How astrocytes change with age

 Salk researchers have discovered that genes that are switched on early in brain development to sever connections between neurons as the brain fine-tunes, are again activated in aging neuronal support cells called astrocytes. Astrocytes may be good therapeutic targets to prevent or reverse the effects of normal aging.

Neuroscientists know that in the young, developing brain, synapses are being activated and deactivated, while in the adult brain they are mostly stable. But in aging brains, neurons start to lose connections and don't communicate as well. Allen and graduate student Matthew Boisvert wondered whether the changes to synapses and neuronal communication during aging might be related to changes in astrocytes.

To find out, the duo decided to compare gene expression in astrocytes in the adult brain versus the aged brain in mice. This would give them an idea of which genes are active at the two stages.o Researchers compare four-month-old mice, who in mouse years are adults, to two-year-old mice, who are quite elderly. They used a molecular technology called ribo-tag that allowed him to find out which genes were being made into proteins by astrocytes. It works by isolating the protein-making machines of cells (called ribosomes), which turn mRNA copies of DNA (genes) into proteins.

By taking a sort of molecular snapshot of an astrocyte's ribosomes, it's possible to see all the mRNA copies in progress and thus know which genes are active. To develop a comprehensive view of astrocyte gene expression, the duo used the technique in four very different areas of the mouse brain: two regions of the cortex and the hypothalamus and cerebellum.

To their surprise, they found that most of the properties that make an astrocyte an astrocyte didn't change much with age-gene expression was fairly consistent with time. But what did change: genes that during development would normally cause the loss of connections between neurons were switched on again in the aging astrocytes.

This suggests that there's some sort of genetic program that's being reactivated in these astrocytes as they age that's causing neurons to lose their connections with each other. Interestingly, the areas in which astrocytes looked the most different were brain areas where neurons are known to function notably less well with age or even to die-the cerebellum and the hypothalamus. This may explain why metabolism decreases and coordination gets worse with age, because these are functions that are coordinated by the hypothalamus and cerebellum.
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Severe obesity linked to gene mutations

Researchers have discovered mutations in a gene related to obesity, offering new treatment possibilities in the fight against the global epidemic. The new study, led by Imperial College London  focused on children suffering from obesity in Pakistan, where genetic links to obesity had been previously identified by the team in about 30% of cases.

This link of genes to obesity is due to recessive mutations that are more likely to be inherited and passed on to children in a region like Pakistan because of the high level of consanguinity (inter-family relationships) in its population. This is because parents who are closely related are more likely to be carrying the same mutation, so a child may inherit from both sides, causing the mutation to take effect.

This new study used genome sequencing and found mutations in one specific gene related to obesity: adenylate cyclase 3 (ADCY3). When mutations occur in ADCY3, the protein it codes for forms abnormally and doesn't function properly. This leads to abnormalities relating to appetite control, diabetes, and even sense of smell.

Early studies into ADCY3 tested mice that were bred to lack that gene, found that these animals were obese and also lacked the ability to smell, known as anosmia. When we tested our patients, we found that they also had anosmia, again showing a link to mutations in ADCY3.

ADCY3 is thought to impact a system that links the hypothalamus to the production of hormones that regulate a wide variety of biological functions, including appetite. This research also found a link between ADCY3 mutations and obesity, a
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Anger causes untimely death

Researchers have discovered that angry men aged 20 to 40 were one-and-a-half times more likely to be dead 35 years later than those who were calmer. They believe this is due to a number of factors linking stress to physiological damage. The frequent release of adrenaline during periods of stress damages DNA, which could lead to life-threatening illnesses such as multiple sclerosis.

Feelings of anger produce a heightened response in the amygdala, the part of the brain associated with survival instincts. Angry emotions prompt the amygdala to signal a heightened state of anxiety to the rest of the brain and the body, increasing blood flow to the limbs and heart, which makes relaxation impossible.

Those exposed to anger-inducing stimuli without discussing how it made them feel are more likely to experience insomnia than those who engage in an emotional ‘debrief’, according to neuroscientists. Writing the cause of anger frees up the space in the head, dampening the fear response and encouraging relaxation.

 Emotions such as excitement or anger result in the release of stress hormones cortisol, adrenaline and testosterone, which put the body into flight-or-flight mode. The chemical surge increases blood flow to the brain and triggers the swelling of both blood vessels and nerves surrounding the brain. The pressure can result in tension and headaches.

Highly hostile individuals performed significantly worse on a simple inhalation task than those who were rated less hostile. When you are angry, neurotransmitters and hormones are sent through the bloodstream which, in turn, increase both the heart rate and muscle tension. Frequent occurrence of this reaction puts a strain on neurons in the hypothalamus, the brain’s ‘stress control centre’, meaning that it becomes harder for the neurons to switch off. And the ‘happy hormone’ serotonin is significantly depleted in some aggressive individuals.

Too much cortisol in the body – released by adrenal glands during angry outbursts can cause an imbalance in blood sugar, repress the thyroid and even decrease bone density. When released initially, cortisol triggers an anti-inflammatory response by the immune system, but prolonged increase of the hormone makes the body more susceptible to viruses. As blood pressure rises thanks to a surge in adrenaline, the heart beats faster, increasing the risk of potentially fatal abnormal heart rhythms. Adrenaline also signals for the release of platelets, which can trigger blood clots or block arteries – particularly dangerous if arteries are restricted by a build-up of cholesterol.

Studies have shown that men in particular who score highly on trait anger scales are three times more likely to suffer from general heart disease. Once the ‘fight or flight’ signal has been issued by the brain, blood supply is directed to areas needed for action such as the limbs. That means blood supply to the digestive system is reduced, with a reduced amount of oxygen provided to keep vital ‘good’ bacteria in the gut alive. A dampened immune system can lead to a weakened gut lining, increasing vulnerability to harmful bacteria entering the area.

Heightened stress reduces the amount of available glucocorticoids -the hormone involved in the synthesis of the skin-plumping compound collagen. Lack of collagen contributes towards saggy, wrinkled skin. The weakened immune system caused by stress responses increases inflammatory reactions to pathogens underneath the skin.

Enhanced periods of anger disrupt the skin-barrier function, making it easier for allergens to penetrate and resulting in skin conditions such as dermatitis and psoriasis. Repressing, rather than expressing anger puts you at an higher risk of developing health problems. This increased risk of hypertension for angry individuals who tended to keep their anger below a level of consciousness. By repressing emotion, excess stress hormones remain in the emotion-processing areas of the brain for longer period making physical reactions chronic.
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Regulating asprosin levels can control appetite and weight

Researchers have discovered a new hormone called asprosin, that regulates blood-glucose levels. New studies on the hormones showed that asprosin also acts on the brain, stimulating the hunger center in the hypothalamus to control appetite and body weight. This opens an intriguing possibility for developing treatments for overweight people. They discovered asprosin when studying individuals affected by a rare medical condition called neonatal progeroid syndrome.

Patients with neonatal progeroid syndrome have a mutation in the FBN1 gene that causes them to lack a small piece of the fibrillin-1 protein. In individuals without the FBN1mutation, this small piece, which we named asprosin, is cut and released into the circulation from the end of the protein.
One of the cardinal features that defines neonatal progeroid syndrome is extreme thinness or very low body weight. This allowed measurement of how much food they ate relative to the number of calories they burned every day.

Compared with individuals with normal weight, neonatal progeroid syndrome patients have abnormally low appetite.
To investigate how the mutation affected the patients' appetite, the researchers genetically engineered mice to carry the same genetic mutation the patients have. The result was mice that mimicked the human condition; they had low blood asprosin levels, low appetite and were very thin.

In the mouse model, researchers were able to reverse the low appetite by administering asprosin to the mice.
To understand how asprosin controls appetite. Asprosin interacts with neurons in the appetite center of the hypothalamus. There are two types of neurons involved in appetite control. One type, the AgRP neurons, stimulates appetite while the other type, POMC neurons, suppresses it.

Asprosin works on both types of neurons in an opposite manner; it activates appetite-stimulating AgRP neurons and it deactivates appetite-suppressing POMC neurons. The resulting effect of these two asprosin actions in the brain is an increase in appetite, a phenomenon that is deficient in individuals and mice with neonatal progeroid syndrome. The researchers also studied individuals with obesity and found that they had increased levels of blood asprosin.
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Effects of estrogen treatment on menopausal women

Hormone replacement therapy may protect menopausal women from stress-related memory loss. The sex hormone estrogen buffers working memory from the impact of stress, which is known to impair short-term working memory. Women going through menopause take hormone replacement therapy HRT which contains estrogen to offset hot flushes, night sweats, sleep disturbances, mood swings, and reduced sex drive. The treatment also blocks fluctuating hormones from affecting memory.

Estrogen can modify women's hormonal response to stress, researchers discovered that the treatment after menopause protects working memory needed for short-term cognitive tasks from the effects of stress. Stress prompts the hormonal system and the hypothalamus to release cortisol. Cortisol interferes with the activity of the hippocampus from making new neurons and neural connections, a process that is key to working memory.

HRT may reduce the response and cortisol, when there are environmental or immune system stressors. Stress can interference with prefrontal cognitive processes such as working memory.
HRT can reduce the HPA response to stress, the hormone may also mitigate the effects of stress on working memory by limiting the cortisol response to the stressor. Researchers examined different study participants, some received estrogen therapy for menopausal symptoms and others received a placebo for five years. The women provided saliva samples so their levels of cortisol, a hormone associated with stress, was measured.

During two separate sessions, each woman completed a memory task where they were instructed to remember the final word of each sentence. Prior to one of the sessions, the women submerged their non-dominant hand in ice water for as long as possible, for a maximum of three minutes. During the other session, the women submerged the same hand in warm water before completing the memory test.

Although the women who were receiving estrogen therapy reported feeling more stressed by the cold water exposure than the women who received the placebo, they had lower levels of cortisol than their counterparts following the stress test. Women receiving HRT performed about the same on the memory task, regardless of whether they were exposed. sed to the cold water stressor in advance or not. Women who were taking the placebo performed worse on the memory task because of exposure to the cold water than they did when they were not exposed to a physical stressor.
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Sleep and caffeine can reduce post operative pain

Sleep is essential for good mental and physical health, insufficient sleep increases the risk for several chronic diseases. Pre and postoperative sleep disturbances worsen pain. Caffeine in coffee and other beverages blocks the actions of adenosine in the brain. Adenosine is an endogenous sleep inducer.

Insufficient sleep enhances pain perception. Using a rat model of surgical pain, the research team tested whether prior sleep deprivation increases postoperative pain and caffeine blocks the increase in postoperative pain caused by sleep deprivation.

Researchers sought to identify a potential brain mechanism by which disrupted sleep worsens pain. The effect of sleep deprivation on pain sensitivity in operated and intact rats was virtually eliminated by pharmacologically blocking the action of adenosine in a brain region in the anterior hypothalamus known to regulate sleep, which is connected to major pain-related areas.

Extended wakefulness prior to surgery significantly enhanced postoperative pain behaviors and extended recovery time after surgery. Caffeine mitigate this effect. It blocked the increase in surgical pain caused by previous sleep loss.

 Caffeine might prevent the increase in pain sensitivity by blocking part of the neurochemical changes induced by sleep deprivation in specific brain areas that control sleep and wakefulness, and project to pain-related sites.
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Brain cells control aging

Scientists have discovered that stem cells in the brain's hypothalamus control how fast aging occurs in the body. This discovery could lead to new method of preventing diseases and increasing lifespan.

The hypothalamus regulates growth, development, reproduction, metabolism and aging. The number of hypothalamic neural stem cells naturally declines and this accelerates aging.
Replenishing stem cells can slow down the process of aging but the loss are not irreversible.

Researchers disrupted the hypothalamic stem cells in middle-aged mice and discovered that disruption accelerated aging. They injected hypothalamic stem cells into the brains of middle-aged mice whose stem cells had been destroyed as well as into the brains of normal old mice.

The treatment showed different measures of aging in both groups. Hypothalamic stem cells exert their anti-aging effects by releasing microRNAs (miRNAs).

The researchers extracted miRNA-containing exosomes from hypothalamic stem cells and injected them into the cerebrospinal fluid of middle-aged mice whose hypothalamic stem cells had been destroyed and normal middle-aged mice.

This treatment slowed aging in both groups of animals as measured by tissue analysis and behavioral testing that involved assessing changes in the animals' muscle endurance, coordination, social behavior and cognitive ability.
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