An optimized 3D inkjet printing process is demonstrated for structuring alginate into a tissue-like microvasculature capable of supporting physiological flow rates. Optimizing the reaction at the single-droplet level enables wet hydrogel droplets to be stacked, thus overcoming their natural tendancy to spread and coalesce. Live cells can be patterned using this process and it can be extended to a range of other hydrogels. _Advanced Materials

The dream is to be able to rapidly grow replacement tissues and organs, to allow for easy autologous replacement for a wide range of clinical reasons and circumstances — including life extension regenerative treatments.

…Thus, it would take just under 2 hours to print a 1 cm thick tissue precursor graft and just over 5 h 30 to print a 3 cm thick kidney precursor. _Advanced Materials PDF

Swiss scientists are using a special inkjet printer to assemble three dimensional living constructs that resemble living tissues. They are still in the early stages of the research, but are achieving some interesting results.

They are working on a technique that should eventually allow them to “print” living constructs resembling human tissues in which cells can develop and interact in a coordinated and physiological manner. Their research results have recently been published in the scientific journal Advanced Materials.

“We have not yet created tissue, strictly speaking,” explains Professor Jürgen Brügger, head of EPFL’s Microsystems 1 Laboratory. “At this stage, we have essentially studied a way in which to structure biological materials in three dimensions; this research will improve cell culture and then will eventually be used as a base for creating tissues.”

…To make up a coherent whole, the cells need an environment that provides the right kinds of signals that induce very specific behavior in each of the cells – proliferation, migration, differentiation or death. In natural tissues, these signals come from molecules that make up a complex extracellular matrix (ECM). By studying the connections and communications taking place between cells and between cells and ECM molecules, the scientists were able to reconstruct this matrix and thus create a new kind of biological ink.

On a technical level, the researchers from EPFL’s two Microsystems Laboratories – under the leadership of professors Jürgen Brugger and Philippe Renaud – focused on developing a gel that could be used as a base from which the tissue could be constructed, as well as a strategy for printing droplets.

…Even though it will still be quite some time before tissue can be constructed, this technology could lead to very promising applications on the medium term. “ An exiting avenue would be to develop 3D constructs that function like human tissues and could be used as models for testing new drugs,” says Lutolf. “This is not only very interesting in a biological sense, but could also reduce the need for animal testing.” _Physorg

Learning to create life-like 3 dimensional cell cultures for research, and learning to create 3-D lab-made living tissues for replacement, are not quite the same things. But the two lines of research are likely to borrow from and contribute to each other, extensively.

This research used fibroblasts. Future research is likely to use a variety of stem cells and other precursor cells for various cell types.

Non-fluorescent NIH 3T3 fibroblasts were used in this printing as to be compatible with the fluorescent Live-Dead assay. The cells were suspended in culture medium supplemented with 0.8% wt. non-fluorescent alginate at a concentration of 1×10 6 mL -1 . Cells were inkjet printed onto 2% wt. gelatin substrates prepared with 0.9% wt. NaCl and 10 mM CaCl2, prepared in a 96-well plate. All cells were incubated for 4h before Live-Dead staining. _Advanced Materials

Al Fin Longevity

“I think we’re getting closer to harnessing neurogenesis to improve cognition and mood in humans. This research may also help explain a bit of a mystery in the field, which we still don’t understand, regarding how the hippocampus can be involved with both cognition – which is its classic function – and in mood and anxiety-related functions. Perhaps the fact that pattern separation affects both the cognitive and mood domains is the beginning of an answer to that paradox,” said Dr. Hen. _StemCells

René Hen, PhD, professor of Neuroscience and Pharmacology, in the Departments of Neuroscience and Psychiatry at Columbia University and the New York State Psychiatric Institute, has discovered a possible escape hatch by which some members of society might escape the Idiocracy. It involves the use of chemicals called “BAX inhibitors.” Particular members of that class of drugs have the potential to preserve newborn stem cells in the brain’s hippocampus. And doing that could make all the difference in the course of a person’s life success and happiness.

After boosting the number of neurons in the hippocampus, an area of the brain involved in memory and mood, the researchers tested the mice in both learning and mood-related tasks and looked for changes in behavior. The researchers found specific effects on learning tasks that involve a process called pattern separation, which is the ability to distinguish between similar places, events and experiences.

“This process is crucial for learning because it enables us to know whether something is familiar or novel,” said Dr. Hen. “If it is familiar, you move on to the next bit of information; if it’s novel, you want to be able to recognize that it’s new and give it meaning. These mice, with just more adult-born neurons, and no other changes in the brain, basically learn better in tasks where they have to discriminate between similar contexts.”

Earlier strategies for manipulating neurogenesis, according to the investigators, were broader and less specific. “In addition to stimulating neurogenesis, these earlier methods exerted many other effects on the brain. As a result, you never knew with these older manipulations what’s due to neurogenesis, or what’s due to the other effects that these manipulations cause, and, indeed, what we find is that when you stimulate just adult neurogenesis, you actually get a subtle effect. Unlike broader manipulations, it does not affect all forms of learning, it’s very specific to tasks that require pattern separation,” said Dr. Hen.

Pattern separation is not only important for learning; it may also be important for anxiety disorders, including post traumatic stress disorder (PTSD) and panic disorder. People with PTSD, say the researchers, have a more generalized fear response, so that when they are placed in a situation that reminds them of even one aspect of their trauma, they frequently have a full fear response.

…The researchers say that the genetic strategy used to stimulate neurogenesis in their experiments can be mimicked pharmacologically, potentially leading to the development of new drugs to reverse pattern separation deficits. One such class of drugs the investigators are currently testing – BAX inhibitors – works by blocking cell death.

“These drugs are basically doing the same thing that we did with our genetic manipulation-namely, increasing the survival of the young neurons which normally undergo a process of cell death that eliminates at least half of these neurons. Now instead of dying, the neurons will go on to survive,” said Dr. Sahay.

Some BAX inhibitors have been developed for stroke research, where the goal has also been to prevent neurons from dying. The Columbia researchers plan to begin testing the BAX inhibitors in mice shortly. And if they produce cognitive benefits, the testing will be extended to clinical trials to determine if there’s also a beneficial effect in humans. _StemCells

This is all related to the length of time required before antidepressants are able to bring about a full “antidepressive response.” The full effect of modern antidepressants requires new stem cell production in the hippocampus — but that takes time to achieve. Drugs capable of rapid and prolonged increases of hippocampal stem cells could conceivably keep anxiety and depression at bay, while improving a person’s cognitive capacity.

No, this is not NZT. As mentioned here previously, a drug that could achieve the effect of the fictional NZT would have to stimulate changes in gene expression on multiple levels, and across a wide range of brain centers.

Smart drugs alone will not achieve the goal of smarter, better-rounded, and happier humans. Educational and environmental interventions would also be necessary, to blunt the Idiocratic brainwashing effect of modern media, modern academia, and modern popular culture, while allowing the brain to develop newer, more functional pathways.

Realistically, it will take 15 years at the earliest to see the early promise of this type of medication come to fulfillment. But a single ray of hope in the distance is worth a lot to a person immersed in the modern rush to Idiocracy.

More 5April2001: An example of rapid brain plasticity in human adults
The PNAS Abstract from the actual study

Previously published at Al Fin

As noted here before, improved neurogenesis in the hippocampus is associated with antidepressant and anti-anxiety behaviours in animal studies — and probably in humans. It does no good to live longer with younger brains if we are unable to enjoy our added time and brainpower.

Al Fin Longevity

Subhash Katewa (Kapahi lab, Buck Institute) talked about the metabolic adaptations that occur in flies whose lifespan is being extended by dietary restriction (DR). Katewa is studying translational control in DR using a method called translational profiling, which uses the number of ribosomes bound to each mRNA as an index of translational activity (more ribosomes = more translation). He found that DR increases translation of messages that encode a variety of mitochondrial functions; this observation led to some interesting findings about the differential turnover of triglycerides in DR vs ad libitum flies.

Adam Freund (Campisi lab, Buck Institute) spoke about the sources of age-related inflammation, focusing on the senescence-associated secretory phenotype (SASP). Freund has elucidated mechanisms of SASP control that intermediate between the most upstream events in senescence (DNA damage) and its downstream effects (secretion of inflammatory factors). I have it on good authority that he has a completed manuscript on the subject, hopefully to be publshed soon, so I won’t say more about his story here. (Mr. Freund happens to be my baymate.)

Dario Valenzano (Brunet lab, Stanford University) is studying the genetic architecture of longevity in a short-lived fish Nothobranchius furzeri, the shortest-living vertebrate that can be reared in captivity. As a graduate student, Valenzano developed a system of biomarkers for tracking the progress of aging in skin, brain and other tissues – not only physical markers like the senescence-associated beta-galactosidase but also behavioral markers that change over the lifespan. He is now proceeding to map the longevity-associated genes in N. furzeri and testing the sufficiency of the genes he finds. Early results indicate that short-lived and long-lived fish are dying from different causes, as evidenced by a bimodal distribution of death rate vs. age.

Adolfo Sánchez-Blanco (Kim lab, Stanford University Medical School) described the “molecular odometer” for aging in the worm C. elegans. He began with the observation that lifespan is variable, even among clonally identical individuals kept under identical conditions. With genetics and environment taken out of the picture, what makes some individuals live longer than others? In order to address this question, SB had to develop a molecular marker (e.g., promoter activity of some gene) that measures physiological age (as opposed to chronological age), and then determine whether the expression level of that marker in individual worms is predictive of lifespan. SB has identified several such genes whose expression at middle age strongly predicts remaining lifespan. He is now actively looking for interventions that abolish the correlation between marker expression and longevity: if the marker gene’s activity is serving to overcome the life-shortening effect of some stress, then removing that stress will not necessarily abolish the variability in the marker, but will eliminate the correlation between marker levels and lifespan. (This is a subtle but important logical issue; I would have thought that one should look for interventions that drove the population distribution of marker levels toward the favorable side of the distribution. It was clear from questions that a lot of audience members had trouble with this logic, and I’m still not sure I understand it myself.)

(next session)

Ouroboros

Oncogenes are damaged versions of normal genes (‘proto-oncogenes’) that control cell growth and differentiation. It is important to realize that a proto-oncogene is a normal gene; it is only through pathological processes that it becomes an oncogene. Cancer is a multistep process in which multiple genetic alterations must occur, usually over many years. Thus, only after a long span of time will cell differentiation, division, and growth be changed. In human cancers, inherited mutations are relatively rare. (more…)

Multiple losses are common as people age, including deaths of spouse, family, and friends. A less obvious form of loss involves the change in relationship quality with a spouse or friend who may be experiencing physical or cognitive impairment. These losses, as well as the awareness of one’s own mortality, often trigger a review and evaluation of unrealized dreams, lost opportunities, and unresolved relationships. This review may activate negative thoughts and maladaptive schema that impede the recovery process. In addition, the loss of meaningful relationships may isolate the older adult and reduce the opportunities for support and social interactions with others.

Cognitive-behavioral therapy interventions that seek to address these concerns can be helpful in reversing the negative spiral and engaging the individual in a more positive and adaptive response. For example, cognitive interventions that identify negative thoughts and challenge their accuracy will facilitate a more positive grief reaction and process. If the person believes that ‘I can’t survive alone,’ ‘My life is a total failure,’ or ‘I’ll never be happy again,’ then the person will find it difficult to interpret experience accurately. Cognitive techniques, such as ‘examining the evidence’ and ‘generating alternative thoughts,’ will facilitate a more positive recovery from loss and bereavement. In combination with behavioral techniques, such as increasing pleasant events and interactions with others, Cognitive-behavioral therapy helps move the person into a more problem-solving and adaptive response.

Cognitive-behavioral therapy (CBT) is an approach to treatment of psychological problems that emphasizes the relationship among cognitive processes (thoughts or beliefs), emotions, and behavior. The assumption is that what one believes about an event or experience impacts how one feels and behaves in that situation. Similarly, the activities or behaviors that one engages in will affect mood and thoughts. Thus, a depressed person is often trapped in a downward spiral of negative thoughts that lead to depressed feelings and disengagement from meaningful and pleasant activities. The approach to treatment assumes that changes in thoughts and behaviors will result in changes in mood. The process of treatment is active and directive, with the therapist and patient working collaboratively to identify and change negative or dysfunctional thoughts and increase participation in meaningful activities. The goal of CBT is to teach the skills needed to change the dysfunctional thinking and behaviors that contribute to negative mood. Thus, Cognitive behavioral interventions therapy emphasizes the teaching of coping skills for dealing with problems rather than ‘curing’ the problem. The expected consequence of teaching these skills is an increase in patients’ sense of self efficacy, competency, and coping abilities. These skills equip them to deal not only with present problems, but also with future problems. The leading figures in the development of general cognitive therapy approaches to treatment of mood disorders are Albert Ellis, Donald Meichenbaum, and Aaron Beck.

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The proportion of elderly at any age without any chronic conditions is small, and disease can trigger a cascade of events resulting in functional deficits and disability. An increase in the number of activities with which an elder has difficulty increases linearly with comorbidity, that is, coexistent medical conditions that further complicate not only the genesis of a functional deficit but also its treatment. For example, rehabilitation for a stroke for an individual who also has painful, degenerative changes in the foot and a low tolerance for stressful activity secondary to angina with exertion would present a particular rehabilitation challenge. Yet, this example encapsulates geriatric rehabilitation specialist’s emphasis on care and function, not cure and disease. (more…)

Married heterosexual couples automatically have a right to visit their loved ones in the hospital and to supervise their spouse’s funeral arrangements after their death. Additionally, they are commonly, if informally, given deference in terms of their spouse’s medical care. These rights and privileges are not automatically granted to same-sex partners. (more…)

Obesity in the elderly is a major health crisis facing our population that may predispose the elderly to the same adverse health outcomes facing the younger, obese population. However, several studies have suggested that the risk of obesity on life span is less in the elderly and may even become insignificant. However, these studies have found an increase in disability in older subjects with obesity. (more…)

Because it expresses my own orientation, I carry in my wallet a membership card to the Society for the Right to Die, which has imprinted on the back a signed statement of my living will.

When the aging process accelerates inexorably, you usually don’t just fail to wake up one morning because of old age. One of the many illnesses that afflict the elderly with increasing frequency will likely be the cause of death and dying. Here is where I feel a living will is important. (more…)

Rheumatoid Arthritis affects approximately 1% of the world’s population. Rheumatoid Arthritis
is a chronic, multisystem, autoimmune, and inflammatory disorder that involves peripheral joints in a symmetric distribution. The potential of the synovial inflammation to cause cartilage damage and bone erosions and subsequent changes in joint integrity is the feature of the disease. (more…)