Acupuncture: An Overview on Its Functions, Meridian Pathways and Molecular Mechanisms.

Recent research has extensively explored the intricate mechanisms that underlie the effectiveness of acupuncture, highlighting the importance of stimulating acupoints, the role of acupuncture techniques in managing diseases, and the interaction between meridian pathways and molecular processes. Studies have underscored the crucial role of acupuncture in activating neurons, modulating the immune system, and influencing vascular activity, all of which contribute significantly to its therapeutic benefits across a wide range of symptoms and conditions. Utilization of imaging modalities enables the identification of changes in cerebral blood flow, brain function, and regional glucose metabolism following acupuncture sessions. The interstitial fluid circulation network within meridians adheres to specific laws that facilitate the transportation of materials. Acupuncture initiates the release of neurotransmitters, neuropeptides, and immune factors, impacting pain perception, inflammation, and physiological functions. It influences the complex neuro-endocrine-immune network by activating pathways involving the nervous system, the hypothalamic-pituitary-adrenal axis, and immune responses. Moreover, acupuncture induces molecular modifications such as phosphorylation, methylation, and histone modification, leading to key molecular changes that ultimately result in anti-inflammatory effects and the regulation of immune responses.

More allogrooming is followed by higher physiological stress in wild female baboons.

Social bonds increase fitness in a range of mammals. One pathway by which social bonds may increase fitness is by reducing the exposure to physiological stress, i.e. glucocorticoid (GC) hormones, that can be detrimental to health and survival. This is achieved through downregulating hypothalamic-pituitary-adrenal (HPA)-axis activity. Indeed, long-term measures of social (grooming) bonds are often negatively correlated with HPA-axis activity. However, the proximate role of physical touch through allogrooming remains an open question in the sociality-health-fitness debate. Demonstrating the potential anxiolytic benefits of grooming in the wild is hindered by methodological limitations. Here, we match accelerometer-identified grooming in wild female chacma baboons (Papio ursinus) to non-invasive faecal GC metabolite concentrations (fGCs). Consistent with previous work, we found a negative (but statistically non-significant) overall relationship between individual averaged fGCs and grooming rates. However, when time-matching grooming to fGCs, we found that both more giving and receiving grooming were followed by higher fGCs. This upregulation of HPA-axis activity suggests that maintaining social bonds (and its ultimate fitness benefits) may come at a shorter-term physiological cost. This finding sheds new light on a ubiquitous social behaviour typically considered 'relaxing' and suggests that sociopositive contact can trigger physiological stress.

The inconsistency of p-curve: Testing its reliability using the power pose and HPA debates.

Recent works have called into question whether p-curve can reliably assess the presence of "evidential value" within a set of studies. To examine an as-yet unexplored issue, we examined the method used to identify p-values for inclusion in a p-curve analysis. We developed iterated p-curve analysis (IPA), which calculates and p-curves every permutation for a set of reported p-values, and applied it to the data reported in several published p-curve analyses. Specifically, we investigated two phenomena for which p-curves have been used to evaluate the presence of evidential value: the power pose and the hypothalamic-pituitary-adrenal (HPA) reactivity debates. The iterated p-curve analyses revealed that the p-curve method fails to provide reliable estimates or reproducible conclusions. We conclude that p-curve should not be used to make conclusions regarding the presence or absence of evidence for a specific phenomenon.

Manipulation of a social signal affects DNA methylation of a stress-related gene in a free-living bird.

Social status directly affects the health of humans and other animals. Low status individuals receive more antagonistic encounters, have fewer supportive relationships and have worse health outcomes. However, the physiological and cellular processes that mediate the relationship between the social environment and health are incompletely known. Epigenetic regulation of the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine pathway that activates in response to stressors, may be one process that is sensitive to the social environment. Here, we experimentally manipulated plumage, a key social signal in female tree swallows (Tachycineta bicolor) and quantified methylation of four genes in the HPA axis before and after treatment. We found that dulling the white breast plumage affected methylation in one gene, CRHR1; however, the effect depended on the original brightness of the bird. Methylation in this gene was correlated with baseline corticosterone levels, suggesting that DNA methylation of CRHR1 helps regulate glucocorticoid production in this species. Methylation in two other genes, FKBP5 and GR, changed over the course of the experiment, independent of treatment. These results show that methylation of these genes is labile into adulthood and suggest that epigenetic regulation of the HPA axis could help birds respond to current environmental conditions.

A kidney-hypothalamus axis promotes compensatory glucose production in response to glycosuria.

The kidneys facilitate energy conservation through reabsorption of nutrients including glucose. Almost all the filtered blood glucose is reabsorbed by the kidneys. Loss of glucose in urine (glycosuria) is offset by an increase in endogenous glucose production to maintain normal energy supply in the body. How the body senses this glucose loss and consequently enhances glucose production is unclear. Using renal Slc2a2 (also known as Glut2) knockout mice, we demonstrate that elevated glycosuria activates the hypothalamic-pituitary-adrenal axis, which in turn drives endogenous glucose production. This phenotype was attenuated by selective afferent renal denervation, indicating the involvement of the afferent nerves in promoting the compensatory increase in glucose production. In addition, through plasma proteomics analyses we observed that acute phase proteins - which are usually involved in the body's defense mechanisms against a threat - were the top candidates which were either upregulated or downregulated in renal Slc2a2 KO mice. Overall, afferent renal nerves contribute to promoting endogenous glucose production in response to elevated glycosuria and loss of glucose in urine is sensed as a biological threat in mice. These findings may be useful in improving the efficiency of drugs like SGLT2 inhibitors that are intended to treat hyperglycemia by enhancing glycosuria but are met with a compensatory increase in endogenous glucose production.

[Noise exposure-induced stress response and its measurement methods].

Noise, as an unavoidable stress (pressure) source in the modern life, affects animals in many ways, both behaviorally and physiologically. Behavioral changes may be driven by changes in hormone secretion in animals. When animals face with noise stress, the neuroendocrine systems, mainly the hypothalamic-pituitary-adrenal (HPA) axis, are activated, which promotes the secretion and release of stress hormones, and then leads to a series of behavioral changes. The behavioral changes can be easily observed, but the changes in physiological indicators such as hormone levels need to be accurately measured. Currently, many studies have measured the variations of stress hormone levels in animals under different noise conditions. Taking glucocorticoid as an example, this paper summarizes the different measurement methods of stress hormones, especially the non-invasive measurement methods, and compares the advantages and shortcomings of them. It provides a variety of measurement choices for the study of related issues, and also helps us to further understand the sources of animal stress, in order to provide a better habitat for animals.

Computational modeling of the synergistic role of GCN2 and the HPA axis in regulating the integrated stress response in the central circadian timing system.

The circadian timing system and integrated stress response (ISR) systems are fundamental regulatory mechanisms that maintain body homeostasis. The central circadian pacemaker in the suprachiasmatic nucleus (SCN) governs daily rhythms through interactions with peripheral oscillators via the hypothalamus-pituitary-adrenal (HPA) axis. On the other hand, ISR signaling is pivotal for preserving cellular homeostasis in response to physiological changes. Notably, disrupted circadian rhythms are observed in cases of impaired ISR signaling. In this work, we examine the potential interplay between the central circadian system and the ISR, mainly through the SCN and HPA axis. We introduce a semimechanistic mathematical model to delineate SCN's capacity for indirectly perceiving physiological stress through glucocorticoid-mediated feedback from the HPA axis and orchestrating a cellular response via the ISR mechanism. Key components of our investigation include evaluating general control nonderepressible 2 (GCN2) expression in the SCN, the effect of physiological stress stimuli on the HPA axis, and the interconnected feedback between the HPA and SCN. Simulation revealed a critical role for GCN2 in linking ISR with circadian rhythms. Experimental findings have demonstrated that a Gcn2 deletion in mice leads to rapid re-entrainment of the circadian clock following jetlag as well as to an elongation of the circadian period. These phenomena are well replicated by our model, which suggests that both the swift re-entrainment and prolonged period can be ascribed to a reduced robustness in neuronal oscillators. Our model also offers insights into phase shifts induced by acute physiological stress and the alignment/misalignment of physiological stress with external light-dark cues. Such understanding aids in strategizing responses to stressful events, such as nutritional status changes and jetlag.NEW & NOTEWORTHY This study is the first theoretical work to investigate the complex interaction between integrated stress response (ISR) sensing and central circadian rhythm regulation, encompassing the suprachiasmatic nucleus (SCN) and hypothalamus-pituitary-adrenal (HPA) axis. The findings carry implications for the development of dietary or pharmacological interventions aimed at facilitating recovery from stressful events, such as jetlag. Moreover, they provide promising prospects for potential therapeutic interventions that target circadian rhythm disruption and various stress-related disorders.

Parents' work demands on next day's cortisol awakening response - the moderating role of family-to-work conflict.

BACKGROUND: Constant availability, overtime and feeling overwhelmed by work can impact employees' wellbeing and their biological stress responses. Especially working parents often struggle to balance the demands of their work and family life and were found to be distracted from their work due to family responsibilities. The Family-to-Work Conflict (FWC) indicates the extent to which participating in work is made difficult by family demands. Recent studies have found associations between FWC and biological outcomes such as the Cortisol Awakening Response (CAR), a measure of an individual's Hypothalamic-Pituitary-Adrenal (HPA)-axis activity. This diary study investigates the effect of parental work demands on next day's cortisol response as well as the moderating role of FWC and the mediating role of fatigue. METHODS: Over the course of five consecutive days (from Monday to Friday), 168 observations were made on a total of 42 parents. Participants had at least one child and worked a minimum of 20 hours per week. Salivary cortisol samples were obtained immediately, 15 and 30 minutes after awakening each day. Work demands, FWC and fatigue were assessed using standardized questionnaires. Within-person effects were examined using multilevel modeling and mediation analyses. RESULTS: Our results indicate that there are no main effects of work demands on next day's cortisol response. The multilevel analysis revealed that FWC predicts lower wakening cortisol levels and confirmed FWC as an increasing moderator between work demands and next day's HPA-axis activity. Further, work overload was found to increase fatigue, which in turn leads to higher CAR on the following day. This indicates that fatigue mediates the relationship between work demands and CAR. Our findings add to a growing body of research demonstrating further predictors for HPA-axis activity and emphasise the importance of considering family related demands when investigating biological outcomes for working parents.

Circadian and ultradian rhythms: Clinical implications.

The hypothalamic-pituitary-adrenal axis is an extremely dynamic system with a combination of both circadian and ultradian oscillations. This state of 'continuous dynamic equilibration' provides a platform that is able to anticipate events, is sensitive in its response to stressors, remains robust during perturbations of both the internal and external environments and shows plasticity to adapt to a changed environment. In this review, we describe these oscillations of glucocorticoid (GC) hormones and why they are so important for GC-dependent gene activation in the brain and liver, and their consequent effects on the regulation of synaptic and memory function as well as appetite control and metabolic regulation. Abnormalities of mood, appetite and metabolic regulation are well-known consequences of GC therapy, and we suggest that the pattern of GC treatment and hormone replacement should be a much higher priority for endocrinologists and the pharmaceutical industry. One of the major impediments to our research on the importance of these cortisol rhythms in our patients has been our inability to measure repeated levels of hormones across the day in patients in their home or work surroundings. We describe how new wearable methodologies now allow the measurement of 24-h cortisol profiles - including during sleep - and will enable us to define physiological normality and allow us both to develop better diagnostic tests and inform, at an individual patient level, how to improve replacement therapy.

The Yin and Yang of the oxytocin and stress systems: opposites, yet interdependent and intertwined determinants of lifelong health trajectories.

During parturition and the immediate post-partum period there are two opposite, yet interdependent and intertwined systems that are highly active and play a role in determining lifelong health and behaviour in both the mother and her infant: the stress and the anti-stress (oxytocin) system. Before attempting to understand how the environment around birth determines long-term health trajectories, it is essential to understand how these two systems operate and how they interact. Here, we discuss together the hormonal and neuronal arms of both the hypothalamic-pituitary-adrenal (HPA) axis and the oxytocinergic systems and how they interact. Although the HPA axis and glucocorticoid stress axis are well studied, the role of oxytocin as an extremely powerful anti-stress hormone deserves more attention. It is clear that these anti-stress effects depend on oxytocinergic nerves emanating from the supraoptic nucleus (SON) and paraventricular nucleus (PVN), and project to multiple sites at which the stress system is regulated. These, include projections to corticotropin releasing hormone (CRH) neurons within the PVN, to the anterior pituitary, to areas involved in sympathetic and parasympathetic nervous control, to NA neurons in the locus coeruleus (LC), and to CRH neurons in the amygdala. In the context of the interaction between the HPA axis and the oxytocin system birth is a particularly interesting period as, for both the mother and the infant, both systems are very strongly activated within the same narrow time window. Data suggest that the HPA axis and the oxytocin system appear to interact in this early-life period, with effects lasting many years. If mother-child skin-to-skin contact occurs almost immediately postpartum, the effects of the anti-stress (oxytocin) system become more prominent, moderating lifelong health trajectories. There is clear evidence that HPA axis activity during this time is dependent on the balance between the HPA axis and the oxytocin system, the latter being reinforced by specific somatosensory inputs, and this has long-term consequences for stress reactivity.

Examining the implications of contextual stress and maternal sensitivity for infants' cortisol responses to the still face paradigm.

Infants' hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stressors are theorized to be shaped by parents' sensitive responsiveness to infants' cues. The strength and direction of the association between maternal sensitivity and infants' HPA responses may depend on the context in which maternal sensitivity is observed and on broader environmental sources of stress and support. In this preregistered study, we used data from 105 mothers and their 7-month-old infants to examine whether two empirically identified forms of contextual stress-poor maternal psychosocial wellbeing and family socioeconomic hardship-moderate the association between maternal sensitivity and infants' cortisol responses to the Still-Face Paradigm (SFP). Results indicated that maternal sensitivity during the free play and family socioeconomic hardship interacted to predict infants' cortisol responses to the SFP. Specifically, maternal sensitivity during this non-distressing interaction was negatively associated with cortisol responses only among infants whose mothers were experiencing relatively high socioeconomic hardship. Exploratory analyses revealed that poor maternal psychosocial wellbeing was positively associated with overall infant cortisol production during the SFP. Altogether, these findings suggest that experiences within early parent-infant attachment relationships and sources of contextual stress work together to shape infant HPA axis activity.

Effects of social environments on male primate HPG and HPA axis developmental programming.

Developmental plasticity is particularly important for humans and other primates because of our extended period of growth and maturation, during which our phenotypes adaptively respond to environmental cues. The hypothalamus-pituitary-gonadal (HPG) and hypothalamus-pituitary-adrenal (HPA) axes are likely to be principal targets of developmental "programming" given their roles in coordinating fitness-relevant aspects of the phenotype, including sexual development, adult reproductive and social strategies, and internal responses to the external environment. In social animals, including humans, the social environment is believed to be an important source of cues to which these axes may adaptively respond. The effects of early social environments on the HPA axis have been widely studied in humans, and to some extent, in other primates, but there are still major gaps in knowledge specifically relating to males. There has also been relatively little research examining the role that social environments play in developmental programming of the HPG axis or the HPA/HPG interface, and what does exist disproportionately focuses on females. These topics are likely understudied in males in part due to the difficulty of identifying developmental milestones in males relative to females and the general quiescence of the HPG axis prior to maturation. However, there are clear indicators that early life social environments matter for both sexes. In this review, we examine what is known about the impact of social environments on HPG and HPA axis programming during male development in humans and nonhuman primates, including the role that epigenetic mechanisms may play in this programming. We conclude by highlighting important next steps in this research area.

Temperature-dependent differences in mouse gut motility are mediated by stress.

Researchers have advocated elevating mouse housing temperatures from the conventional ~22 °C to the mouse thermoneutral point of 30 °C to enhance translational research. However, the impact of environmental temperature on mouse gastrointestinal physiology remains largely unexplored. Here we show that mice raised at 22 °C exhibit whole gut transit speed nearly twice as fast as those raised at 30 °C, primarily driven by a threefold increase in colon transit speed. Furthermore, gut microbiota composition differs between the two temperatures but does not dictate temperature-dependent differences in gut motility. Notably, increased stress signals from the hypothalamic-pituitary-adrenal axis at 22 °C have a pivotal role in mediating temperature-dependent differences in gut motility. Pharmacological and genetic depletion of the stress hormone corticotropin-releasing hormone slows gut motility in stressed 22 °C mice but has no comparable effect in relatively unstressed 30 °C mice. In conclusion, our findings highlight that colder mouse facility temperatures significantly increase gut motility through hormonal stress pathways.

The cortisol awakening response is blunted in healthy women early postpartum.

INTRODUCTION: The dynamic capacity of the hypothalamic-pituitary-adrenal (HPA) axis supports healthy adaptions to stress and play a key role in maintaining mental health. Perinatal adaptations in the HPA-axis dynamics in terms of the Cortisol Awakening Response (CAR), may be involved in dysregulation of perinatal mental health. We aimed to determine if CAR and absolute evening cortisol early postpartum differed from non-perinatal women and evaluate the association between the CAR and maternal mental well-being. METHODS: The CAR was computed as the area under the curve with respect to increase from baseline from serial home-sampling of saliva across 0-60 minutes from awakening. We evaluated differences in CAR and absolute evening cortisol between postpartum women (N=50, mean postpartum days: 38, SD: ±11) and non-perinatal women (N=91) in a multiple linear regression model. We also evaluated the association between CAR and maternal mental well-being in a multiple linear regression model. RESULTS: We found that healthy postpartum women had a blunted CAR (p<0.001) corresponding to 84% reduction and 80% lower absolute evening cortisol (p<0.001) relative to non-perinatal healthy women. In the postpartum group, there was a trend-level association between lower CAR and higher scores on the WHO Well-Being Index (WHO-5) (p=0.048) and lower Edinburgh Postnatal Depression Scale (EPDS) scores (p=0.04). CONCLUSION: Our data emphasize the unique hormonal landscape during the postpartum period in terms of blunted CAR and lower absolute evening cortisol in healthy women early postpartum compared to non-perinatal. Our findings show a potential association between a reduced CAR and improved mental well-being during early motherhood, which suggests that reduced CAR might reflect healthy adjustment to early motherhood.

Surface temperatures are influenced by handling stress independently of corticosterone levels in wild king penguins (Aptenodytes patagonicus).

Assessing the physiological stress responses of wild animals opens a window for understanding how organisms cope with environmental challenges. Since stress response is associated with changes in body temperature, the use of body surface temperature through thermal imaging could help to measure acute and chronic stress responses non-invasively. We used thermal imaging, acute handling-stress protocol and an experimental manipulation of corticosterone (the main glucocorticoid hormone in birds) levels in breeding king penguins (Aptenodytes patagonicus), to assess: 1. The potential contribution of the Hypothalamo-Pituitary-Adrenal (HPA) axis in mediating chronic and acute stress-induced changes in adult surface temperature, 2. The influence of HPA axis manipulation on parental investment through thermal imaging of eggs and brooded chicks, and 3. The impact of parental treatment on offspring thermal's response to acute handling. Maximum eye temperature (Teye) increased and minimum beak temperature (Tbeak) decreased in response to handling stress in adults, but neither basal nor stress-induced surface temperatures were significantly affected by corticosterone implant. While egg temperature was not significantly influenced by parental treatment, we found a surprising pattern for chicks: chicks brooded by the (non-implanted) partner of corticosterone-implanted individuals exhibited higher surface temperature (both Teye and Tbeak) than those brooded by glucocorticoid-implanted or control parents. Chick's response to handling in terms of surface temperature was characterized by a drop in both Teye and Tbeak independently of parental treatment. We conclude that the HPA axis seems unlikely to play a major role in determining chronic or acute changes in surface temperature in king penguins. Changes in surface temperature may primarily be mediated by the Sympathetic-Adrenal-Medullary (SAM) axis in response to stressful situations. Our experiment did not reveal a direct impact of parental HPA axis manipulation on parental investment (egg or chick temperature), but a potential influence on the partner's brooding behaviour.

Physiological Stress Responses to a Live-Fire Training Evolution in Career Structural Firefighters.

OBJECTIVE: This study assessed firefighters' physiological stress response to a live fire training evolution (LFTE). METHODS: Seventy-six ( n = 76) firefighters completed an LFTE. Salivary samples were collected pre-, immediately post, and 30-min post-LFTE and analyzed for α-amylase (AA), cortisol (CORT), and secretory immunoglobulin-A (SIgA). RESULTS: Concentrations of AA, CORT, and SIgA were elevated immediately post LFTE versus pre (P<0.001) and 30-min post (P<0.001). Cohen's d effect size comparing pre and immediately-post means were 0.83, 0.77, and 0.61 for AA, CORT, and SIgA and were 0.54, 0.44, and 0.69 for AA, CORT, and SIgA, comparing immediately-post and 30-min post, respectively. CONCLUSIONS: These data demonstrate the stress response and activation of the hypothalamic-pituitary-adrenal/sympathetic-adreno-medullar axis and immune system immediately after real-world firefighting operations. Future work is needed to understand the impact of elevated stress biomarkers on firefighter performance and disease risk.

Early life conditions reduce similarity between reproductive partners in HPA axis response to stress.

Social environments modulate endocrine function, yet it is unclear whether individuals can become like their social partners in how they physiologically respond to stressors. This social transmission of hypothalamic-pituitary-adrenal (HPA) axis reactivity could have long-term consequences for health and lifespan of individuals if their social partners react to stressors with an exaggerated HPA axis response. We tested whether glucocorticoid levels in response to stress of breeding partners changes after breeding depending on whether partners had similar or dissimilar postnatal conditions. We manipulated postnatal conditions by mimicking early life stress in zebra finch chicks (Taeniopygia guttata) via postnatal corticosterone exposure. When they reached adulthood, we created breeding pairs where the female and male had experienced either the same or different early life hormonal treatment (corticosterone or control). Before and after breeding, we obtained blood samples within 3 min and after 10 min or 30 min of restraint stress (baseline, cort10, cort30). We found that corticosterone levels of individuals in response to restraint were affected by their own and their partner's early life conditions, but did not change after breeding. However, across all pairs, partners became more similar in cort30 levels after breeding, although differences between partners in cort10 remained greater in pairs with a corticosterone-treated female. Thus, we show that HPA axis response to stressors in adulthood can be modulated by reproductive partners and that similarity between partners is reduced when females are postnatally exposed to elevated glucocorticoids.

The effect of cognitive reappraisal and early-life maternal care on neuroendocrine stress responses.

Early-life adversity (ELA) is related to profound dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, reflected in both, blunted or exaggerated cortisol stress responses in adulthood. Emotion regulation strategies such as cognitive reappraisal might contribute to this inconsistent finding. Here, we investigate an interaction of early-life maternal care (MC), where low MC represents a form of ELA, and instructed emotion regulation on cortisol responses to acute stress. Ninety-three healthy young women were assigned to a low (n = 33) or high (n = 60) MC group, based on self-reported early-life MC. In the laboratory, participants received regulation instructions, asking to cognitively reappraise (reappraisal group, n = 45) or to focus on senses (control group, n = 48) during subsequent stress exposure, induced by the Trier Social Stress Test. Salivary cortisol and subjective stress levels were measured repeatedly throughout the experiment. Multilevel model analyses confirmed a MC by emotion regulation interaction effect on cortisol trajectories, while controlling for hormonal status. Individuals with low MC in the control compared with the reappraisal group showed increased cortisol responses; individuals with high MC did not differ. These results highlight the significance of emotion regulation for HPA axis stress regulation following ELA exposure. They provide methodological and health implications, indicating emotion regulation as a promising target of treatment interventions for individuals with a history of ELA.

Modelling the role of glucocorticoid receptor as mediator of endocrine responses to environmental challenge.

Glucocorticoid hormones (GCs) modulate acute 'stress' responses in vertebrates, exerting their actions across many physiological systems to help the organism face and overcome challenges. These actions take place via binding to the glucocorticoid receptor (GR), which determines not only the magnitude of the GC-mediated physiological response but also the negative feedback that downregulates GCs to restore homeostasis. Although GR function is assumed to determine GC regulation capacity, the associations between GR abundance and individuals' coping abilities remain cryptic. We developed a dynamic model fitted to empirical data to predict the effects of GR abundance on both plasma GC response patterns and the magnitude of GC-mediated physiological response. Individuals with higher GRs showed lower GC exposure, stronger physiological responses and greater capacity to adjust this response according to stressor intensity, which may be translated into more resilient and flexible GC phenotypes. Our results also show that among-individual variability in GR abundance challenges the detectability of the association between plasma GC measurements and physiological responses. Our approach provides mechanistic insights into the role of GRs in plasma GC measurements and function, which point at GR abundance fundamentally driving complex features of the GC regulation system in the face of environmental change. This article is part of the theme issue 'Endocrine responses to environmental variation: conceptual approaches and recent developments'.

Long-COVID-19 autonomic dysfunction: An integrated view in the framework of inflammaging.

The recently identified syndrome known as Long COVID (LC) is characterized by a constellation of debilitating conditions that impair both physical and cognitive functions, thus reducing the quality of life and increasing the risk of developing the most common age-related diseases. These conditions are linked to the presence of symptoms of autonomic dysfunction, in association with low cortisol levels, suggestive of reduced hypothalamic-pituitary-adrenal (HPA) axis activity, and with increased pro-inflammatory condition. Alterations of dopamine and serotonin neurotransmitter levels were also recently observed in LC. Interestingly, at least some of the proposed mechanisms of LC development overlap with mechanisms of Autonomic Nervous System (ANS) imbalance, previously detailed in the framework of the aging process. ANS imbalance is characterized by a proinflammatory sympathetic overdrive, and a concomitant decreased anti-inflammatory vagal parasympathetic activity, associated with reduced anti-inflammatory effects of the HPA axis and cholinergic anti-inflammatory pathway (CAP). These neuro-immune-endocrine system imbalanced activities fuel the vicious circle of chronic inflammation, i.e. inflammaging. Here, we refine our original hypothesis that ANS dysfunction fuels inflammaging and propose that biomarkers of ANS imbalance could also be considered biomarkers of inflammaging, recognized as the main risk factor for developing age-related diseases and the sequelae of viral infections, i.e. LC.