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Summary: Study reveals the function of specific immune cells, well documented as playing a significant role in gut health, is directly controlled by our circadian clock.

Source: Champalimaud Center for the Unknown

It is well known that individuals who work night-shifts, or travel often across different time zones, have a higher tendency to become overweight and suffer from gut inflammation. The underlying cause for this robust phenomenon has been the subject of many studies that tried to relate physiological processes with the activity of the brain’s circadian clock, which is generated in response to the daylight cycle.

Now, the group of Henrique Veiga-Fernandes, at the Champalimaud Centre for the Unknown in Lisbon, Portugal, discovered that the function of a group of immune cells, which are known to be strong contributors to gut health, is directly controlled by the brain’s circadian clock. Their findings were published today in the scientific journal Nature.

“Sleep deprivation, or altered sleep habits, can have dramatic health consequences, resulting in a range of diseases that frequently have an immune component, such as bowel inflammatory conditions”, says Veiga-Fernandes, the principal investigator who led the study. “To understand why this happens, we started by asking whether immune cells in the gut are influenced by the circadian clock.”

The big clock and the little clock

Almost all cells in the body have an internal genetic machinery that follows the circadian rhythm through the expression of what are commonly known as “clock genes”. The clock genes work like little clocks that inform cells of the time of day and thereby help the organs and systems that the cells make up together, anticipate what is going to happen, for instance if it’s time to eat or sleep.

Even though these cell clocks are autonomous, they still need to be synchronised in order to make sure that “everyone is on the same page”. “The cells inside the body don’t have direct information about external light, which means that individual cell clocks can be off”, Veiga-Fernandes explains. “The job of the brain’s clock, which receives direct information about daylight, is to synchronise all of these little clocks inside the body so that all systems are in synch, which is absolutely crucial for our wellbeing”.

Among the variety of immune cells that are present in the intestine, the team discovered that Type 3 Innate Lymphoid Cells (ILC3s) were particularly susceptible to perturbations of their clock genes. “These cells fulfill important functions in the gut: they fight infection, control the integrity of the gut epithelium and instruct lipid absorption”, explains Veiga-Fernandes. “When we disrupted their clocks, we found that the number of ILC3s in the gut was significantly reduced. This resulted in severe inflammation, breaching of the gut barrier, and increased fat accumulation.”

These robust results drove the team to investigate why is the number of ILC3s in the gut affected so strongly by the brain’s circadian clock. The answer to this question ended up being the missing link they were searching for.

It’s all about being in the right place at the right time

When the team analysed how disrupting the brain’s circadian clock influenced the expression of different genes in ILC3s, they found that it resulted in a very specific problem: the molecular zip-code was missing! It so happens that in order to localise to the intestine, ILC3s need to express a protein on their membrane that works as a molecular zip-code. This ‘tag’ instructs ILC3s, which are transient residents in the gut, where to migrate. In the absence of the brain’s circadian inputs, ILC3s failed to express this tag, which meant they were unable to reach their destination.

According to Veiga-Fernandes, these results are very exciting, because they clarify why gut health becomes compromised in individuals who are routinely active during the night. “This mechanism is a beautiful example of evolutionary adaptation”, says Veiga-Fernandes. “During the day’s active period, which is when you feed, the brain’s circadian clock reduces the activity of ILC3s in order to promote healthy lipid metabolism. But then, the gut could be damaged during feeding. So after the feeding period is over, the brain’s circadian clock instructs ILC3s to come back into the gut, where they are now needed to fight against invaders and promote regeneration of the epithelium.”

“It comes as no surprise then”, he continues, “that people who work at night can suffer from inflammatory intestinal disorders. It has all to do with the fact that this specific neuro-immune axis is so well-regulated by the brain’s clock that any changes in our habits have an immediate impact on these important, ancient immune cells.”

This study joins a series of groundbreaking discoveries produced by Veiga-Fernandes and his team, all drawing new links between the immune and nervous systems. “The concept that the nervous system can coordinate the function of the immune system is entirely novel. It has been a very inspiring journey; the more we learn about this link, the more we understand how important it is for our wellbeing and we are looking forward to seeing what we will find next”, he concludes.

Source:
Champalimaud Center for the Unknown
Media Contacts:
Maria João Soares – Champalimaud Center for the Unknown
Image Source:
The image is in the public domain.

Original Research: Closed access
“Light-entrained and brain-tuned circadian circuits regulate ILC3 and gut homeostasis”. Cristina Godinho-Silva, Rita G. Domingues, Miguel Rendas, Bruno Raposo, Helder Ribeiro, Joaquim Alves da Silva, Ana Vieira, Rui M. Costa, Nuno L. Barbosa-Morais, Tania Carvalho, Henrique Veiga-Fernandes.
Nature doi:10.1038/s41586-019-1579-3.

Abstract

Light-entrained and brain-tuned circadian circuits regulate ILC3 and gut homeostasis

Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism1. ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence2,3. Nevertheless, it is unclear whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3s, intestinal homeostasis, gut defence and host lipid metabolism in mice. We found that enteric ILC3s display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, a deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut ‘postcode receptors’ of ILC3s. Strikingly, light–dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals being the major entraining cues of ILC3s. Accordingly, surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3s, shaping intestinal health, metabolism and organismal homeostasis.

Summary: Closer social relationships in childhood and being raised by a family with higher socioeconomic status was linked to people being more optimistic during midlife and increased chances of living to an older age. Those who were more disadvantaged growing up and experienced psychosocial stressors tended to experience more stressful events during midlife and had an increased risk of early death.

Source: Boston University School of Medicine

After years of generalized theories and hypothesis, research has finally pinpointed certain aspects of childhood experience linked to people living longer.

Individuals raised in families with higher socioeconomic status were more optimistic in midlife, and in turn, lived longer. Those who experienced more psychosocial stressors, such as parental death, frequent moves and harsh discipline, tended to encounter more stressful life events in midlife, and had greater risk of dying.

Prior research has shown that adverse childhood experiences are associated with higher mortality risk. However, the effects appear to be driven by a small proportion of individuals who experienced multiple “hits” of severe stressors, such as physical abuse and domestic violence. Little is known about the potential effects of milder but more common stressors and the potential benefits of favorable childhood experiences on longevity. How different aspects of childhood experiences come to influence life span has rarely been studied. These questions are addressed in a new study in the journal Psychology and Aging.

The study involved 1,042 men who had been followed since 1961 in the Normative Aging Study. Three aspects of childhood experiences, including socioeconomic status, psychosocial stressors and presence of close relationships were assessed at study entry and in 1995. Optimism, life satisfaction, stressful life events and negative affect in midlife were assessed from 1985-91. Mortality status was tracked through 2016.

A key finding was that men who recalled having more childhood stressors also tended to experience more stressors as adults, and in turn, had greater risk of dying. For example, when comparing men who had five versus one childhood psychosocial stressors, those with more childhood stressors had a three percent greater risk of dying that was due to having more adulthood stressors. These findings suggest that a continuous pattern of stressor exposure from childhood to midlife may act as a precursor to reduced lifespan.

The researchers also looked at whether and how favorable aspects of childhood experiences may contribute to longevity. In particular, men raised in families with higher socioeconomic status tended to report higher levels of optimism and life satisfaction in midlife, and in turn, had greater likelihood of having longer lives. These findings suggest that optimism and life satisfaction are resilience pathways which convey the benefits of childhood socioeconomic resources onto longer lives.

“Our findings offer novel evidence on unique and shared pathways linking specific dimensions of early life experiences to longevity,” said corresponding author Lewina Lee, PhD, clinical research psychologist at the National Center for PTSD at VA Boston and assistant professor of psychiatry at Boston University School of Medicine. “We hope that our research will stimulate further work to identify and intervene on factors which lie on the pathways linking childhood experiences to later-life health.”

Source:
Boston University School of Medicine
Media Contacts:
Press Office – Boston University School of Medicine
Image Source:
The image is in the public domain.

Original Research: Closed access
“The long arm of childhood experiences on longevity: Testing midlife vulnerability and resilience pathways”. Lewina Lee et al.
Psychology and Aging doi:10.1037/pag0000394.

Abstract

The long arm of childhood experiences on longevity: Testing midlife vulnerability and resilience pathways

Adverse early experiences have been associated with higher mortality risk, but evidence varies by type of experiences, and relatively little is known about the role of favorable early experiences on health in later life. This study evaluated the independent contributions to longevity of favorable and unfavorable early experiences, including psychosocial stressors, childhood socioeconomic status (SES), and close relationships. We also examined 4 midlife psychosocial factors as vulnerability and resilience pathways potentially mediating these associations. The sample included 1,042 men from the VA Normative Aging Study. Early experiences were assessed retrospectively in 1961–1970 and 1995. Midlife psychosocial factors were measured in 1985–1991 and included stressful life events (SLEs), negative affect, life satisfaction, and optimism. Mortality was assessed through 2016. In multiple mediator structural equation models, which account for the overlap among pathways, higher number of SLEs in midlife mediated the association of having more childhood psychosocial stressors to reduced longevity, supporting stress continuity as a vulnerability pathway. Higher optimism in midlife also mediated the association of higher childhood SES to greater longevity. In single mediator models, higher life satisfaction in midlife transmitted the benefits of higher childhood SES and presence of close relationships onto longevity. Higher optimism also mediated the association of fewer childhood psychosocial stressors to longevity. However, these indirect effects were attenuated when accounting for shared variance among mediators, suggesting overlapping pathways. Findings offer novel evidence on unique and shared pathways linking specific dimensions of early experiences to longevity.