Posts Tagged ‘ageing’

A research team at University of Copenhagen including a researcher from the Faculty of Health and Medical Sciences has discovered a circuit in the brains of mice connecting circadian rhythm to aggressive behaviour. The discovery is particularly interesting to Alzheimer’s patients who experience increased aggression at night. The researchers have developed special protein tools capable of turning off the cells in the brain causing the behaviour.

Each year around 8,000 Danes are diagnosed with a form of dementia. Alzheimer’s disease is one of them. The disease manifests itself in memory difficulties in particular, but can also result in personality changes and mood swings.

When the sun sets 20 per cent of all Alzheimer’s patients experience increased bewilderment, anxiety, unease, disorientation, irritation and aggression. This phenomenon is called ‘sundowning’ or sundown syndrome. At worst, the condition can mean that the patient must be left in professional care, as it can be difficult for family members to handle. The cause of the condition is unknown, but previous research has suggested that it is connected to the circadian rhythm.

A research team including a researcher from the Department of Drug Design and Pharmacology at the University of Copenhagen is now able to confirm this connection. The researchers have identified and mapped a circuit between the part of the brain containing the circadian clock or circadian rhythm and a part of the brain controlling aggression.

’We have shown that the circadian clock in mice is closely linked to an aggression centre in the mouse brain by a cell circuit. The human brain has those same groups of cells that the circuit goes through. With this knowledge, we are now enabled to target this circuit pharmacologically and target cells that make people aggressive at the end of the day’, says Assistant Professor Timothy Lynagh from the Department of Drug Design and Pharmacology at the University of Copenhagen.

Turn off the Aggression
The inner clock or circadian rhythm is located in the part of the brain called suprachiasmatic nucleus. One of the parts of the brain that control aggressive behaviour is called the ventromedial hypothalamus. Researchers have previously observed a connection between the two parts of the brain, though none have had knowledge of the specific circuit connecting them.

Using electrophysiology and microscopy, the researchers measured the activity of the brain cells at main author Clifford Saper’s laboratory in Boston. They also turned off parts of the cell circuit in the brains of mice to map the circuit and to identify the cells connecting the two parts of the brain. To map circuits in the brain you need a protein tool that can turn off the various cells to determine their function. Assistant Professor Timothy Lynagh has designed precisely such a tool.

‘We take a receptor and mutate it, so that it is not sensitive to anything in the brain, but very sensitive to a particular drug. The tool works like an on/off switch. When you put the protein tool in the mouse brain, under normal circumstances, nothing will happen. But when you give the animal the drug, the cells that have the receptor on them will be turned off’, Timothy Lynagh explains.

Using this tool, the researchers can thus in theory turn off the cells that cause people suffering from sundown syndrome to become more aggressive at night.

May Be Used on Humans 20 Years into the Future
The tool can also be used in other contexts than sundown syndrome. In other studies, Tim Lynagh’s tool has been used to turn off cells in rats linked to anxiety and fear.

‘If you can start understanding which cells in the brain lead to which problems, you can then put this tool into any of those parts of the brain. The person who takes the drug will then have the cells causing the problem turned off’, Timothy Lynagh says.

Even though the study was conducted on mice, the tool and the knowledge the research has generated can potentially be used in the treatment of humans.

‘Because of the huge advances that are coming along with CRISPR, I would be tempted to say that based on a recent demonstration of gene therapy for brain disease, potentially, it could be used in the human brain in 20 years’ time. Of course it needs a lot more research’, he says.

Todd, W. D., Fenselau, H., Wang, J. L., Zhang, R., Machado, N. L., Venner, A., … & Lowell, B. B. (2018). A hypothalamic circuit for the circadian control of aggression. Nature neuroscience, 1.


Roughly the same number of new nerve cells (dots) exist in the hippocampus of people in their 20s (three hippocampi shown, top row) as in people in their 70s (bottom). Blue marks the dentate gyrus, where new nerve cells are born.


Healthy people in their 70s have just as many young nerve cells, or neurons, in a memory-related part of the brain as do teenagers and young adults, researchers report in the April 5 Cell Stem Cell. The discovery suggests that the hippocampus keeps generating new neurons throughout a person’s life.

The finding contradicts a study published in March, which suggested that neurogenesis in the hippocampus stops in childhood (SN Online: 3/8/18). But the new research fits with a larger pile of evidence showing that adult human brains can, to some extent, make new neurons. While those studies indicate that the process tapers off over time, the new study proposes almost no decline at all.

Understanding how healthy brains change over time is important for researchers untangling the ways that conditions like depression, stress and memory loss affect older brains.

When it comes to studying neurogenesis in humans, “the devil is in the details,” says Jonas Frisén, a neuroscientist at the Karolinska Institute in Stockholm who was not involved in the new research. Small differences in methodology — such as the way brains are preserved or how neurons are counted — can have a big impact on the results, which could explain the conflicting findings. The new paper “is the most rigorous study yet,” he says.

Researchers studied hippocampi from the autopsied brains of 17 men and 11 women ranging in age from 14 to 79. In contrast to past studies that have often relied on donations from patients without a detailed medical history, the researchers knew that none of the donors had a history of psychiatric illness or chronic illness. And none of the brains tested positive for drugs or alcohol, says Maura Boldrini, a psychiatrist at Columbia University. Boldrini and her colleagues also had access to whole hippocampi, rather than just a few slices, allowing the team to make more accurate estimates of the number of neurons, she says.

To look for signs of neurogenesis, the researchers hunted for specific proteins produced by neurons at particular stages of development. Proteins such as GFAP and SOX2, for example, are made in abundance by stem cells that eventually turn into neurons, while newborn neurons make more of proteins such as Ki-67. In all of the brains, the researchers found evidence of newborn neurons in the dentate gyrus, the part of the hippocampus where neurons are born.

Although the number of neural stem cells was a bit lower in people in their 70s compared with people in their 20s, the older brains still had thousands of these cells. The number of young neurons in intermediate to advanced stages of development was the same across people of all ages.

Still, the healthy older brains did show some signs of decline. Researchers found less evidence for the formation of new blood vessels and fewer protein markers that signal neuroplasticity, or the brain’s ability to make new connections between neurons. But it’s too soon to say what these findings mean for brain function, Boldrini says. Studies on autopsied brains can look at structure but not activity.

Not all neuroscientists are convinced by the findings. “We don’t think that what they are identifying as young neurons actually are,” says Arturo Alvarez-Buylla of the University of California, San Francisco, who coauthored the recent paper that found no signs of neurogenesis in adult brains. In his study, some of the cells his team initially flagged as young neurons turned out to be mature cells upon further investigation.

But others say the new findings are sound. “They use very sophisticated methodology,” Frisén says, and control for factors that Alvarez-Buylla’s study didn’t, such as the type of preservative used on the brains.

M. Boldrini et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell. Vol. 22, April 5, 2018, p. 589. doi:10.1016/j.stem.2018.03.015.

S.F. Sorrells et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. Vol. 555, March 15, 2018, p. 377. doi: 10.1038/nature25975.

lzheimer’s disease is a neurodegenerative condition that causes the decline of cognitive function and the inability to carry out daily life activities. Past studies have suggested depression and other neuropsychiatric symptoms may be predictors of AD’s progression during its “preclinical” phase, during which time brain deposits of fibrillar amyloid and pathological tau accumulate in a patient’s brain. This phase can occur more than a decade before a patient’s onset of mild cognitive impairment. Investigators at Brigham and Women’s Hospital examined the association of brain amyloid beta and longitudinal measures of depression and depressive symptoms in cognitively normal, older adults. Their findings, published today by The American Journal of Psychiatry, suggest that higher levels of amyloid beta may be associated with increasing symptoms of anxiety in these individuals. These results support the theory that neuropsychiatric symptoms could be an early indicator of AD.

“Rather than just looking at depression as a total score, we looked at specific symptoms such as anxiety. When compared to other symptoms of depression such as sadness or loss of interest, anxiety symptoms increased over time in those with higher amyloid beta levels in the brain,” said first author Nancy Donovan, MD, a geriatric psychiatrist at Brigham and Women’s Hospital. “This suggests that anxiety symptoms could be a manifestation of Alzheimer’s disease prior to the onset of cognitive impairment. If further research substantiates anxiety as an early indicator, it would be important for not only identifying people early on with the disease, but also, treating it and potentially slowing or preventing the disease process early on.” As anxiety is common in older people, rising anxiety symptoms may prove to be most useful as a risk marker in older adults with other genetic, biological or clinical indicators of high AD risk.

Researchers derived data from the Harvard Aging Brain Study, an observational study of older adult volunteers aimed at defining neurobiological and clinical changes in early Alzheimer’s disease. The participants included 270 community dwelling, cognitively normal men and women, between 62 and 90 years old, with no active psychiatric disorders. Individuals also underwent baseline imaging scans commonly used in studies of Alzheimer’s disease, and annual assessments with the 30-item Geriatric Depression Scale (GDS), an assessment used to detect depression in older adults.

The team calculated total GDS scores as well as scores for three clusters symptoms of depression: apathy-anhedonia, dysphoria, and anxiety. These scores were looked at over a span of five years.

From their research, the team found that higher brain amyloid beta burden was associated with increasing anxiety symptoms over time in cognitively normal older adults. The results suggest that worsening anxious-depressive symptoms may be an early predictor of elevated amyloid beta levels – and, in turn AD — and provide support for the hypothesis that emerging neuropsychiatric symptoms represent an early manifestation of preclinical Alzheimer’s disease.

Donovan notes further longitudinal follow-up is needed to determine whether these escalating depressive symptoms give rise to clinical depression and dementia stages of Alzheimer’s disease over time.

Paper cited: Donovan et al. “Longitudinal Association of Amyloid Beta and Anxious-Depressive Symptoms in Cognitively Normal Older Adults” The American Journal of Psychiatry DOI: 10.1176/appi.ajp.2017.17040442

If you’re between 55 and 75 years old, you may want to try playing 3D platform games like Super Mario 64 to stave off mild cognitive impairment and perhaps even prevent Alzheimer’s disease.

That’s the finding of a new Canadian study by Université de Montréal psychology professors Gregory West, Sylvie Belleville and Isabelle Peretz. Published in PLOS One, it was done in cooperation with the Institut universitaire de gériatrie de Montréal (IUGM), Benjamin Rich Zendel of Memorial University in Newfoundland, and Véronique Bohbot of Montreal’s Douglas Hospital Research Centre.

In two separate studies, in 2014 and 2017, young adults in their twenties were asked to play 3D video games of logic and puzzles on platforms like Super Mario 64. Findings showed that the gray matter in their hippocampus increased after training.

The hippocampus is the region of the brain primarily associated with spatial and episodic memory, a key factor in long-term cognitive health. The gray matter it contains acts as a marker for neurological disorders that can occur over time, including mild cognitive impairment and Alzheimer’s.

West and his colleagues wanted to see if the results could be replicated among healthy seniors.

The research team recruited 33 people, ages 55 to 75, who were randomly assigned to three separate groups. Participants were instructed to play Super Mario 64 for 30 minutes a day, five days a week, take piano lessons (for the first time in their life) with the same frequency and in the same sequence, or not perform any particular task.

The experiment lasted six months and was conducted in the participants’ homes, where the consoles and pianos, provided by West’s team, were installed.

The researchers evaluated the effects of the experiment at the beginning and at the end of the exercise, six months later, using two different measurements: cognitive performance tests and magnetic resonance imaging (MRI) to measure variations in the volume of gray matter. This enabled them to observe brain activity and any changes in three areas:

the dorsolateral prefrontal cortex that controls planning, decision-making and inhibition;
the cerebellum that plays a major role in motor control and balance; and
the hippocampus, the centre of spatial and episodic memory.
According to the MRI test results, only the participants in the video-game cohort saw increases in gray matter volume in the hippocampus and cerebellum. Their short-term memory also improved.

The tests also revealed gray matter increases in the dorsolateral prefrontal cortex and cerebellum of the participants who took piano lessons, whereas some degree of atrophy was noted in all three areas of the brain among those in the passive control group.

What mechanism triggers increases in gray matter, especially in the hippocampus, after playing video games? “3-D video games engage the hippocampus into creating a cognitive map, or a mental representation, of the virtual environment that the brain is exploring.,” said West. “Several studies suggest stimulation of the hippocampus increases both functional activity and gray matter within this region.”

Conversely, when the brain is not learning new things, gray matter atrophies as people age. “The good news is that we can reverse those effects and increase volume by learning something new, and games like Super Mario 64, which activate the hippocampus, seem to hold some potential in that respect,” said West. Added Belleville: “These findings can also be used to drive future research on Alzheimer’s, since there is a link between the volume of the hippocampus and the risk of developing the disease.”

“It remains to be seen,” concluded West, “whether it is specifically brain activity associated with spatial memory that affects plasticity, or whether it’s simply a matter of learning something new.”

By Robert Preidt

In remote Italian villages nestled between the Mediterranean Sea and mountains lives a group of several hundred citizens over the age of 90. Researchers at the University of Rome La Sapienza and University of California San Diego School of Medicine have identified common psychological traits in members of this group.

The study, publishing in International Psychogeriatrics, found participants who were 90 to 101 years old had worse physical health, but better mental well-being than their younger family members ages 51 to 75.

“There have been a number of studies on very old adults, but they have mostly focused on genetics rather than their mental health or personalities,” said Dilip V. Jeste MD, senior author of the study, senior associate dean for the Center of Healthy Aging and Distinguished Professor of Psychiatry and Neurosciences at UC San Diego School of Medicine. “The main themes that emerged from our study, and appear to be the unique features associated with better mental health of this rural population, were positivity, work ethic, stubbornness and a strong bond with family, religion and land.”

There were 29 study participants from nine villages in the Cilento region of southern Italy. The researchers used quantitative rating scales for assessing mental and physical health, as well as qualitative interviews to gather personal narratives of the participants, including topics such as migrations, traumatic events and beliefs. Their children or other younger family members were also given the same rating scales and additionally asked to describe their impressions about the personality traits of their older relatives.

“The group’s love of their land is a common theme and gives them a purpose in life. Most of them are still working in their homes and on the land. They think, ‘This is my life and I’m not going to give it up,'” said Anna Scelzo, first author of the study with the Department of Mental Health and Substance Abuse in Chiavarese, Italy

Interview responses also suggested that the participants had considerable self-confidence and decision-making skills.

“This paradox of aging supports the notion that well-being and wisdom increase with aging even though physical health is failing,” said Jeste, also the Estelle and Edgar Levi Chair in Aging and director of the Sam and Rose Stein Institute for Research on Aging at UC San Diego.

Some direct quotes from the study’s interviews include:
•”I lost my beloved wife only a month ago and I am very sad for this. We were married for 70 years. I was close to her during all of her illness and I have felt very empty after her loss. But thanks to my sons, I am now recovering and feeling much better. I have four children, ten grandchildren and nine great-grandchildren. I have fought all my life and I am always ready for changes. I think changes bring life and give chances to grow.”
•”I am always thinking for the best. There is always a solution in life. This is what my father has taught me: to always face difficulties and hope for the best.”
•”I am always active. I do not know what stress is. Life is what it is and must be faced … always.”
•”If I have to say, I feel younger now than when I was young.”

“We also found that this group tended to be domineering, stubborn and needed a sense of control, which can be a desirable trait as they are true to their convictions and care less about what others think,” said Scelzo. “This tendency to control the environment suggests notable grit that is balanced by a need to adapt to changing circumstances.”

The researchers plan to follow the participants with multiple longitudinal assessments and compare biological associations with physical and psychological health.

“Studying the strategies of exceptionally long-lived and lived-well individuals, who not just survive but also thrive and flourish, enhances our understanding of health and functional capacities in all age groups,” said Jeste.

Study co-authors include: Salvatore Di Somma, University of Rome La Sapienza; David Brenner, Nicholas Schork and Lori Montross, UC San Diego; and Paola Antonini, 3B Biotech Research.

Story Source:

Materials provided by University of California – San Diego. Original written by Michelle Brubaker.

Journal Reference:
1.Anna Scelzo, Salvatore Di Somma, Paola Antonini, Lori P. Montross, Nicholas Schork, David Brenner, Dilip V. Jeste. Mixed-methods quantitative–qualitative study of 29 nonagenarians and centenarians in rural Southern Italy: focus on positive psychological traits. International Psychogeriatrics, 2017; 1 DOI: 10.1017/S1041610217002721

By Ashley P. Taylor

During adulthood, the mouse brain manufactures new neurons in several locations, including the hippocampus and the subventricular zone of the forebrain. The hypothalamus, previously identified as an area with an important role in aging, also generates new neurons from neural stem cells. In a study published July 26 in Nature, Dongsheng Cai and his team at the Albert Einstein College of Medicine in New York connect the dots between these two observations, reporting that hypothalamic neural stem cells have widespread effects on the rate of aging in mice.

In what David Sinclair, who studies aging at Harvard Medical School and who was not involved in the work, calls a “Herculean effort,” the researchers “discovered that stem cells in the hypothalamus of the mouse play a role in overall health and life span,” he tells The Scientist.

Cai and his team found that killing hypothalamic neural stem cells accelerates aging, and transplantation of additional neural stem cells into the same brain region slows it down. Further, the stem cells’ anti-aging effects could be reproduced simply by administering the cells’ secreted vesicles, called exosomes, containing microRNAs (miRNAs).

“If this is true for humans, one could imagine a day when we are treated with these small RNAs injected into our bodies or even implanted with new hypothalamic stem cells to keep us younger for longer,” Sinclair adds.

Researchers who study aging have long been searching for a central location that controls the process system-wide. In a 2013 paper, Cai and his team reported aging-associated inflammation in the hypothalamus of the mouse, which they could experimentally manipulate to speed up or slow down various types of aging-related decline, from muscle endurance to cognitive skills.

This study, Cai says, suggested the hypothalamus might be that central locus in control of aging. The researchers wanted to understand more about how this region of the brain drives aging and what role hypothalamic neural stem cells might play in that process, so they undertook a series of experiments.

Age-defying stem cells

The researchers first confirmed that cells bearing protein markers of neural stem cells (Sox2 and Bmi1) were present in the hypothalamus of early-to-middle-aged mice (11 to 16 months old) and that the number of those cells decreased in older mice.

Next, they destroyed neuronal stem cells in the hypothalamus by injecting the third ventricle, adjacent to the hypothalamic region where the stem cells are found, with a lentivirus that converted an administered compound into a toxin in cells expressing the stem-cell marker Sox2. Three or four months later, the researchers compared a variety of aging-related measures, including muscle endurance, coordination, social behaviors, novel object recognition, and cognitive performance, between mice injected with the virus and various control groups of mice that received a brain injection of some sort but in which the toxin could not be produced and the hypothalamic stem cells were consequently not ablated.

The mice in the experimental group lost 70 percent of their hypothalamic stem cells and, based on results of the physiological tests, had accelerated aging. Mice with ablated hypothalamic stem cells also died earlier than control mice.

Next, the researchers implanted middle-aged mice with neural stem cells derived from newborn mice to see if the additional stem cells would slow aging. But the implanted stem cells almost all died, which the researchers believe was a result of the inflammatory environment of the aging hypothalamus. Newborn neuronal stem cells genetically engineered to withstand that environment, on the other hand, did survive, and mice implanted with those cells lived longer and performed better on aging-related measures than control mice.

“What’s cool about this study is that they specifically delete a population of cells in the hypothalamus of the brain . . . and they show pretty striking alterations in whole-body aging,” says Anna Molofsky, a psychiatrist at the University of California, San Francisco, who studies glial cells and whose graduate work focused on neuronal stem cells and aging. “That’s really showing that there’s a mechanism within the brain that’s regulating whole-body organismal aging,” she adds. Molofsky, who was not involved in the work, says that these results support the idea of the hypothalamus as a central regulator of aging.

Anti-aging mechanism

Although neural stem cells are known for their ability to produce new neurons, that doesn’t seem to be their primary method for protecting against aging. The anti-aging effects of these hypothalamic stem cells were visible at around four months—not long enough, the authors write, for significant adult neurogenesis to have taken place.

The authors looked instead for some other factor that might be responsible for the stem cells’ effects. In the hypothalamic neural stem cells, the researchers detected exosomes—secreted vesicles that can contain RNA and proteins—containing a variety of miRNAs, short RNA molecules that inhibit the expression of targeted genes. These exosomes were not present in non-stem cells of the hypothalamus.

To test the effects of the exosomes alone on aging, the researchers purified the vesicles from cultured hypothalamic neural stem cells and transplanted them into middle-aged mice, finding that the exosome-treated mice aged more slowly than vehicle-treated controls. They also found that the exosomes could ameliorate the aging symptoms of mice whose hypothalamic neurons had been ablated.

Cai says microRNAs could be a potential mechanism by which hypothalamic neural stem cells have such wide-ranging effects on aging, yet he believes that neurogenesis may also be involved.

Regardless of the mechanism, Molofsky says, “the medical applications could be pretty profound.” The phenotypes, such as muscle mass and skin thickness, affected by these stem cells are the same ones that cause age-related disease, she notes. “The fact that you can reverse that with a brain-specific modulation, potentially, in a cell type that one could pharmacologically target, I think potentially that could be very profound, assuming that the mouse work translates to humans.”

Y. Zhang et al., “Hypothalamic stem cells control ageing speed partly through exosomal miRNAs,” Nature, doi:10.1038/nature23282, 2017.

Every hour you run extends your life span by seven hours, a new study has revealed.

Scientists say that running just one hour a week is the most effective exercise to increase life expectancy.

This holds true no matter how many miles or how fast you run, the researchers claim.
For those that take this advice to heart and run regularly, they say you can extend your life span by up to three years.

The study, conducted at Iowa State University, reanalyzed data from The Cooper Institute, in Texas, and also examined results from a number of other recent studies that looked at the link between exercise and mortality.

Scientists found that the new review reinforced the findings of earlier research.
At whatever pace or mileage, a person’s risk of premature death dropped by 40 percent when he or she took up running.

This applied even when researchers controlled for smoking, drinking or a history of health problems such as obesity.

Three years ago, the same team conducted a study that analyzed more than 55,000 adults, and determined that running for just seven minutes a day could help slash the risk of dying from heart disease.

They followed participants over a period of 15 years, and found that of the more than 3,000 who died, only one-third of deaths were from heart disease.

Co-author Dr Duck-chul High-mileage runners also questioned if they were overperforming and if, at some point, running would actually contribute to premature mortality.
After analyzing the data in the new study, scientists determined that hour for hour, running statistically returns more time to people’s lives than it consumes.
In The Cooper Institute study, participants reported an average of two hours running per week.
The amount ran over the course of 40 years would add up to fewer than six months, but it could increase life expectancy by more than three years.

The researchers also determined that if every non-runner who had been part of the reviewed studies took up the sport, there would have been 16 percent fewer deaths over all, and 25 percent fewer fatal heart attacks.

Other types of exercise were also found to be beneficial. Walking and cycling dropped the risk of premature death by about 12 percent.

Dr Lee says scientists remain uncertain as to why running helps with longevity.

But he says it’s likely because the sport combats many common risk factors for early death, including high blood pressure and extra body fat, especially around the middle.

It also raises aerobic fitness, one of the best-known indicators for long-term health.
Running, however, does not make you immortal and the life expectancy rates don’t increase beyond three years.

Improvements in life expectancy generally plateaued at about four hours of running per week, Dr Lee said. But they did not decline.

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