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Wednesday, December 26, 2018

Good genes are nice, but joy is better 12-27





 Harvard study, almost 80 years old, has proved that embracing community helps us live longer, and be happier...

Second in an occasional series on how Harvard researchers are tackling the problematic issues of aging.

When scientists began tracking the health of 268 Harvard sophomores in 1938 during the Great Depression, they hoped the longitudinal study would reveal clues to leading healthy and happy lives.

They got more than they wanted. 
 After following the surviving Crimson men for nearly 80 years as part of the Harvard Study of Adult Development, one of the world’s longest studies of adult life, researchers have collected a cornucopia of data on their physical and mental health.
Of the original Harvard cohort recruited as part of the Grant Study, only 19 are still alive, all in their mid-90s. Among the original recruits were eventual President John F. Kennedy and longtime Washington Post editor Ben Bradlee. (Women weren’t in the original study because the College was still all male.)
In addition, scientists eventually expanded their research to include the men’s offspring, who now number 1,300 and are in their 50s and 60s, to find out how early-life experiences affect health and aging over time. Some participants went on to become successful businessmen, doctors, lawyers, and others ended up as schizophrenics or alcoholics, but not on inevitable tracks.
During the intervening decades, the control groups have expanded. In the 1970s, 456 Boston inner-city residents were enlisted as part of the Glueck Study, and 40 of them are still alive. More than a decade ago, researchers began including wives in the Grant and Glueck studies.

Over the years, researchers have studied the participants’ health trajectories and their broader lives, including their triumphs and failures in careers and marriage, and the finding have produced startling lessons, and not only for the researchers.
“The surprising finding is that our relationships and how happy we are in our relationships has a powerful influence on our health,” said Robert Waldinger, director of the study, a psychiatrist at Massachusetts General Hospital and a professor of psychiatry at Harvard Medical School. “Taking care of your body is important, but tending to your relationships is a form of self-care too. That, I think, is the revelation.”
Close relationships, more than money or fame, are what keep people happy throughout their lives, the study revealed. Those ties protect people from life’s discontents, help to delay mental and physical decline, and are better predictors of long and happy lives than social class, IQ, or even genes. That finding proved true across the board among both the Harvard men and the inner-city participants.
The long-term research has received funding from private foundations, but has been financed largely by grants from the National Institutes of Health, first through the National Institute of Mental Health, and more recently through the National Institute on Aging.
Researchers who have pored through data, including vast medical records and hundreds of in-person interviews and questionnaires, found a strong correlation between men’s flourishing lives and their relationships with family, friends, and community. Several studies found that people’s level of satisfaction with their relationships at age 50 was a better predictor of physical health than their cholesterol levels were.
“When we gathered together everything we knew about them about at age 50, it wasn’t their middle-age cholesterol levels that predicted how they were going to grow old,” said Waldinger in a popular TED Talk. “It was how satisfied they were in their relationships. The people who were the most satisfied in their relationships at age 50 were the healthiest at age 80.”
He recorded his TED talk, titled “What Makes a Good Life? Lessons from the Longest Study on Happiness,” in 2015, and it has been viewed 13,000,000 times.
The researchers also found that marital satisfaction has a protective effect on people’s mental health. Part of a study found that people who had happy marriages in their 80s reported that their moods didn’t suffer even on the days when they had more physical pain. Those who had unhappy marriages felt both more emotional and physical pain.
Those who kept warm relationships got to live longer and happier, said Waldinger, and the loners often died earlier. “Loneliness kills,” he said. “It’s as powerful as smoking or alcoholism.”
According to the study, those who lived longer and enjoyed sound health avoided smoking and alcohol in excess. Researchers also found that those with strong social support experienced less mental deterioration as they aged.
In part of a recent study, researchers found that women who felt securely attached to their partners were less depressed and more happy in their relationships two-and-a-half years later, and also had better memory functions than those with frequent marital conflicts.



“Good relationships don’t just protect our bodies; they protect our brains,” said Waldinger in his TED talk. “And those good relationships, they don’t have to be smooth all the time. Some of our octogenarian couples could bicker with each other day in and day out, but as long as they felt that they could really count on the other when the going got tough, those arguments didn’t take a toll on their memories.”
Since aging starts at birth, people should start taking care of themselves at every stage of life, the researchers say.
“Aging is a continuous process,” Waldinger said. “You can see how people can start to differ in their health trajectory in their 30s, so that by taking good care of yourself early in life you can set yourself on a better course for aging. The best advice I can give is ‘Take care of your body as though you were going to need it for 100 years,’ because you might.”
The study, like its remaining original subjects, has had a long life, spanning four directors, whose tenures reflected their medical interests and views of the time.
Under the first director, Clark Heath, who stayed from 1938 until 1954, the study mirrored the era’s dominant view of genetics and biological determinism. Early researchers believed that physical constitution, intellectual ability, and personality traits determined adult development. They made detailed anthropometric measurements of skulls, brow bridges, and moles, wrote in-depth notes on the functioning of major organs, examined brain activity through electroencephalograms, and even analyzed the men’s handwriting.
Now, researchers draw men’s blood for DNA testing and put them into MRI scanners to examine organs and tissues in their bodies, procedures that would have sounded like science fiction back in 1938. In that sense, the study itself represents a history of the changes that life brings.
Psychiatrist George Vaillant, who joined the team as a researcher in 1966, led the study from 1972 until 2004. Trained as a psychoanalyst, Vaillant emphasized the role of relationships, and came to recognize the crucial role they played in people living long and pleasant lives.



In a book called “Aging Well,” Vaillant wrote that six factors predicted healthy aging for the Harvard men: physical activity, absence of alcohol abuse and smoking, having mature mechanisms to cope with life’s ups and downs, and enjoying both a healthy weight and a stable marriage. For the inner-city men, education was an additional factor. “The more education the inner city men obtained,” wrote Vaillant, “the more likely they were to stop smoking, eat sensibly, and use alcohol in moderation.”
Vaillant’s research highlighted the role of these protective factors in healthy aging. The more factors the subjects had in place, the better the odds they had for longer, happier lives.
“When the study began, nobody cared about empathy or attachment,” said Vaillant. “But the key to healthy aging is relationships, relationships, relationships.”
The study showed that the role of genetics and long-lived ancestors proved less important to longevity than the level of satisfaction with relationships in midlife, now recognized as a good predictor of healthy aging. The research also debunked the idea that people’s personalities “set like plaster” by age 30 and cannot be changed.
“Those who were clearly train wrecks when they were in their 20s or 25s turned out to be wonderful octogenarians,” he said. “On the other hand, alcoholism and major depression could take people who started life as stars and leave them at the end of their lives as train wrecks.”
The study’s fourth director, Waldinger has expanded research to the wives and children of the original men. That is the second-generation study, and Waldinger hopes to expand it into the third and fourth generations. “It will probably never be replicated,” he said of the lengthy research, adding that there is yet more to learn.
“We’re trying to see how people manage stress, whether their bodies are in a sort of chronic ‘fight or flight’ mode,” Waldinger said. “We want to find out how it is that a difficult childhood reaches across decades to break down the body in middle age and later.”
Lara Tang ’18, a human and evolutionary biology concentrator who recently joined the team as a research assistant, relishes the opportunity to help find some of those answers. She joined the effort after coming across Waldinger’s TED talk in one of her classes.
“That motivated me to do more research on adult development,” said Tang. “I want to see how childhood experiences affect developments of physical health, mental health, and happiness later in life.”
Asked what lessons he has learned from the study, Waldinger, who is a Zen priest, said he practices meditation daily and invests time and energy in his relationships, more than before.
“It’s easy to get isolated, to get caught up in work and not remembering, ‘Oh, I haven’t seen these friends in a long time,’ ” Waldinger said. “So I try to pay more attention to my relationships than I used to.”

Monday, December 24, 2018

When love and science double date 24-12








 Sure, your heart thumps, but let’s look at what’s happening physically and psychologically....
 

Love’s warm squishiness seems a thing far removed from the cold, hard reality of science. Yet the two do meet, whether in lab tests for surging hormones or in austere chambers where MRI scanners noisily thunk and peer into brains that ignite at glimpses of their soulmates.
When it comes to thinking deeply about love, poets, philosophers, and even high school boys gazing dreamily at girls two rows over have a significant head start on science. But the field is gamely racing to catch up.
One database of scientific publications turns up more than 6,600 pages of results in a search for the word “love.” The National Institutes of Health (NIH) is conducting 18 clinical trials on it (though, like love itself, NIH’s “love” can have layered meanings, including as an acronym for a study of Crohn’s disease). Though not normally considered an intestinal ailment, love is often described as an illness, and the smitten as lovesick. Comedian George Burns once described love as something like a backache: “It doesn’t show up on X-rays, but you know it’s there.”

Richard Schwartz, associate professor of psychiatry at Harvard Medical School (HMS) and a consultant to McLean and Massachusetts General (MGH) hospitals, says it’s never been proven that love makes you physically sick, though it does raise levels of cortisol, a stress hormone that has been shown to suppress immune function.
Love also turns on the neurotransmitter dopamine, which is known to stimulate the brain’s pleasure centers. Couple that with a drop in levels of serotonin — which adds a dash of obsession — and you have the crazy, pleasing, stupefied, urgent love of infatuation.
It’s also true, Schwartz said, that like the moon — a trigger of its own legendary form of madness — love has its phases.
“It’s fairly complex, and we only know a little about it,” Schwartz said. “There are different phases and moods of love. The early phase of love is quite different” from later phases.
During the first love-year, serotonin levels gradually return to normal, and the “stupid” and “obsessive” aspects of the condition moderate. That period is followed by increases in the hormone oxytocin, a neurotransmitter associated with a calmer, more mature form of love. The oxytocin helps cement bonds, raise immune function, and begin to confer the health benefits found in married couples, who tend to live longer, have fewer strokes and heart attacks, be less depressed, and have higher survival rates from major surgery and cancer.
Schwartz has built a career around studying the love, hate, indifference, and other emotions that mark our complex relationships. And, though science is learning more in the lab than ever before, he said he still has learned far more counseling couples. His wife and sometime collaborator, Jacqueline Olds, also an associate professor of psychiatry at HMS and a consultant to McLean and MGH, agrees.
Love also turns on the neurotransmitter dopamine, which is known to stimulate the brain’s pleasure centers. Couple that with a drop in levels of serotonin — which adds a dash of obsession — and you have the crazy, pleasing, stupefied, urgent love of infatuation.
It’s also true, Schwartz said, that like the moon — a trigger of its own legendary form of madness — love has its phases.
“It’s fairly complex, and we only know a little about it,” Schwartz said. “There are different phases and moods of love. The early phase of love is quite different” from later phases.
During the first love-year, serotonin levels gradually return to normal, and the “stupid” and “obsessive” aspects of the condition moderate. That period is followed by increases in the hormone oxytocin, a neurotransmitter associated with a calmer, more mature form of love. The oxytocin helps cement bonds, raise immune function, and begin to confer the health benefits found in married couples, who tend to live longer, have fewer strokes and heart attacks, be less depressed, and have higher survival rates from major surgery and cancer.
Schwartz has built a career around studying the love, hate, indifference, and other emotions that mark our complex relationships. And, though science is learning more in the lab than ever before, he said he still has learned far more counseling couples. His wife and sometime collaborator, Jacqueline Olds, also an associate professor of psychiatry at HMS and a consultant to McLean and MGH, agrees. 

Tuesday, December 18, 2018

Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome 12-17




Neuroinflammation, Fatigue and Pain Lab Stop

We were having a case of déjà vu as we drove around the surprisingly large campus. Getting into the NIH to see Avindra Nath had been a nightmare.  It turned out that the NIH would only allow the big van through one access point and we’d ended up mortifyingly late to our appointment. Now here we were in another big campus with what my partner felt were inadequate directions. 

 I thought Jarred and I had it going, though. He said he would meet us at the parking lot and let us through the gate, but there were lots of parking lots. Plus, because we couldn’t stop, we had to keep driving around the campus and hope we met up with him at the right parking lot at the right time. It did seem a little dicey but I was confident I’d figured it out.

My partner, though, wasn’t having it with the sketchy directions or the reliance on male directional genes.  She could see it happening – we were going to be late again.

“Men,” she said, “how do you ever get anything done?”
As it turned out, Jarred and I were in sync: we both showed up at the gate at about the same time and he led us into his surprisingly large facility. Once again, we forgot to take pictures, but our timing couldn’t have been better; Younger had just wrapped up one of the most exciting studies in memory.
But first a little history…
 Neuroinflammation – The Japanese Way
Researchers have thought for decades that neuroinflammation is probably present in chronic fatigue syndrome (ME/CFS), but it’s only recently that the technology has been able to pick up the lower levels of neuroinflammation believed present in diseases like ME/CFS and fibromyalgia. The Japanese were the first to take a crack at it. 
 They have long believed that inflammation produces central fatigue (fatigue emanating from the brain), which plays a major role in ME/CFS. In 2013, Watanabe proposed that inflammation in the brain was whacking the “facilitation system” which pops up when we are fatigued to boost signals from the motor cortex to keep our muscles moving. He also hypothesized that an inhibition system was turning up the fatigue in ME/CFS.
A 2016 study rounded the circle when it found evidence of reduced dopaminergic activity from a part of the brain (the basal ganglia) which activates the motor cortex. That fit in just fine with Miller’s results, which suggested that problems with the basal ganglia could be producing both the fatigue and the motor activity problems in ME/CFS.
The big breakthrough came in 2014 when the Japanese startled just about everyone with a PET scan study which found widespread neuroinflammation in the brains of ME/CFS patients. The study was small (n=19) but the findings appeared strong. 


The neuroinflammation was widespread but was highest in the areas of the brain (thalamus, amygdala, midbrain, hippocampus) that had shown up in ME/CFS before. Plus, the Japanese were able to link specific regions of inflammation to specific symptoms. Inflammation in the thalamus was associated with cognitive impairment, fatigue and pain; inflammation in the amygdala was associated with cognitive issues; and inflammation of the hippocampus was associated with depression.
Anthony Komaroff called the findings the most exciting in decades. The Japanese began a much larger (n=120) neuroinflammation study. This year they published a large number of papers on ME/CFS in the Japanese Journal, “Shinkei Kenkyu No Shinpo” (Brain and Nerve). One of the papers was specifically on neuroinflammation but the findings have not yet been published in English journals.

Neuroinflammation – The Younger Way

Jarred Younger – who runs the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama at Birmingham has also long believed that neuroinflammation plays a major role in chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM).
In 2015, he noted what a hot subject neuroinflammation had become.  Seven years ago, he said, there was almost nothing on the microglia at the pain conferences. Now they’re loaded with presentations on microglia.
These immune cells are sensitive to so many factors and can be triggered in so many ways that virtually any stressor, from an infection to toxins to psychological stress, can potentially trigger a state of microglial sensitization in the right individual. With their ability to produce dozens of different inflammatory mediators, Younger believes that the difference between ME/CFS and FM could simply come down to small differences in how the microglia are tweaked.
Both diseases could be triggered by high rates of immune activation which, over time, sensitizes the microglia to such an extent that they start pumping out inflammatory factors at the first sign of a stressor.





New Non-Invasive Technique

Younger had just finished up his ME/CFS brain thermometry study. He used a new, less invasive way of assessing the brain called magnetic resonance spectroscopic thermometry (MRSt). The technique, which aims to create a thermometer for the brain, uses a magnetic resonance imaging (MRI) scanner. While Younger was assessing the temperature of the brain, he was also examining its chemical makeup.
taking temperature of the brain
Using temperature as a measure of inflammation, Younger is taking the temperature of the brain.
My partner asked him how he glommed onto the heat mapping idea?  It turned out that Younger had been trying for quite some time to find a non-invasive way to assess neuroinflammation.  He needed a technique he could safely use again and again in his longitudinal (Good Day/Bad Day) studies.
None of the present techniques, however, fit the bill; they were all heavily invasive. The PET scan approach uses radiation to image the brain. Another approach using magnetized nano particles is supposed to be safe but it still requires putting little bits of metal into peoples’ brains…
After hitting several dead ends, he hypothesized that because inflammation produces temperature increases, he could try and create a heat map of the brain. Looking through the literature, he realized that thermometry was already being used in the brain to assess stroke and cancer patients. It turns out that the brain’s attempts to repair the damage from stroke and cancer results in huge temperature increases. The stroke and cancer researchers, though, were just focused on small areas of the brain.
Because Younger didn’t know exactly where in the brain to search in ME/CFS, that technique wouldn’t work for him. He had to develop a method that would produce a heat map and a chemical signature of the entire brain, and found a Florida researcher who developed a way to do that.
With this technique, it takes just 20 minutes in the machine to get an entire 3-D heat and chemistry map of an ME/CFS patient’s brain. After The Solve ME/CFS Initiative (SMCI) provided funding, he got to work and ultimately scanned the brains of 15 ME/CFS women and 15 age and sex matched healthy controls.

Widespread Neuroinflammation Found in ME/CFS Patients’ Brains

“The markers were truly elevated” Jarred Younger
It turned out that Younger’s brain-wide search technique was right on. Looking at single areas of the brain in ME/CFS patients would have produced misleading data. It turned out there was no single area or even a group of areas in the brain that were abnormal in ME/CFS: most of the brain was.
Younger found lactate – a product of anaerobic metabolism – widely distributed across the brains of people with ME/CFS. He opened a chart showing an amazing array of lactate-engorged brain regions. He picked out a few: the insula, hippocampus, thalamus, and putamen, which had particularly high levels. They were virtually the same regions the Japanese had found in their 2015 study. The fact that the temperature increases overlapped with the lactate increases provided further confidence that Younger had identified some key areas.
The cingulate cortex - which Younger called the "seat of suffering" was particularly inflamed
The cingulate cortex – which Younger called the “seat of suffering” was particularly inflamed.
The interior cingulate cortex, in particular, which Younger called “the seat of suffering” in the brain, showed up in spades. It’s associated with a lot of nasty symptoms (malaise, fatigue and pain) and it’s shown up in both ME/CFS and fibromyalgia studies in the past. The high choline signal in that region of the brain suggested that inflammation there was producing a pattern of destruction and replacement; i.e. quite a bit of damage – even possibly neuronal damage – was happening there.
Overall, the lactate levels weren’t as high as in other diseases – they were just consistently present. Younger didn’t expect to see really high levels; really high lactate levels would have meant irretrievably damaged neurons – the kind of neuronal damage seen in M.S., Parkinson’s and Alzheimer’s – the kind of neuronal damage that is really hard to reverse. The fact that Younger saw inflammation in ME/CFS but not neuron-destroying inflammation is good news indeed for people with ME/CFS.
It’s possible that some damage such as neuronal reprogramming and synaptic pruning could be occurring, but determining that would take an autopsy.  (Some groups are collecting ME/CFS brains at a couple of autopsies that have been done.)
Remarkably, the healthy controls didn’t show evidence of a single analyte such as lactate being elevated or a single area of the brain being heated up. It’s highly unusual to find zero evidence of an abnormality in the healthy controls. Usually the results of studies apply to groups, not individuals; some healthy controls typically will have findings that are similar to the MEC/CFS patients and vice-versa, but not here – the two groups were absolutely distinct.  Even though this was a small study, such black/white results strongly suggest that neuroinflammation of the brain is a key element of ME/CFS.

Lactate

Magnetic spectroscopy studies have found increased lactate in the ventricles of the brain in ME/CFS before but not in the brain itself.  Shungu’s spectroscopy studies have, in fact, produced some of the most consistent results in all of ME/CFS research. Three times he’s probed the ventricles and three times he’s found increased lactate.  Shungu, however, is examining an area just outside of the brain. His findings may indicate inflammation is present in the brain or it could be confined to the cerebral spinal fluid. 

Younger’s new approach looked at the entire brain and found signs of inflammation almost everywhere. When asked what could cause that, Younger said that any neurodegenerative/ neuroinflammatory disorder like MS or a severe brain injury that tweaks the microglia (immune cells in the brain) enough to produce a sustained period of inflammation, burns up the oxygen in the system. Once that happens, the cells resort to anaerobic metabolism and lactate builds up just as it does in the muscles during exercise.
My partner asked another intriguing question. (Thank god her brain was functioning.) What about intervention studies?  What about whacking ME/CFS patients with exercise and seeing what happens to their brains? Younger, it turned out, had already laid the groundwork for that study.

Therapeutic Implications

Documenting that neuroinflammation is present and is affecting functioning in ME/CFS could have dramatic treatment implications.  It could lead the scientific and medical communities to focus less on drugs that target the nervous system and more on ways to reduce inflammation. For example, attempts could be made to modify current anti-inflammatories so that they pass through the blood brain barrier (most do not). Health Rising will focus on some way that might happen in a future blog.

Fast Mover

Throughout this process, Younger has moved extremely quickly. He completed the thermometry study as quickly as possible, and then as the dramatic results began to come in, rapidly applied for a nice, fat ROI grant from the NIH. The results were so convincing, in fact, that he didn’t wait for them all to come in and applied for the grant using half the data from the study.
It’s hard to imagine that that grant application won’t get funded.  When it is, Younger will have plenty of money to pursue the neuroinflammation angle further, including challenging ME/CFS patients with exercise – something he’s never done before – and seeing what that does to the inflammation in their brain. It’ll be fascinating to see if it rises, how long the inflammation lasts, how it tracks with post-exertional symptoms, and where it’s most evident.

Cause?


Younger speculated that people with ME/CFS have an immune-triggered metabolic disorder.  The widespread neuroinflammation provides a clue, he thinks, to what’s going on. That pattern suggests that immune cells are breaching the blood-brain barrier in multiple areas; like a flood overwhelming a dike they’re essentially pouring through gaps across the brain. Why that may be happening he’s not sure, but his next step in ME/CFS is to demonstrate that that’s happening. How he proposes to do that is the subject of the next blog.  

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