The Threat of Sepsis in Old Age
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Sepsis is a disastrous runaway failure state of the immune system and metabolism that can occur in the wake of a severe infection. It leads to organ failure and can rapidly kill you even if the infection that caused it is dealt with. Sepsis is more of a looming threat for the old than the young, those with age-damaged immune systems and other frailties. For all this, it isn't something that receives all that much attention in comparison to other common fatal age-related conditions such as heart failure and cancer. With that in mind, here is an open access paper that provides an overview of the present state of knowledge of sepsis, while introducing us to the gloomy situation that exists with regards to treatment options for sepsis in the old:

Sepsis in Old Age: Review of Human and Animal Studies

Sepsis is a serious problem among the geriatric population as its incidence and mortality rates dramatically increase with advanced age. Despite a large number of ongoing clinical and basic research studies, there is currently no effective therapeutic strategy that rescues elderly patients with severe sepsis. Recognition of this problem is relatively low as compared to other age-associated diseases.

Sepsis has been the tenth leading cause of death in patients over the age of 65 in the US since 2001. Older people make up a greater proportion (58-65%) of sepsis patients, and both incidence and mortality rates are significantly greater in the aged. Importantly, in addition to increased mortality rates for the elderly, older sepsis patients die earlier during hospitalization, and those that do survive often require additional care in long-term nursing facilities to regain functional status.

A recent study evaluated long-term mortality in elderly severe sepsis patients (only those surviving at three months post sepsis were included) and found an overall mortality rate of 55% with a 30.6% one-year morality rate and a 43% two-year mortality rate. This means that more than half of the elderly patients who survive sepsis through hospital discharge will be dead within two years.

The authors here suggest that many of the present issues in the sepsis research community - lack of progress towards more effective treatments foremost among them - stem from a poor choice of animal models used in studies.

The incidence of sepsis increases exponentially from childhood to geriatric age with a magnitude of approximately 100-times. Mortality from sepsis also increases progressively with age. The incidence of sepsis is steadily increasing as our population ages. Despite these problems, little is known about the pathophysiology of sepsis which is specific to older patients.

Sepsis patients, in addition to being a heterogeneous population, have large variations in disease course factors including severity, source of infection, comorbidities, and timing of hospital admission. While caution has to be paid for biological differences between men and rodents, the use of laboratory animals is essential for understanding the detailed pathophysiology of sepsis.

Despite the fact that there is clearly an increased precedence of elderly patients suffering from sepsis, the majority of basic research on sepsis has been conducted using young animals. This mismatch introduces a serious disconnect in interpretation of sepsis studies using mice or men because most humans with sepsis are over 50 years old, and most mice used in sepsis research are less than 3 months old, comparable to a person under 20 years of age.

For example, immune responses to infection are clearly altered by aging, thus, the use of aged animals in sepsis research would provide important information that would greatly differ from data obtained using young animals. The number of studies on sepsis using aged animals (i.e. rodents) is surprisingly small. By utilizing the PubMed journal search engine, we estimate that among all published studies using animal models of sepsis, less than 1% used appropriately aged animals.

The paper goes into greater detail as to noteworthy differences in the progression and character of sepsis between young and old individuals, and explains why these differences matter in practice. It's worth reading the whole thing.

A Sampling of Recent Alzheimer's Research
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Alzheimer's disease is one of the few areas of research into age-related conditions that needs comparatively little assistance at this time: public awareness of the issue of dementia is growing and so is support for greater funding. The research community is already large and energetic, and at least some well-funded groups are working on technologies - such as immune therapies aimed at removal of amyloid deposits - that will probably be of use to other efforts to reverse the causes of aging. This avalanche is well underway.

All that said, it is still a very complex problem as yet comparatively poorly understood, for all that tangible progress is taking place year after year. Much like cancer research, I expect to see Alzheimer's research - already large in comparison to much of the rest of the field of aging research - grow further to consume a great deal of funding, spur the accelerating development of biotechnology, and generate much new knowledge of the intricate relationship between metabolism and aging, as well as the fine details of the operation of the human brain. Below you'll find two fairly representative samples of recent research from the Alzheimer's research community.

Loss of Memory in Alzheimer's Mice Models Reversed through Gene Therapy

[Researchers] have discovered the cellular mechanism involved in memory consolidation and were able to develop a gene therapy which reverses the loss of memory in mice models with initial stages of Alzheimer's disease. The therapy consists in injecting into the hippocampus - a region of the brain essential to memory processing - a gene which causes the production of a protein blocked in patients with Alzheimer's, the "Crtc1" (CREB regulated transcription coactivator-1). The protein restored through gene therapy gives way to the signals needed to activate the genes involved in long-term memory consolidation.

In persons with the disease, the formation of amyloid plaque aggregates, a process known to cause the onset of Alzheimer's disease, prevents the Crtc1 protein from functioning correctly. "When the Crtc1 protein is altered, the genes responsible for the synapses or connections between neurons in the hippocampus cannot be activated and the individual cannot perform memory tasks correctly this study opens up new perspectives on therapeutic prevention and treatment of Alzheimer's disease, given that we have demonstrated that a gene therapy which activates the Crtc1 protein is effective in preventing the loss of memory in lab mice".

A new approach to treating Alzheimer's disease

Cellular processes are not perfect. They, like us, make mistakes. Sometimes, the by-products of those mistakes are harmless. Other times, they can lead to disease or even death. With Alzheimer's disease, the mistake occurs when a protein called neuron's membrane is cut in the wrong place, leading to a buildup of abnormal fragments called amyloid-beta. These fragments clump together to form a plaque around neurons, eventually interfering with brain function.

But the cell has systems to deal with mistakes. A protein complex called retromer acts like a cellular garbage truck, collecting faulty gene products and trafficking them to be destroyed or recycled. For years, Alzheimer's research has focused on preventing the formation of amyloid-beta with little success. But instead of trying to stop mistakes, what if researchers improved the system for dealing with them? A team of researchers [did] just that. They have devised a novel approach to the treatment of Alzheimer's disease that significantly increases retromer levels while decreasing amyloid-beta levels in neurons, without harming the cell.

Pharmacological chaperones stabilize retromer to limit APP processing

Retromer is a multiprotein complex that trafficks cargo out of endosomes. The neuronal retromer traffics the amyloid-precursor protein (APP) away from endosomes, a site where APP is cleaved into pathogenic fragments in Alzheimer's disease. Here we determined whether pharmacological chaperones can enhance retromer stability and function.

First, we relied on the crystal structures of retromer proteins to help identify the 'weak link' of the complex and to complete an in silico screen of small molecules predicted to enhance retromer stability. Among the hits, an in vitro assay identified one molecule that stabilized retromer against thermal denaturation. Second, we turned to cultured hippocampal neurons, showing that this small molecule increases the levels of retromer proteins, shifts APP away from the endosome, and decreases the pathogenic processing of APP.

These findings show that pharmacological chaperones can enhance the function of a multiprotein complex and may have potential therapeutic implications for neurodegenerative diseases.

Antisenescence Effects of Stem Cell Therapies
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With advancing age ever more cells in your body enter a state of senescence. They stop dividing and emit signals that both degrade surrounding tissue structures and raise the odds of nearby cells also becoming senescent. This is an adaptation of a mechanism involved in embryonic development that lowers the odds of suffering cancer: senescent cells appear in response to cellular damage in a range of circumstances, and the types of damage that provoke cellular senescence either raise the risk of cancerous cells emerging or accompany a rising risk of cancer in normal aging. So cellular senescence is a part of the balance that evolution has come to in humans between declining ability to function on the one hand and fatal cancer on the other.

The research community, however, is going to become very good at dealing with cancer in the decades ahead. Cellular senescence isn't a great partner for a technologically sophisticated humanity, as the downside in aging very much outweighs whatever good is being done. For my money I think that the first generation of effective treatments that reverse the contribution of cellular senescence to degenerative aging will be blunt efforts that involve the targeted destruction of near-all senescent cells. This targeted destruction in fact goes on all the time in younger years, as one of the jobs of the immune system is to seek out and remove problem cells. Unfortunately like all biological systems it becomes damaged and disarrayed in later life, and alongside the damage that provokes a greater incidence of cellular senescence this is one of the reasons why the body accumulates ever more senescent cells as the years pass. We don't need these senescent cells, they can be removed, and we will benefit from their removal. The technologies used will be very similar to those already in trials for the targeted destruction of cancer cells: immune therapies, nanoparticles, engineered viruses, and so forth.

Later forms of treatment may be more sophisticated, however. Why destroy senescent cells if they can be reprogrammed into a non-senescent state? The field of cellular programming is still in its infancy at this point, and even the most impressive results are half happenstance and incompletely understood in the context of the bigger picture. Researchers throw compounds at cells to see what happens, and out of this assemble theories that inform the next set of efforts to throw compounds at cells to see what happens. Cells are enormously complex mechanisms, but from these efforts will eventually emerge a field in which any cell can be instructed to act as we want it to - even while within the body.

Stem cell treatments are leading to a greater knowledge of the mechanisms by which senescent cells might be coerced back into a more useful and functional state. Just as the delivery of stem cells causes regeneration by changing the local tissue environment and releasing signals that convince native cells to get back to work, it seems that this may also beneficially influence the balance of signals that leads to greater or lesser levels of cellular senescence. This possibility is illustrated in the following research using cell cultures. When researchers cultured and stressed their cell lines in the presence of signals emitted by stem cells, there was measurably less cellular senescence than was the case without those signals:

Rat Induced Pluripotent Stem Cells Protect H9C2 Cells from Cellular Senescence via a Paracrine Mechanism

Cellular senescence may play an important role in the pathology of heart aging. We aimed to explore whether induced pluripotent stem cells (iPSCs) could inhibit cardiac cellular senescence via a paracrine mechanism.

We collected iPSC culture supernatant as conditioned medium (CM) for the rat cardiomyocyte-derived cell line H9C2. Then we treated H9C2 cells, cultured with or without CM, with hypoxia/reoxygenation to induce cellular senescence and measured senescence-associated β-galactosidase (SA-β-gal) activity, G1 cell proportion and expressionM of the cell cycle regulators p16INK4a, p21Waf1/Cip1 and p53 at mRNA and protein levels in H9C2 cells. In addition, we [measured] concentrations of trophic factors in iPSC-derived CM.

We found that iPSC-derived CM reduced SA-β-gal activity, attenuated G1 cell cycle arrest and reduced the expression of p16INK4a, p21Waf1/Cip1 and p53 in H9C2 cells. Furthermore, the CM contained more trophic factors, e.g. tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor, than H9C2-derived CM.

[We conclude that] paracrine factors released from iPSCs prevent stress-induced senescence of H9C2 cells by inhibiting p53-p21 and p16-pRb pathways. This is the first report demonstrating that antisenescence effects of stem cell therapy may be a novel therapeutic strategy for age-related cardiovascular disease.

Working to Remove the Heaps of Unburnable Cellular Trash that Contribute to Degenerative Aging
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Every cell in your body is a busy factory, constantly engaged in turning raw materials into complex proteins via the processes of gene expression, following the blueprints in your DNA. The source of much of the necessary supply of raw materials is the cell itself: a great deal of recycling takes place as damaged proteins and larger structures such as organelles are broken down into constituent molecules that are promptly fed back into the factory process.

This recycling isn't just a matter of obtaining parts: it is quality control for cellular machinery vital to life. Autophagy is the name given to the collection of processes by which unwanted and damaged cellular components are identified and then fed into the furnaces known as lysosomes. A lysosome is a specialized organelle packed with enzymes capable of dismantling near everything it is likely to receive in the course of its duties. It engulfs the refuse and destroys it, producing useful raw materials in the process.

With time, however, our lysosomes do in fact ingest a range of items that they cannot deal with. In our long-lived cells, many of which must last a lifetime, lysosomes become bloated and malfunctioning, packed to the gills with harmful materials collectively known as lipofusin. The ability of cells to keep themselves damage-free and functional deteriorates as a consequence, and this is one of the contributing causes of degenerative aging as a whole. It is particularly important in conditions such as macular degeneration, but a long laundry list of other age-related conditions - many of them ultimately fatal - have lysosomal dysfunction and lipofuscin accumulation noted as contributed causes.

We know that this happens, and we know that it causes great harm, but what can be done to prevent it and reverse it? To answer that question, here is the latest in a series of posts on rejuvenation research by philanthropist Jason Hope.

SENS Research Foundation Targets Lysosomal Aggregates

Cells create waste products and, left unaddressed, these byproducts disable body cells to cause serious illnesses. Scientists at SENS Research Foundation Research Center are currently developing ways to remove these waste products, known as lysosomal aggregates, from cells, in order to restore the cells to health and thereby treat these illnesses or prevent their onset. To understand the nature of the scientists' work, it helpful to create a working analogy that makes understanding lysosomal aggregates easier.

Lysosomal aggregates are like non-biodegradable plastic bags and other garbage rising over the tops of landfills to pollute nearby land. Left unaddressed, unhealthy substances from the garbage disrupt the lives of plants and animals surrounding the landfill to the point of causing disease and death to those organisms. The nature of the illness and disease depends largely on the type of waste polluting the landscape. Plastic bags might entangle a bird, for example, or antifreeze may poison a passing coyote. Each toxin causes a specific effect on a particular organism.

Each particular lysosomal aggregate tends to form in a specific type of body cell. When the amount of aggregate is large enough to interfere with normal cell function, the cell can no longer carry out its function, and as more and more cells of a given type become dysfunctional it leads to illness. Age-related macular degeneration, or AMD, is an excellent example of this action. Special cells in the retina of the eye, known as retinal pigment epithelium or RPE cells, produce the waste material A2E. Many scientists think the accumulation of A2E disables RPE cells to cause the vision loss associated with AMD.

The Lysosomal Aggregates team at SENS Research Foundation Research Center is working to identify optimal A2E-degrading enzymes, and to deliver them directly into the lysosomes in the eye. In their previous work, the team had been able to identify many enzymes capable of stopping A2E in a petri dish but was unable to deliver these enzymes into an actual lysosome in an eye. They are working to develop methods to deliver these enzymes to the lysosomes. One procedure in particular, known as SENS20, works both in vitro and in actual RPE cells, but others may work even better.

Lysosomal aggregates [are also] associated with atherosclerosis, commonly known as hardening of the arteries. Oxidation can cause breakdown of the "bad cholesterol" LDL in the bloodstream. This breakdown increases the levels of 7-ketocholesterol, or 7KC, known to cause the narrowed arteries and poor cardiac function associated with atherosclerosis. Researchers from Rice University are working to develop enzymes that reduce 7KC in hopes of reversing the processes that cause atherosclerosis.

SENS Research Foundation is making great strides in reducing the devastating health effects caused by lysosomal aggregates. With continued research, the scientists hope to someday treat or prevent widespread debilitating illnesses like age-related macular degeneration and atherosclerosis.

Somatic Cell Nuclear Transfer Achieved in Adult Human Cells
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The future of cell therapies includes regenerative treatments and tissue engineering, as well as many other possibilities, but it all depends on the development of highly efficient, low-cost ways to generate a ready supply of cells of any given type from a patient's own cells, such as a skin sample. The lower the cost the faster that research progresses today, and the establishment of low-cost methods of generating patient-specific cells is very much required to enable widespread use of affordable therapies tomorrow.

A little more than a decade ago it looked like the best way to create these cell supplies was to work on a technique called somatic cell nuclear transfer (SCNT), in which the nucleus from a patient's cell is introduced into an egg cell that has had its nucleus removed. The result recapitulates some of the early development of a blastocyst from which pluripotent cells can be harvested and developed into any type of human cell. Unfortunately this turned out to be more challenging than expected from a technical point of view, and as you may recall there was in addition a great deal of foolish political intervention that made it even harder to move forward. Then not so long afterwards the techniques for generating induced pluripotent stem (IPs) cells by direct reprogramming were discovered and the majority of the research community jumped ship for that much easier methodology.

Some researchers kept working on the roadblocks preventing implementation of SCNT in human cells, however, and have now finally achieved an initial success with adult human cells. This is the sort of result that can lead to the infrastructure necessary to generate patient-specific cells, but in this case it has more of the feel of the closing of a chapter. The leading edge of the research community now works with induced pluripotency and related forms of direct cell reprogramming, and is making rapid progress with those techniques. Success with SCNT is to be praised, but I think unlikely that it will gather much support in the present environment.

First Embryonic Stem Cells Cloned From A Man's Skin

Last year, scientists in Oregon said they'd finally done it, using DNA taken from infants. Robert Lanza, chief scientific officer at Advanced Cell Technology, says that was an important step, but not ideal for medical purposes. "There are many diseases, whether it's diabetes, Alzheimer's or Parkinson's disease, that usually increase with age," Lanza says. So ideally scientists would like to be able to extract DNA from the cells of older people - not just cells from infants - to create therapies for adult diseases.

"What we show for the first time is that you can actually take skin cells, from a middle-aged 35-year-old male, but also from an elderly, 75-year-old male" and use the DNA from those cells in this cloning process, Lanza says. They injected it into 77 human egg cells, and from all those attempts, managed to create two viable cells that contained DNA from one or the other man. Each of those two cells is able to divide indefinitely, "so from a small vial of those cells we could grow up as many cells as we would ever want."

Scientists use cloning to make stem cells matched to two adults

Lanza and his colleagues said their experiments revealed that some eggs were better at it than others. Researchers used 49 eggs from three women, though eggs from only two of them produced results. "The magic is in the egg," Lanza said.

Lanza said that most stem cell scientists have "jumped on the iPS bandwagon," but he argued that stem cells created by SCNT could still play a vital role in regenerative medicine. He envisions a day when multiple lines of stem cells are kept in banks and made available to patients based on their biological similarity, much the way blood and donor organs are now handled. "If we had these banks, we would have the raw material to do tissue engineering and grow up organs, or to grow up vessels, tendons or whatever you want."

Human Somatic Cell Nuclear Transfer Using Adult Cells

Derivation of patient-specific human pluripotent stem cells via somatic cell nuclear transfer (SCNT) has the potential for applications in a range of therapeutic contexts. However, successful SCNT with human cells has proved challenging to achieve, and thus far has only been reported with fetal or infant somatic cells. In this study, we describe the application of a recently developed methodology for the generation of human embryonic stem cells via SCNT using dermal fibroblasts from 35- and 75-year-old males. Our study therefore demonstrates the applicability of SCNT for adult human cells and supports further investigation of SCNT as a strategy for regenerative medicine.