Amyloid in the Brains of People Without Alzheimer's Disease
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If surveying what is known of the pathology of age-related conditions, we find an array of cellular damage and metabolic waste accumulation that happens in everyone. The people with age-related medical conditions have a lot more of one or more types of this damage and waste, however. That is the root cause of their dysfunction and frailty. Aging isn't a linear process and damage causes further damage, so small differences early on can always snowball into large differences later. Accumulating damage and waste byproducts as the result of the normal operation of metabolism is common to all of us, and this makes it a good place to look for therapeutic targets. If spending billions and decades on medical research, better to emerge with a treatment that can benefit everyone.

Alzheimer's disease progresses hand in hand with the accumulation of amyloid-β (Aβ) in brain tissues. Much of the comparatively well funded field of Alzheimer's research is focused on clearing amyloid or interfering in the mechanisms thought to link it to cell death and neurodegeneration. There are plenty of other opinions in the field on the relevance of this approach, given that it is proving harder than expected to produce meaningful results in clinical trials, but for now that is where most of the funding goes. This will hopefully produce a technology platform for amyloid clearance, such as via immunotherapies, that can be generalized to clear the other score or so forms of amyloid that accumulate in tissues with advancing age. In some cases it isn't so clear as to exactly what harm they are causing, but they are not present in young tissues in significant amounts, so the prudent course of action is to remove them anyway. Clearance followed by observing the results will probably teach us more about their role in aging than the same amount of time and money spent on more conventional studies.

Amyloid accumulation takes place in everyone, not just those with enough resulting damage to officially qualify as an Alzheimer's patient. The dividing line isn't sharp at all: more amyloid correlates with more cognitive dysfunction, and at some point that tips over the margin. It isn't a road that anyone really wants to be on at all, of course, but nonetheless here we all are until new applications of medical science arrive to rescue us. That will require large amounts of funding and public support, both of which are presently far smaller in scale than they might be. Ours is a society that likes circuses and bonfires in preference to science and progress. When does the damage of aging start? It starts in youth, but takes decades to rise to the point at which it is noticeable. Here are two recent reports of research on this topic:

Alzheimer amyloid clumps found in young adult brains

Scientists examined basal forebrain cholinergic neurons to try to understand why they are damaged early and are among the first to die in normal aging and in Alzheimer's. These vulnerable neurons are closely involved in memory and attention. Researchers examined these neurons from the brains of three groups of deceased individuals: 13 cognitively normal young individuals, ages 20 to 66; 16 non-demented old individuals, ages 70 to 99; and 21 individuals with Alzheimer's ages 60 to 95.

Scientists found amyloid molecules began accumulating inside these neurons in young adulthood and continued throughout the lifespan. Nerve cells in other areas of the brain did not show the same extent of amyloid accumulation. The amyloid molecules in these cells formed small toxic clumps, amyloid oligomers, which were present even in individuals in their 20's and other normal young individuals. The size of the clumps grew larger in older individuals and those with Alzheimer's. "This points to why these neurons die early. The small clumps of amyloid may be a key reason. The lifelong accumulation of amyloid in these neurons likely contributes to the vulnerability of these cells to pathology in aging and loss in Alzheimer's."

Brain Amyloid-β Burden Is Associated with Disruption of Intrinsic Functional Connectivity within the Medial Temporal Lobe in Cognitively Normal Elderly

The medial temporal lobe is implicated as a key brain region involved in the pathogenesis of Alzheimer's disease (AD) and consequent memory loss. Tau tangle aggregation in this region may develop concurrently with cortical Aβ deposition in preclinical AD, but the pathological relationship between tau and Aβ remains unclear.

We used task-free fMRI with a focus on the medical temporal lobe, together with Aβ PET imaging, in cognitively normal elderly human participants. We found that cortical Aβ load was related to disrupted intrinsic functional connectivity of the perirhinal cortex, which is typically the first brain region affected by tauopathies in AD. There was no concurrent association of cortical Aβ load with cognitive performance or brain atrophy. These findings suggest that dysfunction in the medial temporal lobe may represent a very early sign of preclinical AD and may predict future memory loss.

Posters for the MILE Demonstration on March 21st
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The Movement for Indefinite Life Extension (MILE) is one of a number of grassroots initiatives in which ordinary folk like you or I are doing their part to help raise awareness and funding for rejuvenation research. Every great journey is made one small step at a time, and the tipping point at which the public at large begins to accept and supports longevity science in the same way as is the case for cancer research today will be crossed by one such modest effort among many. The community of people who understand and support efforts to bring an end to degenerative aging through medical science grows and diversifies as the years pass. The more of us there are the more that we can do to help advance research and educate the public. There is a role for everyone in this, and at all levels of effort, whether it is donating millions to establish a new research program or persuading a few of your friends that it's pretty silly to be for cancer research but against a cure for all age-related frailty and disease.

MILE is organizing an online demonstration on March 21st to coincide with live meetups in Chicago, Los Angeles, and Washington D.C. I was asked to provide a poster or two, and so bearing in mind that this is a demonstration I ran up something very simple that should be legible at distance. Less is more for this sort of thing, and it is easy enough to cut and paste other taglines and URLs. The font is Liberation Sans Bold, but any generic sans-serif font works just fine at this size.

Support Rejuvenation Research Poster: 4200 x 2800px

Fund More Research Poster: 4200 x 2800px

The Role of Age-Related Extracellular Matrix Restructuring in Heart Conduction Disorders
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The extracellular matrix (ECM) is the complex structure of proteins surrounding and supporting cells. The varied mechanical properties of different tissues derive from the particular arrangement and types of molecules making up this structure: the elasticity of skin and blood vessels, the load bearing resilience of bone and cartilage, and so forth. Some of the fundamental forms of cellular and molecular damage that cause aging produce degenerative effects through changes to the extracellular matrix that degrade its properties. For example, cross-links formed by sugary metabolic waste glue together structural proteins. The most persistent types of cross-link accumulate over the years and their presence contributes to the loss of elasticity in skin and blood vessel walls, as well as to the growing fragility of bones in the elderly.

A different type of problem is caused by senescent cells, which have removed themselves from the cell cycle in response to damage or a potentially damaging local tissue environment. Senescent cells adopt what is known as a senescent-associated secretory phenotype, releasing a mix of compounds that encourage other nearby cells to become senescent, but which also degrade or restructure the surrounding extracellular matrix. Cellular senescence may be a repurposed tool of embryonic development, a mechanism that helps shape growing organs, and its activities in attacking the extracellular matrix are a holdover from that role. Whether or not this is the case, senescent cells are destructive and degrade the structural properties of the extracellular matrix where they gather in numbers.

Both senescent cells and cross-links could be dealt with in the very near future, removing and reversing their contributions to degenerative aging, given sufficient funding for research. Selective destruction of senescent cells has been demonstrated in principle, and a few research groups are working on different approaches to making a therapy of this approach. On the cross-link side of the house, the single most important type of cross-link in humans is formed of a single compound, glucosepane. Thus drug development has a single target to hit: all it takes is for the tools to be produced and for one laboratory to find a good drug candidate. This work is also underway in the early stages, carried out by a few small research groups. Neither of these lines of research is anywhere near well enough funded, or appropriately funded for the size of the potential benefits, however. A sizable chunk of the presently ongoing work is funded by one organization, the SENS Research Foundation, and supported entirely by philanthropic donations. This is the story for much of the potential rejuvenation toolkit that could be built in the years ahead - but which will take much longer to realize than it might, because funding and interest are the limiting factors. This is exactly why advocacy and education for this cause are so very important.

Structural properties of tissue determined by the extracellular matrix go beyond elasticity and strength. There is also the matter of electrical properties, important in the heart and nervous system. Degradation of the extracellular matrix in heart tissues and its impact on the heart's electrical conduction system is probably a contributing factor the increased prevalence of arrhythmias and similar issues with advancing age.

The role of extracellular matrix in age-related conduction disorders: a forgotten player?

Prevalence of cardiac arrhythmias increases over time during aging, carrying significantly higher morbidity and mortality in the elderly. Defective impulse generation and conduction and ECM disarray with augmented intramyocardial fibrosis during aging are considered the main biological processes responsible of these disturbances.

In this context, in spite of the interest addressed by the literature to the "aged cardiomyocyte" as the main pathological responsible of age-related conduction disturbances, there are several lines of evidence pointing at changes in the structure and function of the extracellular matrix (ECM) as an important actor. At the biophysical level, cardiac ECM exhibits a peculiar degree of anisotropy, which is responsible for the elastic and compliant properties of the ventricle and for the structural properties of heart valves. However, ECM components and their arrangement are also the main determinants of the conductive properties of the specialized electrical conduction system. Moreover, cardiac ECM is actively sending biological signals regulating cellular function and tissue homeostasis. Alterations of ECM function in the elderly might additionally exert a detrimental effect on the normal function of the conduction system and on overall ventricular function and cardiac performance. Age-associated alterations of cardiac ECM are therefore able to profoundly affect the function of the conduction system with striking impact on the patient clinical conditions.

The function of the sinoatrial node (SAN) deteriorates with age with an increase in the nodal conduction time and a decrease in the intrinsic heart rate. Collectively, those alterations translate at the clinical side in the so-called sick sinus syndrome, whose manifestations include bradycardia, sinus arrest, and sinus exit block. Additionally, considering the hemodynamic changes occurring with aging, which are basically constituted by a reduction of ventricular compliance and an increased contribution of atrial contraction to ventricular filling, dual chamber pacemakers maintaining synchrony between atria and ventricles are advantageous in older adults. During the aging process, the described structural and functional changes occurring in the left ventricle are interlaced with malfunction of the conduction system, which in turn results in non-efficient and non-synchronous activation of both ventricles, fostering a vicious circle eventually worsening the detrimental effects on cardiac performance.

Conduction disturbances are frequent among the elderly and carry significant morbidity and mortality representing a clinical and economical burden. Complex cellular interplay and paracrine biological signaling underlie this phenomenon and targeting fibrosis generation and its pathological characteristics might be a promising therapeutical approach for age-related arrhythmic disease. Deepening knowledge on ECM age-associated alterations might be important in the development of novel therapeutical approaches in the widespread panorama of age-related disease.

The Grail of Calorie Restriction Benefits Without the Calorie Restriction
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Seeking to recreate the benefits of calorie restriction - greater health and longer life - without the part of the process wherein you must eat less is a grail for modern medical research. The calorie restriction response is of greater benefit to basically healthy people than that produced by any currently available medical technology. Putting forward the idea that people should eat fewer calories is not a popular position in this modern age of comparatively wealth and comfort, however. It is entirely reasonable to expect that any new medicine that safely produced even a sizable fraction of the long term health improvements and slowing of aging triggered by the practice of calorie restriction would make a great deal of money. Thus there is a willingness in the research and development community to invest large amounts in scientific programs that have a chance of making this happen. Based on the pace of progress over the past two decades we shouldn't expect this grail to materialize any time soon, however. Calorie restriction changes near everything that can be measured in the operation of metabolism, and picking apart the complexity of this response costs billions and years even for a tiny slice of progress in understanding. Look at the history of sirtuin research, for example: a lot of hype at the outset, and nothing to show for it today but very expensive knowledge, a tiny addition to a vast catalog yet to be written.

Nonetheless the grail continues to attract attention. To the extent that this draws new funding into human life science research, this is all to the good: there's no such thing as too much life science research. Recreating calorie restriction isn't, however, an effective path to rejuvenation. It's just another way to tinker with the operation of metabolism to gently slow down the damage of aging. This is not particularly helpful to the old, who are already heavily damaged, and if takes decades for the research community to get anywhere, as seems most likely, it is not all that helpful to today's middle aged folk either. Research will always move forward, and tomorrow will be better than today, but it is very important that rejuvenation research aimed at dramatically cutting the rate of death and disease caused by aging moves as rapidly as possible to as beneficial an outcome as possible. Hundreds of millions of lives are the cost of a few years of delay. Calorie restriction mimetic development is a poor, expensive path. We should be focused on repair based strategies like SENS instead, those capable of producing rejuvenation and greatly extended healthy life spans as an outcome.

All things considered practicing calorie restriction now is a great plan. You can do it for next to nothing, and it has an expected beneficial effect considerably larger than any tinkering you can do with supplements and available medical technologies, assuming you're a basically healthy individual. Investing billions and decades and waiting for a drug that can do less for you than eating less? Not such a great plan. Decades and billions should be delivering far better results than that in terms of treatments for degenerative aging.

Here is news of work on a more recent approach to mimicking the effects of calorie restriction: it has become apparent that sensory neurons have a large effect on the calorie restriction response in lower animals, independent of actual calorie intake. This raises the possibility of some form of top-down manipulation in which at least some of the metabolic changes associated with calorie restriction are induced by altering the biochemistry of these sensory neurons. I should note that this is still all very early stage research, however. The grail is really no closer because of it.

Perception of food consumption overrides reality

The study focused on a molecule called AMP-activated protein kinase, or AMPK, which acts as a molecular fuel gauge to detect energy levels. It's been known that AMPK plays important roles in all cell types, but researchers didn't understand which of these activities were most critical to regulating longevity. The researchers found that AMPK inhibited the activity of a protein called CRTC-1 in mitochondria - the primary energy-producing organelles in cells - throughout the organism, by altering production of a neurotransmitter.

The researchers were struck by the fact that altering the AMPK pathway in just a limited set of neurons was sufficient to override its effects on metabolism and longevity in other tissues. Aging was influenced more by what the animals perceived they were eating than what they actually ate. The study suggests that manipulating this energy-sensing pathway can cause organisms to perceive their cells to be in a low-energy state, even if they are eating normally and energy levels are high. Drugs targeting the cells' energy-sensors in this way could potentially address age-related diseases, including cancer and neurodegeneration, and may offer an alternative to calorie restriction.

Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal

Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell nonautonomously by CRTC-1 in the nervous system. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging.
Presentation Videos from Rejuvenation Biotechnology 2014
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Ours is an era on the verge of developing means to treat the root causes of degenerative aging and thereby extend healthy life, eliminate age-related disease, and rejuvenate the old. The decades ahead are a critical time, in which the best and most promising approaches to research and development either take off or falter. There are all too many examples from the past in which promising new technologies languished long past the point at which they could have been created and made widely available. We don't want that to happen here, as it means the difference between health or frailty, life or death for all of us.

The first in a series of Rejuvenation Biotechnology conferences organized by the SENS Research Foundation was held late last year, and by all accounts went very well. You should certainly take a look at the BioWatch News special issue devoted to the conference and its goals if you have not already done so. It is a thoughtful look at some of the issues facing research and development in those parts of the field of aging research focused on intervention and cures.

The aim of the Rejuvenation Biotechnology conference series is to lay the groundwork for closer collaboration between industry and research establishments in the development of near future therapies to treat degenerative aging. The scientific foundations needed for rejuvenation therapies are progressing at a pace that is far slower than we'd all like, but it is nonetheless time to prepare the way for clinical translation of research results. That process takes time, and to pick one example, initial attempts at clearance of senescent cells might be only a few years away from initial clinical trials at this point: a for-profit startup company was recently founded to work on one approach. While it is easy to imagine that any practical treatment for aging would be mobbed by developers seeking to bring it to market as soon as it makes it out of early stage research, in truth that sort of outcome only happens when sufficient preparation has taken place. That means at the very minimum building a network of relationships and knowledge.

Videos of presentations given at the Rejuvenation Biotechnology conference were recently posted by the SENS Research Foundation staff. I think you'll find them interesting. Many more than are shown here can be found at the SENS Research Foundation YouTube channel.

The Rejuvenation of Aged Skeletal Muscle by Systematic Factors

The primary research focus of the Jang laboratory is to understand the molecular and biochemical mechanisms of age-related muscle loss and function. The Jang laboratory applies bioengineering approaches and stem cell-based therapies to study skeletal muscle dysfunction during aging and in age-associated muscle diseases. The laboratory develops and applies novel tools using a combination of animal and stem cell models.

A Twist of Fate - Generating New Neocortical Neurons

The line of investigation aims to establish ways of regenerating the principle neurons of the adult cerebral cortex when these neurons are lost due to trauma or degeneration, including degeneration due to aging. Since endogenous precursors do not replace cortical neurons when they are lost, two strategies are being developed: manipulating these precursors with molecular genetic techniques to start generating neurons and transplanting engineered precursors that are programmed to disperse in the cortex and differentiate into cortical projection neurons.

Building a Rejuvenation Biotechnology Industry - Panel Discussion

This panel synthesized the discussions from all of the conference sessions and panels. A cross-section of academics, pharmaceutical reps, policy makers, and other presenters revisited the merits of a damage repair paradigm to address the diseases of aging considered at this conference. Panelists considered the changes that would be required to lay the groundwork for a new industry perspective focused on addressing damage indications for the diseases of aging either through preventing or repairing such damage.