Having positive experiences can help reduce the risk of Alzheimer’s

Mood is key to protecting brain health and preventing or delaying cognitive decline, and having more positive experiences in life is associated with lower odds of developing brain disorders such as Alzheimer’s disease, and even greater longevity. However, it remains unclear how feelings and experiences translate into physical changes that protect or harm the brain.

A study by researchers at Columbia University now suggests that the brain’s mitochondria may play a key role. Mitochondria supply energy to the brain, and the new study shows that the molecular machinery used by mitochondria to transform energy is enhanced in older adults who experienced less psychological stress during their lives, compared to those who had more negative experiences.

“We are showing that the mental state of older people is related to the biology of brain mitochondria, and it is the first time that subjective psychosocial experiences are related to brain biology,” said Caroline Trumpff, assistant professor of medical psychology, who led the research along with Martin Picard, an associate professor of behavioral medicine at Columbia University Vagelos College of Physicians and Surgeons and the Robert N. Butler Center on Aging at Columbia.

“We think that mitochondria in the brain are like antennas, picking up molecular and hormonal signals and transmitting information to the cell nucleus, changing the life course of each cell,” says Picard. “And if mitochondria can change cellular behavior, they can change the biology of the brain, the mind and the person as a whole.”

The new research used data collected by two large studies of nearly 450 older adults in the United States. Each study collected detailed psychosocial information from participants over two decades of their lives. Study participants donated their brains after their deaths for further analysis, which provided data on the state of the participants’ brain cells.

Trumpff created indices that converted patients’ reports of positive and negative psychosocial factors into a single score of overall psychosocial experience. She also scored each participant on seven domains that represent distinct genetic networks active in mitochondria.

“The use of multivariate mitotype indices is an important innovation because we were able to more easily interpret the biological state of mitochondria with networks of related genes than with an analysis of thousands of individual genes,” says Picard. The results have been published in the journal PNAS and show that a mitochondrial domain, which assessed the organelle’s energy-transforming machinery, was associated with psychosocial scores.

“Greater well-being was linked to a higher abundance of proteins in mitochondria needed for energy transformation, while negative mood was linked to lower protein content,” Trumpff explained. “This may be why chronic psychological stress and negative experiences are harmful to the brain, because they damage or impair mitochondrial energy transformation in the dorsolateral prefrontal cortex, the part of the brain responsible for high-level cognitive tasks.”

The researchers also looked at mitochondria in specific types of brain cells and found that the associations between mitochondria and psychosocial factors were not driven by the brain’s neurons, but by its glial cells, which may be playing roles beyond those traditionally assumed to be ‘supportive’.

“This part of the study, made possible by our collaboration with Columbia’s Center for Translational and Computational Neuroimmunology, is what I think makes it particularly significant,” Picard says. “Asking questions at this level of cellular resolution in the brain is unprecedented in the mitochondrial field.” “Neurons have been the focus of neuroscience, but we are waking up to the fact that other cells in the brain may be driving the disease,” he adds.

Although the current study cannot determine whether participants’ psychosocial experiences altered their brain mitochondria, or whether innate or acquired mitochondrial states contributed to those experiences, other studies suggest that the relationship between mitochondria and mood works both ways.

In animal studies, the evidence that chronic stress impairs mitochondrial energy processing is very strong, Picard says. And in humans, a recent study by Picard and collaborator Elissa Epel at UCSF found the first evidence that mood can affect mitochondria: In that study, positive mood predicted greater mitochondrial energy production in participants’ blood cells on later days, but mitochondrial activity did not predict mood on later days.

A growing body of work in animals and humans also indicates that mitochondria themselves can alter behavior. “It’s possible that these mechanisms reinforce each other,” Trumpff says. “Chronic stress could alter an individual’s mitochondrial biology in ways that subsequently affect their perception of social events, creating more stress. The emerging picture in the literature is that all of these pathways are interactive.”

Although the brain’s energy-transforming machinery was greater in participants with higher psychosocial scores, researchers don’t yet know whether that leads to greater energy transformation. Trumpff and Picard are currently conducting those studies with hundreds of brains from the same cohorts of participants. The team is also exploring a way to measure brain mitochondrial health, which could be used in doctors’ offices in the future.

“Mitochondria are the source of health and life, but we don’t have ways to quantify health, only disease,” Picard says. “We need a science of health. We need tests that show how healthy and resilient a person is.” “This would be clinically valuable for monitoring changes in health before the onset of disease, and could transform medical research by giving scientists something to focus on other than decades of protein deposits building up or other forms of long-term damage.”