this disease. Hence, it is increasingly attracting people's attentions to figure out how to prevent its occurrence. In the preventative perspective, Alzheimer's risk factors can be roughly categorized into two types: unmodifiable factors and modifiable factors. The former majorly refers to genetic underpinnings, aging and sex (female), et al.; and the latter comprises seven domains, including pre-existing physical disease, lifestyle, occupation, clinical drugs/therapy, blood biochemistry, diet, and mental psychology, which are exactly the potential targets for preventative strategies.

The team spent about one year in database searching, paper screening, data collecting and analyzing. Finally, 323 eligible papers in which 93 modifiable factors were identified were selected from roughly 17,000 literatures. The study found the significant associations of 36 factors categorized into six domains (including drugs, diet, biochemistry, mental health, lifestyle and pre-existing disease) with Alzheimer's occurrence. The most significant risk factor is heavy smoking while the most significant protective factor is healthy diet, for example the Mediterranean diet. Furthermore, we graded the evidence strength of meta-analysis for each factor based on two major domains: pooled sample size and the heterogeneity of each analysis. We found 11 risk factor with grade I evidence strength, including heavy smoking, low diastolic blood pressure, high BMI in midlife, carotid atherosclerosis, type 2 diabetes in Asian population, low BMI, low educational attainment, high total homocystein level, depression, systolic blood pressure more than 160 mmHg and frailty.

Among these risk factors, a total of 9 risk factors (including obesity in mid-life, current smoking in Asian population, carotid atherosclerosis, type 2 diabetes in Asian population, low educational attainment, high total homocysteine level, depression, high systolic blood pressure ≥160 mmHg, and frailty) for which global prevalence was accessible were selected for calculating population attributable risk (PAR). The combined PAR% indicated that these nine potentially modifiable risk factors were associated with up to roughly 66% of AD cases globally. Additionally, our study also found grade I evidence for 18 protective factors, including coffee/caffeine drinking, high folate intake, cognitive activity, high vitamin E intake, high vitamin C intake, current statin use, arthritis, light-to-moderate drinking, ever alcohol use, ever use of estrogens, anti-hypertensive medications, NASIDs use, high BMI in late-life, high Aβ42/40 ratio and some pre-existing diseases including arthritis, heart disease, metabolic syndrome, and cancer.

Tuesday, November 3, 2015

Researchers have of late investigated the role of Janus kinases in the processes of chronic inflammation, with an eye towards intervening to reduce inflammation levels. Chronic inflammation grows with aging due to a variety of underlying causes, such as immune system dysfunction and the presence of senescent cells, but is also generated by with poor lifestyle choices such as smoking or being overweight. Inflammation contributes to the development of many common age-related conditions, ranging from dementia to sarcopenia to cardiovascular conditions. Thus methods of safely and greatly reducing chronic inflammation should prove helpful when it comes to improving the health of older people:

Chronic inflammation, closely associated with frailty and age-related diseases, is a hallmark of aging. Researchers found that Janus kinase (JAK) inhibitors, drugs that work to block activity of JAK enzymes, decreased the factors released by human senescent cells in culture dishes. Senescent cells are cells that contribute to frailty and diseases associated with aging. Also, these same JAK inhibitors reduced inflammatory mediators in mice. Researchers examined aged mice, equivalent to 90-year-old people, before and after JAK inhibitors. Over the course of two months, the researchers found substantial improvement in the physical function of the aged mice, including grip strength, endurance and physical activity.

"One of the things we want to do is find some kind of treatment for frailty other than prescribing better wheelchairs or walkers, or other kinds of things that we are stuck with now that are Band-Aid solutions. Our goal is not necessarily to increase life span, and certainly not life span at all costs. Our goal is to enhance health span - the period during life when people are independent. This drug approach and others we are developing look like they might hold some promise in reaching that goal."

Tuesday, November 3, 2015α-synuclein-in-parkinsons-disease.php

Parkinson's disease, like dementia with Lewy bodies, is a synucleinopathy, a condition characterized by the buildup of aggregates of misfolded, toxic α-synuclein that cause cell death in the brain. The mix of age-related cellular damage, evolved reactions to that damage, and individual genetic variance that leads to the creation of these aggregates is highly complex and poorly understood. As for other diseases involving forms of protein aggregate that harm tissues, such as the varied forms of amyloidosis, one possible shortcut to meaningful treatment is to clear the aggregates on a regular basis. The research community is making some inroads in this direction, such as the production of immunotherapies that can target misfolded proteins, but it has been slow going so far:

Accumulation and misfolding of the α-synuclein protein are core mechanisms in the pathogenesis of Parkinson's disease. While the normal function of alpha-synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial activity, as well as proteasome and autophagic degradation of proteins. Remarkably, these functions are also affected when the renewal of macromolecules and organelles becomes impaired during the normal aging process. As aging is considered a major risk factor for Parkinson's disease, it is critical to explore its molecular and cellular implications in the context of the alpha-synuclein pathology.

Ninety percent of all diagnosed Parkinson's disease cases have a multifactorial origin, which is likely to combine genetic and environmental components. Changes in the expression level and folding state of the α-syn protein, combined with the formation of various α-syn multimeric species, define the transition towards pathological conditions. Although it is recognized that aging is a major risk factor for Parkinson's disease, the time-dependent molecular changes that underlie the development of the pathology are only partially understood. Rationally, pathways implicated in protein and organelle recycling by the proteasome and autophagy, as well as the biogenesis and quality control of mitochondria are gaining attention, because they are critically affected both in Parkinson's disease and aging. In neurons exposed to the combined effects of α-syn and aging, these cellular mechanisms may undergo vicious circles precipitating neuronal demise.

However, compared to normal aging, Parkinson's disease pathology has clear specificities showing that this process cannot be merely considered as a form of accelerated aging. Therefore, it is critical to explore the effect of the α-syn pathology in the context of the neurons that are selectively vulnerable to the converging effects of aging and α-syn proteotoxicity. In particular, the morphology and the metabolic needs of dopaminergic neurons, together with molecular specificities associated with dopamine neurotransmission, are critical factors for α-syn to exert its toxic effects. Using animal models dedicated to the study of the aging process, it will be important to understand the interaction between aging and α-syn in nigral dopaminergic neurons. By identifying therapeutic targets in this context, disease-modifying treatments may be found, that could be applicable to a broad population of patients.

Wednesday, November 4, 2015

Researchers here note a correlation between age-related arterial stiffening, likely the primary cause of hypertension, and rising levels of calcium in the blood. It is an open question as the degree to which calcification contributes to stiffening of blood vessel tissues in comparison to the contribution of cross-links to that stiffening. The processes leading to calcification are arguably not as comprehensively understood as those of cross-linking, but at least some of it is a secondary consequence of specific mechanisms - such as inflammation - in blood vessel walls that lead to atherosclerosis.

The progression of arterial stiffness is accelerated by aging, although the underlying mechanisms have not yet been clarified. This prospective observational study was conducted to clarify whether longitudinal changes in the serum calcium/phosphate levels are associated with the accelerated progression of arterial stiffness with age. In a cohort of employees at a construction company (1507 middle-aged Japanese men), the serum calcium/phosphate levels and brachial-ankle pulse wave velocity (baPWV) were measured at the start and at the end of a 3-year study period.

A general linear model multivariate analysis revealed a significant interaction of the 2 factors - age and longitudinal changes of the serum calcium levels (delCa) during the follow-up period - on the longitudinal changes of the baPWV during the study period (delPWV). The delCa was significantly correlated with the delPWV even after adjustments for covariates in subjects aged ≥48 years. The delPWV in subjects aged ≥48 years with the delCa in the upper tertile was significantly larger than that in the other groups even after adjustments for covariates. Thus the association between the arterial stiffness and serum calcium levels differed with age. Pathophysiological abnormalities related to increased serum calcium levels appeared to be associated with accelerated progression of arterial stiffness with age.

Wednesday, November 4, 2015

The research linked below isn't the first time scientists have proposed that what we currently call Alzheimer's disease is in fact a collection of different and distinct ways to end up with a similar end result. You might lump this in with other portions of the theorizing and exploration of alternatives that is taking place at least partially in reaction to the slow pace of progress towards working therapies based on the dominant amyloid hypothesis. The development of immunotherapies to clear amyloid is the current leading edge of that work, but trials have been disappointing to date. It may well be that this is simply because building a robust platform for immunotherapies targeting the brain is inherently challenging, rather than issues with amyloid as a target, but that hasn't stopped a great many competing hypotheses from emerging in the meanwhile.

Deciphering the mechanism that underlies the development of Alzheimer's disease in certain families but not in others, researchers have proposed that the malady is actually a collection of diseases that probably should be treated with a variety of different approaches. The late onset feature typical to distinct neurodegenerative diseases, and the common temporal emergence patterns of these maladies, raise key questions: first, why do individuals who carry disease-linked mutation show no clinical signs until their fifth or sixth decade of life? In addition, why do apparently distinct disorders share a common temporal emergence pattern? One possible explanation is that as people age, the efficiency of the mechanisms that protect younger people from the toxic aggregation of proteins declines, thus exposing them to disease. Indeed, previous studies clearly indicate that the aging process plays key roles in enabling neurodegenerative disorders to onset late in life.

Since neurodegenerative disorders stem from aberrant protein folding, an international research team postulated that an aging-associated decline in the activity of proteins that assist other proteins to fold properly may be one mechanism that exposes the elderly to neurodegeneration. To identify such mechanisms, they searched for similar mutational patterns in different proteins that are linked to the development of distinct neurodegenerative disorders. Their research showed that the development of Alzheimer's disease in certain families, and of a familial prion disorder in other families, originate from very similar mutational patterns. Based on this discovery, they identified that the malfunction of the protein cyclophilin B, which helps nascent proteins to attain their proper spatial structures, is responsible for the manifestation of both maladies. They also comprehensively characterized the mechanism that underlies the development of Alzheimer's disease in individuals who carry these mutations, and found that it has no relevance to the emergence of the disease in patients who carry other Alzheimer's-linked mutations. "This study provides important new insights: first, it shows that the development of distinct neurodegenerative disorders stems from a similar mechanism. More importantly, it indicates that Alzheimer's disease can emanate from more than one mechanism, suggesting that it is actually a collection of diseases that should be classified."

Thursday, November 5, 2015

A lot of the present work on stem cell biology in aging focuses on the muscle stem cells known as satellite cells. This includes some of the interesting lines of research aimed at restoring the activity of old stem cell populations via the use of signal molecules such as GDF-11 identified in parabiosis studies. This open access paper is a caution for those following the field, noting that outside of limb muscles comparatively little is known of the biochemistry of muscle stem cells, and they are perhaps better thought of as scores of different populations with different characteristics, one per muscle group. In other words there is probably a lot more work ahead here than you might have thought was the case:

The human body contains approximately 640 individual skeletal muscles. Despite the fact that all of these muscles are composed of striated muscle tissue, the biology of these muscles and their associated muscle stem cell populations are quite diverse. Skeletal muscles are affected differentially by various muscular dystrophies (MDs), such that certain genetic mutations specifically alter muscle function in only a subset of muscles. Additionally, defective muscle stem cells have been implicated in the pathology of some MDs. The biology of muscle stem cells varies depending on the muscles with which they are associated, and such diversity likely contributes to the pathologic sensitivities of different skeletal muscles to aging and disease.

Skeletal muscles are composed of myofibers, large syncytial cells containing hundreds of post-mitotic myonuclei. Juxtaposed between the basal lamina and the myofiber cell membrane, satellite cells reside at the periphery of skeletal myofibers. Recent studies have demonstrated that satellite cells expressing paired box protein 7 (Pax7) are the primary myogenic cell required for muscle regeneration. The majority of knowledge concerning satellite cell biology arises from studies examining larger muscles of the limbs, which collectively represent less than 2% of all skeletal muscles. Intriguingly, satellite cells present in other muscle groups, including trunk, diaphragm, larynx, tongue, extraocular, masseter, and pharynx, deviate from the canonical biology of their limb counterparts.

Unfortunately, little is known about the effects of age or disease on non-limb muscles as a whole or what factors predispose them to the effects of pathologic conditions. Additionally, satellite cells could serve as pathologic determinants in some dystrophies; however, our knowledge of non-limb satellite cells and their role in muscle biology is severely lacking. Recognizing and elucidating the distinct differences in satellite cell biology between different skeletal muscles could be the key to unraveling the conundrum of muscle specificity between the various MDs.

Thursday, November 5, 2015

Here researchers investigate some of the mechanisms involved in the relationship between calorie restriction (CR) and inflammation. The practice of calorie restriction is known to reduce inflammation in the short term, and over the long term it also reduces the growth in chronic inflammation that occurs with aging and which contributes to the development of many age-related conditions. Given that excess visceral fat tissue provides a potent contribution to inflammation, it is tempting to think that the effects of calorie restriction in this case result from practitioners becoming lean. However lack of visceral fat is never the whole story in anything relating to calorie restriction; a lot of other changes take place in cellular biochemistry in response to reduced nutrient intake:

Much of the aging phenotype, including immunosenescence, can be explained by an imbalance between inflammatory and anti-inflammatory networks, resulting in a chronic low-grade pro-inflammatory status. In previous studies, CR has been shown to play a significant role in the anti-inflamm-aging process by decreasing the levels of inflammatory markers in aging tissues. However, thus far, the anti-inflammatory effects of CR have only been superficially examined, and the underlying mechanism has not yet been elucidated. The present study is for the first time to demonstrate the possible regulatory mechanism by which CR induces anti-inflamm-aging and to explore the expression of the upstream and downstream molecules.

Toll-like receptor (TLR) 4 is a type of pattern recognition receptor (PRR) that recognizes molecules that are broadly shared by pathogens but distinguishable from host molecules; collectively, these molecules are referred to as pathogen-associated molecular patterns (PAMPs). TLRs, together with the interleukin-1 (IL-1) receptor (IL-1R), form a receptor superfamily known as the 'IL-1R/TLR superfamily'; all of the members of this family have a so-called Toll/IL-1R (TIR) domain in common. TLRs recognize PAMPs and initiate an intracellular kinase cascade to trigger an immediate defense response.

Fisher 344 rats in a CR group were fed an amount of food corresponding to 60% of that fed to an ad libitum-fed (AL) group for 8 months. Biochemical analyses and renal pathological grading were used to analyze physiological status. Important signaling molecules in the Toll-like receptor/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR/NF-κB) pathway were also analyzed. Compared with AL feeding, CR decreased aging-mediated increases in both biochemical marker levels and renal pathological grading. Single immunoglobulin IL-1 (IL-1)-related receptor (SIGIRR) expression decreased with increasing age, but CR led to overexpression. The expression of TLR4 was significantly higher in the CR group than in the AL group. SIGIRR overexpression decreased the expression of the adaptor molecules myeloid differentiation factor 88 (MyD88), IL-1 receptor-associated kinase 4 (IRAK4) and tumor necrosis factor receptor-associated factor 6 (TRAF6). The levels of the inflammatory markers phospho-IκBα and phospho-NF-κB p65 decreased in the CR group.

We conclude that the inflammatory response might be alleviated by SIGIRR via blockade of the TLR4/NF-κB signaling pathway. Therefore, CR can decrease inflammation via SIGIRR overexpression, and SIGIRR might be a new target to delay aging.

Friday, November 6, 2015

Some types of cataract involve the formation of amyloid deposits in the lens of the eye made up of damaged crystallin. Researchers have made progress of late in finding sterols that clear this form of amyloid. This is of general interest as there are many types of amyloid that form in tissues in increasing amounts with advancing age, some of which are clearly linked to the pathology of specific age-related conditions. Progress towards effective means of clearance for any one amyloid might turn out to be the starting point for the development of a broader technology platform for therapies, so it is worth paying attention. Here is an update on the development of sterol compounds targeting crystallin amyloid:

In order for our lenses to function well, a permanent, finite reservoir of crystallins must maintain both the transparency of fiber cells and their flexibility, as the eyes' muscles constantly stretch and relax the lens to allow us to focus on objects at different distances. The crystallins accomplish these duties with the help of aptly named proteins known as chaperones, which act "kind of like antifreeze, keeping crystallins soluble in a delicate equilibrium that's in place for decades and decades." This state-of-affairs is "delicate" because pathological, clumped-together configurations of crystallins are far more stable than properly folded, healthy forms, and fiber-cell chaperones must continually resist the strong tendency of crystallins to clump. A similar process underlies other disorders related to aging, such as Alzheimer's disease, but in each of these diseases the specific protein that clumps together and the place in the body that clumping occurs is different. In all cases, these clumped-together proteins are called amyloids.

Because the melting point of amyloids is higher than that of normal crystallins, the team focused on finding chemicals that that lowered the melting point of crystallin amyloids to the normal, healthy range. The group began with 2,450 compounds, eventually zeroing in on 12 that are members of a chemical class known as sterols. One of these, known as lanosterol, was shown to reverse cataracts, but because lanosterol has limited solubility the group who published that study had to inject the compound into the eye for it to exert its effects. Using lanosterol and other sterols as a clue, the researchers assembled and tested 32 additional sterols, and eventually settled on one, which they call "compound 29," as the most likely candidate that would be sufficiently soluble to be used in cataract-dissolving eye drops. In laboratory dish tests, the team confirmed that compound 29 significantly stabilized crystallins and prevented them from forming amyloids. They also found that compound 29 dissolved amyloids that had already formed. Through these experiments, "we are starting to understand the mechanism in detail. We know where compound 29 binds, and we are beginning to know exactly what it's doing."

In addition to compound 29's potential for cataract treatment, the insights gained through the research could have broader applications. "If you look at an electron micrograph at the protein aggregates that cause cataracts, you'd be hard-pressed to tell them apart from those that cause Alzheimer's, Parkinson's, or Huntington's diseases. By studying cataracts we've been able to benchmark our technologies and to show by proof-of-concept that these technologies could also be used in nervous system diseases, to lead us all the way from the first idea to a drug we can test in clinical trials."

Friday, November 6, 2015

Here is yet another study that demonstrates a correlation between a moderate level of physical fitness and a slower progression of specific aspects of aging in the brain. The conventional wisdom is that this sort of association is mediated by the effects of fitness on cardiovascular health, slowing the deterioration of blood vessel networks in the brain and the damage caused by their structural failure. There are no doubt numerous other mechanisms at work as well, however:

A new study shows that age-related differences in brain health - specifically the strength of connections between different regions of the brain - vary with fitness level in older adults. The findings suggest that greater cardiorespiratory fitness - a measure of aerobic endurance - relates to stronger brain connections and likely improves long-term brain function in aging populations. There are many ways to measure brain health across the lifespan. One popular technique measures the strength of connections between different parts of the brain while the person is completing a task or during wakeful rest. The latter is known as resting-state functional connectivity. Research has shown that some of these connections weaken with increasing age and indicate deteriorating brain health. Using functional magnetic resonance imaging, researchers measured the strength of these connections throughout the brain in younger and older adults at rest. As expected, the team confirmed that most connections were weaker for older adults when compared with younger adults.

Building on these findings, the researchers examined the role of cardiorespiratory fitness on resting-brain connectivity in older adults. Fitness is determined by how efficiently someone uses oxygen during physical activity such as running on a treadmill. Other factors aside from habitual physical activity may alter how fitness affects brain health. For example, a person's genetic makeup can influence his or her fitness and general brain health. The researchers found a relationship between fitness and the strength of the connections between certain brain regions in older adults at rest that was independent of their level of physical activity. "An encouraging pattern in the data from our study and others is that the benefits of fitness seem to occur within the low-to-moderate range of endurance, suggesting that the benefits of fitness for the brain may not depend on being extremely fit. The idea that fitness could be related to brain health regardless of one's physical activity levels is intriguing because it suggests there could be clues in how the body adapts for some people more than others from regular activity. This will help our understanding of how fitness protects against age-related cognitive decline and dementia."


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