Longevity Manual 109 [How to Fight Dementia Part 15] Even for Lonely People, It Is Possible to Secrete 'Oxytocin,' a Hormone That Protects the Brain and Prevents Cognitive Decline
Brain atrophy caused by 'social isolation' where connections with others are severed
Last time, I explained the molecular pathology of how cortisol, released from the adrenal glands due to chronic stress, drives the 'hippocampus'—the command center for memory—into a vulnerable state. This time, as the second installment of the [Stress & Mind Edition], we will delve into another invisible stressor rapidly expanding in modern society: the structural damage that 'loneliness (social isolation)' inflicts on the brain, and the mystery of the brain hormone that repairs it.
From living alone in the city to the loss of community after retirement, modern people are exposed to unprecedented 'risks of isolation.' We tend to dismiss loneliness as a mere emotional issue, but a meta-analysis by Dr. Holt-Lunstad and colleagues at Brigham Young University in the U.S., which integrated data from 70 studies and approximately 3 million people (Holt-Lunstad J, et al. Loneliness and social isolation as risk factors for mortality: a meta-analytic review.), has shown that the increase in mortality risk due to social isolation and loneliness is comparable to that of smoking or excessive alcohol consumption. While this analysis covered overall mortality risk, subsequent research has specifically clarified the impact of isolation on the brain itself.
How does a daily life devoid of connections with others erode the inside of the brain and increase the risk of Alzheimer's disease? We will unravel the physiological truth.
Humans are inherently highly social animals that have evolved to survive by cooperating in groups. Therefore, the very structure of the brain is designed on the premise of 'interacting with others.'
In a study by a research team at the Universities of Warwick and Cambridge in the U.K. that analyzed large-scale data from the UK Biobank (Shen C, et al. Associations of social isolation and loneliness with later dementia.), the brains of over 30,000 participants were scanned with MRI to examine the relationship between social isolation and brain structure. The results revealed that people with extremely limited interaction with others have smaller gray matter volume in brain regions involved in memory and learning, and that social isolation is a factor that increases the subsequent risk of developing dementia, independent of 'loneliness' itself. It has been pointed out that the cessation of daily input to the brain, such as social stimulation, may be involved in the process by which the brain prunes away unused neural circuits.
'Oxytocin,' a brain-protecting hormone released from the hypothalamus
A hormone called 'oxytocin' has the potential to stop this spiral of brain atrophy caused by loneliness at the molecular level.
Oxytocin is a hormone often called the 'bonding hormone,' which is secreted from the hypothalamus of the brain during physical contact with others, conversations with trusted individuals, interactions with pets, and even when performing acts of kindness. In a study conducted by Dr. Jumpei Takahashi and his group at the Tokyo University of Science using mice (Takahashi J, et al. Oxytocin reverses Aβ-induced impairment of hippocampal synaptic plasticity in mice.), it was shown for the first time in the world that hippocampal synaptic plasticity (long-term potentiation) impaired by amyloid-beta can be restored by the administration of oxytocin.
Although this study was basic research using mouse brain slices and has not proven a direct therapeutic effect in humans, the same group subsequently reported that administering oxytocin into the brains of mice also improves the memory impairment caused by amyloid-beta itself. A review article summarizing the relationship between oxytocin and Alzheimer's disease (Saitoh A, et al. The role of oxytocin in Alzheimer's disease and its relationship with social interaction.) also concludes that while loneliness is a risk factor for Alzheimer's disease, oxytocin may have neuroprotective effects, and its application to future treatments is anticipated.
Changes in gene switches of immune cells caused by an environment of isolation
It is known that loneliness affects not only the brain but also the functioning of the entire immune system. A research group led by Dr. Cole at the University of California, Los Angeles, compared gene expression patterns in white blood cells (immune cells) in the blood of people who felt chronically lonely versus those who did not (Cole SW, et al. Social regulation of gene expression in human leukocytes.). The results revealed that in people with strong feelings of loneliness, the expression of gene groups that promote inflammation increased, while the expression of gene groups involved in antibody production against viruses and the like decreased. Subsequent research (Cole SW, Hawkley LC, Arevalo JMG, Cacioppo JT. Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes.) also identified that these changes primarily originate from specific immune cells such as monocytes and dendritic cells.
What this research shows is not a change in the gene switches of 'brain cells themselves,' but rather in the gene switches of 'immune cells circulating throughout the body.' However, it has been pointed out that if inflammatory substances continue to increase in the blood due to chronic isolation, they may be carried to the brain via the bloodstream, placing a burden on the brain's defense line (the blood-brain barrier) and indirectly creating an environment where amyloid-beta is more likely to accumulate. The sense of security that comes from belonging to a healthy community with others is thought to work in a direction that suppresses such inflammatory gene expression, and it is possible that bonds with others, through the functioning of the immune system, are ultimately linked to brain health as well.
To prevent the effects of social isolation on the brain and to support the brain's defense line in the hippocampus by promoting the secretion of oxytocin, I propose three manuals to implement starting today.
Manual 1: Introduce 'two-way dialogue (catch-ball)' into daily conversations
One-way viewing of videos on televisions or smartphones does not provide social stimulation to the brain. Starting today, please incorporate two-way communication into your schedule, such as exchanging 'thank yous' with store clerks when shopping, or having casual chats with family and friends about 'how was your day today?' Interactions where you recognize each other's facial expressions and tone of voice are thought to stimulate the brain's social network and help promote the secretion of oxytocin.
Manual 2: Incorporate 'altruistic behavior' of delivering kindness to others once a week into your schedule
The feeling of 'being useful to someone' (self-utility) is thought to give the brain a sense of security and promote the secretion of oxytocin. Whether it is participating in local volunteer activities, picking up trash on the roadside, speaking to someone in need, or expressing a small word of gratitude to someone close to you, any small act is fine. Spontaneously choosing to act with consideration for others will, in turn, lead to protecting your own brain.
Manual 3: Incorporate interactions with animals or the act of 'hugging' a cushion
Even if interacting with others is difficult for you right now, there are ways to stimulate the secretion of oxytocin. Multiple studies have shown that making eye contact with and gently petting animals, such as dogs or cats, brings oxytocin to both the human and the animal. Additionally, 'tactile stimulation,' such as hugging a soft cushion or a body pillow, is thought to help shift the autonomic nervous system into a resting mode.
Managing your mental state in the fight against dementia is not about silently continuing brain training exercises on your own. The warm activities of human society—choosing to engage with others, build bonds, and care for one another—are scientifically backed defensive measures that will protect your brain well into your later years.
Next time, we will move on to the 'Five Senses and Stimulation' section, focusing on 'Hearing (The Mystery of Why Hearing Loss Maximizes Dementia Risk).'
References
Meta-analysis on social isolation, loneliness, and mortality risk
Paper Title: Loneliness and Social Isolation as Risk Factors for Mortality: A Meta-Analytic Review.
Authors: Holt-Lunstad J, Smith TB, Baker M, Harris T, Stephenson D
Journal: Perspectives on Psychological Science (2015)
Summary: A meta-analysis integrating data from 70 studies and approximately 3 million people. It demonstrated that social isolation, feelings of loneliness, and living alone significantly increase mortality risk, with an impact comparable to smoking or excessive alcohol consumption.
Relationship between social isolation, loneliness, and brain structure/dementia risk (UK Biobank)
Paper Title: Associations of Social Isolation and Loneliness With Later Dementia.
Authors: Shen C, Rolls ET, Cheng W, et al.
Journal: Neurology (2022)
Summary: A cohort study examining the relationship between social isolation, loneliness, and the onset of dementia in UK Biobank participants. It showed that social isolation is a risk factor for dementia independent of feelings of loneliness and is associated with a reduction in gray matter volume in brain regions involved in memory and learning.
Recovery of amyloid-β-induced synaptic impairment by oxytocin (mice)
Paper Title: Oxytocin Reverses Aβ-Induced Impairment of Hippocampal Synaptic Plasticity in Mice.
Authors: Takahashi J, Yamada D, Ueta Y, Iwai T, Koga E, Tanabe M, Oka JI, Saitoh A
Journal: Biochemical and Biophysical Research Communications (2020)
Summary: The first study in the world to demonstrate that synaptic plasticity (long-term potentiation) impaired by amyloid-β in mouse hippocampal slices is restored by the administration of oxytocin.
Review on oxytocin, Alzheimer's disease, and social interaction
Paper Title: The Role of Oxytocin in Alzheimer's Disease and Its Relationship with Social Interaction.
Authors: Saitoh A, et al.
Journal: Cells (2023)
Summary: A review paper that organizes the mechanisms by which oxytocin may act neuroprotectively while loneliness is a risk factor for Alzheimer's disease, and summarizes prospects for therapeutic application.
Changes in gene expression patterns of immune cells (leukocytes) associated with loneliness
Paper Title: Social Regulation of Gene Expression in Human Leukocytes.
Authors: Cole SW, Naliboff BD, Kemeny ME, Griswold MP, Fahey JL, Zack JA
Journal: Genome Biology (2007)
Summary: A study showing that in the white blood cells of people with chronic feelings of loneliness, the expression of pro-inflammatory gene groups is increased, while the expression of antiviral-related gene groups is decreased.
Identification of the origin cells for gene expression changes in immune cells related to loneliness
Paper Title: Transcript Origin Analysis Identifies Antigen-Presenting Cells as Primary Targets of Socially Regulated Gene Expression in Leukocytes.
Authors: Cole SW, Hawkley LC, Arevalo JMG, Cacioppo JT
Journal: Proceedings of the National Academy of Sciences (PNAS) (2011)
Summary: A study that identified that the gene expression changes in immune cells associated with loneliness are primarily derived from specific immune cells such as monocytes and dendritic cells.
[Notice from the Longevity Manual] While chasing the meaning of 'lifespan,' I arrived at the question of 'what it means to be human.'
I have tried to explore this question in the form of a novel.
Written by Takashi Kajioka.
Starting June 15th, I am releasing one chapter a day of the 16-part series, 'Cells Mourn You for Twenty Years.' You can read it from here after the first chapter is released.
#CellsMournYouForTwentyYears