Wednesday, June 15, 2022

Studying two highly divergent phyla of worms that contain numerous parasites that cause human and livestock diseases, new research sheds light on how sexual reproduction and subsequent great diversity of sex chromosomes might have evolved

Yifeng Wang, Robin B. Gasser, Deborah Charlesworth, Qi Zhou. Evolution of sexual systems, sex chromosomes and sex-linked gene transcription in flatworms and roundworms. Nature Communications, 2022; 13 (1). Jun 10 2022. DOI: 10.1038/s41467-022-30578-z


Abstract: Many species with separate male and female individuals (termed ‘gonochorism’ in animals) have sex-linked genome regions. Here, we investigate evolutionary changes when genome regions become completely sex-linked, by analyses of multiple species of flatworms (Platyhelminthes; among which schistosomes recently evolved gonochorism from ancestral hermaphroditism), and roundworms (Nematoda) which have undergone independent translocations of different autosomes. Although neither the evolution of gonochorism nor translocations fusing ancestrally autosomal regions to sex chromosomes causes inevitable loss of recombination, we document that formerly recombining regions show genomic signatures of recombination suppression in both taxa, and become strongly genetically degenerated, with a loss of most genes. Comparisons with hermaphroditic flatworm transcriptomes show masculinisation and some defeminisation in schistosome gonad gene expression. We also find evidence that evolution of sex-linkage in nematodes is accompanied by transcriptional changes and dosage compensation. Our analyses also identify sex-linked genes that could assist future research aimed at controlling some of these important parasites.


Popular version: Parasitic worms reveal new insights into the evolution of sex and sex chromosomes Two worm phyla give clues on how sex chromosomes might have evolved. Jun 15 2022. https://www.sciencedaily.com/releases/2022/06/220615102849.htm


Discussion

The evolution of sex chromosomes in some taxa involves the primary transition from a hermaphroditic system or from environmental sex determination to a dioecious/gonochoristic species with genetic sex determination. Such transitions usually are accompanied by potential suppression of recombination in and around the sex-determining gene(s), and the recombination suppression sometimes even extends to other sex chromosome regions. In other species, turnover events may create new sex-determining regions, which may also evolve into non-recombining regions. In either case, autosomal regions that fused or translocated to sex chromosomes may sometimes also become completely sex-linked, either in species that lack recombination in the heterogametic sex26, or potentially in species with recombination in both sexes through subsequent recombination loss.

Schistosomes have evolved gonochorism from hermaphroditism and exhibit strong morphological sexual dimorphism (see above). As explained earlier, the first step in such a primary transition must either involve a mutation creating females (producing a gynodioecious population), or one creating males (producing an androdioecious population). A mutation in the highly conserved oogenesis-related or feminising gene mag-1 might have produced males in the ancestor of schistosomes. However, it seems unlikely that such a mutation could have greatly increased male fitness, compared with that of the ancestral hermaphrodite, as required for the establishment of androdioecy. Females could have arisen due to a dominant mutation in the reported W-linked candidate sex-determining gene U2AF2 (Fig. 5k)85,86. The involvement of these genes in the evolution of schistosome sex-determination needs to be tested in the future.

Our finding that the evolution of the present schistosome sex-linked regions was followed by transcriptional changes of many genes in gonads (Fig. 5d–g) is consistent with the hypothesis of sexual antagonism in the hermaphroditic ancestor, favouring re-allocation of resources after separate sexes evolved75. Assuming that higher transcription levels reflect advantageous changes, the results in schistosomes suggest that conflicts were resolved and a new optimum reached more frequently in males (masculinisation and overwhelming defeminisation) than in females (feminisation) in the gonads. In the transition to dioecy in Silene latifolia, with male, instead of female heterogamety, and an XY sex chromosome system, transcriptional changes occurred most frequently in females92. The results suggest transcriptional changes after the X or Z chromosome became hemizygous in one sex, resulting in masculinisation of the schistosome Z (as shown in Supplementary Fig. 16) and feminisation of the X chromosome in S. latifolia.

Following the origin of gonochorism, both schistosome and nematode ancestral sex chromosomes have undergone translocations of autosomes, like those in many other taxa26,56 (Figs. 3 and 5a). The translocated autosomes, or large parts of them, have become completely non-recombining in both phyla, and in nematodes they have become strongly degenerated like the ancestral sex chromosomes. How loss of recombination happened is an interesting question. Recombination between the autosomes involved in a fusion or translocation with sex chromosomes often maintain autosomes’ former recombination patterns. However, the study of fusions between the C. elegans X chromosome and chromosome IV62 suggested that crossovers may be re-positioned away from the fusion junction, creating a new chromosome with two arm regions (whereas the two participating chromosomes each contained two arm regions). In the fused chromosome, a potentially large former arm region close to the fusion point may thus have greatly reduced recombination, and if the fusion involves the X chromosome, this will occur specifically in males. Such events can therefore create new sex-linked regions without involving selection for suppressed recombination.

Translocations of autosomes to ancestral sex chromosomes may be common in nematodes because some, though not all, nematodes have holocentric chromosomes93. Such chromosomes may be more prone to fusions or fissions than monocentric ones, in which such rearrangements may lead to a loss or multiplication of centromeres94. However, a recent comparison of insects with different centromere types found no evidence supporting this hypothesis95.

Finally, we annotated many Y- or W-linked genes additional to those already known in the flatworm and roundworm species studied here (Figs. 4 and 5). We also found homologs of C. elegans sex-determination pathway genes that may have undergone duplications in different nematode species. These genes could be involved in the divergence of the sex-determination pathways, as has already been documented between C. elegans vs. C. briggsae96. Functional verification in other nematode species is needed in the future. The present study could not identify further changes that may have occurred after lineage-specific duplications of these genes, and possible changes also need to be studied further. For example, gld-1 was independently recruited into the sex-determination pathways of C. elegans and C. briggsae; in C. elegans it acts to promote spermatogenesis, but it promotes oogenesis in C. briggsae97. Its co-factor, fog-2, evolved by a duplication and acquisition of a new GLD-1-binding domain in C. elegans88,98. The newly annotated, candidate sex-determining genes could be a useful resource for future studies of parasite control through interfering with their sexual life cycles.

We cannot read the generosity of others from their facial features, but we are convinced that the good looking are more generous

You Cannot Judge a Book by Its Cover: Evidence from a Laboratory Experiment on Recognizing Generosity from Facial Information. Ninghua Du, Fei Song, C. Bram Cadsby. Journal of Behavioral and Experimental Economics, June 14 2022, 101909. https://doi.org/10.1016/j.socec.2022.101909

• People cannot glean information about other-regarding preferences from facial information

• People make systematic errors when they try to identify generosity from facial information

• Those who are rated as more attractive are perceived to be more generous

• There is no actual relationship between physical attractiveness and generosity

Abstract: People form first impressions of others and may make judgments about their social traits and character on the basis of facial perceptions. We implement a controlled laboratory experiment to investigate whether people can glean information about another person's other-regarding preferences from uncropped photographs of their face. To do so, we conduct a dictator game with an allocator and a recipient, and then present pairs of allocator photos to observers. Each pair portrays one relatively generous allocator and another who has demonstrated less generosity. The experimental results show that the observers cannot accurately recognize more generous allocators, but instead make systematic errors. In particular, the observers believe that allocators who are rated more attractive by others are more generous, despite there being no actual relationship between physical attractiveness and generosity.

Keywords: Face-based JudgmentExperimentDictator GameOther-regarding PreferencesGenerosityAppearance


Feeling younger than one's chronological age was associated with better mental and physical health, presence of meaning in life, successful aging, optimism, personal mastery, resilience, curiosity, hope, and social support

Subjective age and its relationships with physical, mental, and cognitive functioning: A cross-sectional study of 1,004 community-dwelling adults across the lifespan. Awais Aftab et al. Journal of Psychiatric Research, June 14 2022. https://doi.org/10.1016/j.jpsychires.2022.06.023

Abstract: Perceived younger age is associated with positive health outcomes in existing literature. Few studies have examined these associations using a wide range of variables in large sample of adults of all ages. The objective of present study was to characterize the discrepancy between chronological age (CA) and subjective age (SA) in a large sample of community-dwelling adults across the lifespan, investigate associations with mental, physical, and cognitive health, and examine how it is related to a broad array of psychosocial variables relevant to well-being. Cross-sectional data from 1,004 individuals aged 21–100+ years from the Successful AGing Evaluation (SAGE) study were used for this analysis. Data included self-report measures of physical health (SF-36 – Physical Component), mental health composite score (created using CES-D Happiness scale, Satisfaction with Life Scale, SF-36 Mental Component, Brief Symptom Inventory Anxiety Scale, Patient Health Questionnaire-9, and Perceived Stress Scale), Telephone Interview for Cognitive Status - modified (TICS-m), and validated measures of various positive psychological variables such as meaning in life and optimism. On average, SA was 11.5 years younger than CA (SD 11.3). The discrepancy increased with CA. A younger SA compared to CA was associated with better mental and physical health in all age groups and was positively associated with measures of presence of meaning in life, successful aging, optimism, personal mastery, resilience, curiosity, hope, and social support. The association between age discrepancy and cognitive functioning was not statistically significant. These findings indicate that SA is potentially valuable for the purposes of clinical assessment and intervention, and this possibility should be investigated in future research.

Keywords: Positive psychiatryMeaning in lifeSuccessful agingOptimismPersonal masteryResilience


High social status, good looks, and being well-off and influential did not belong to the traits found desirable in a friend, and women held higher expectations for friends than men

Friendship Preferences: Examining Desirable and Undesirable Traits in a Friend. Menelaos Apostolou & Panagiota Vetsa. Evolutionary Psychological Science, Jun 14 2022. https://link.springer.com/article/10.1007/s40806-022-00329-w

Abstract: Friendship constitutes a human universal, with people across different times and places forming friendly relationships. Yet, people are selective in whom they befriend. The current research aimed to identify friendship preferences, that is, the traits that people find desirable or undesirable in a friend. More specifically, Study 1 employed open-ended questionnaires and identified 50 traits that participants preferred their friends to have, and 43 traits that they preferred their friends not to have. Study 2 employed a sample of 706 Greek-speaking participants and classified desirable traits into 10 broader factors; the most important one was being honest, followed by being ethical, pleasant, and available. Study 3 employed a sample of 865 Greek-speaking participants and classified undesirable traits into three broader factors. The most undesirable one was being dishonest, followed by being competitive and being impatient. In both studies, women tended to give higher scores than men. In addition, significant age effects were found for most factors in both studies.


The biological basis of intelligence

The biological basis of intelligence: Benchmark findings. Kirsten Hilger et al. Intelligence, Volume 93, July–August 2022, 101665. https://doi.org/10.1016/j.intell.2022.101665

Highlights

• Focused overview of research on the biological basis of intelligence.

• Benchmark findings from EEG, neuroimaging, and genetic research.

• Critical open questions and future directions.

Abstract: The scientific study of the biological basis of intelligence has been contributing to our understanding of individual differences in cognitive abilities for decades. In particular, the ongoing development of electrophysiological, neuroimaging, and genetic methods has created new opportunities to gain insights into pressing questions, allowing the field to come closer towards a comprehensive theory that explains how genotypes exert their influence on human intelligence through intermediate biological and cognitive endophenotypes. The aim of this article is to provide a focused overview of empirical benchmark findings on biological correlates of intelligence. Specifically, we summarize benchmark findings from electrophysiological, neuroimaging, and genetic research. Moreover, we discuss four open questions: (1) The robustness of research findings; (2) the relation between neural parameters and cognitive processes; (3) promising methodological developments; and (4) theory development. The aim of this paper is to assemble the most important and robust findings on the biological basis of intelligence to stimulate future research and to contribute to theory development.

Keywords: NeuroscienceElectroencephalographyMagnet resonance imaging (MRI)GeneticsIntelligenceCognitive abilities


Tuesday, June 14, 2022

Can we blame social media for polarization? Counter-evidence against filter bubble claims during the COVID-19 pandemic

Can we blame social media for polarization? Counter-evidence against filter bubble claims during the COVID-19 pandemic. S Mo Jones-Jang, Myojung Chung. New Media & Society, June 13, 2022. https://doi.org/10.1177/14614448221099591

Abstract: Although collective efforts are essential to fight COVID-19, public opinion in the United States is sharply divided by partisan attitudes and health beliefs. Addressing the concern that media use facilitates polarization, this study investigated whether social and traditional media use for COVID-19 information attenuates or reinforces existing disparities. This article focuses on two important areas where the public is highly polarized: partisan affect and vaccine attitudes. Contradicting the filter bubble claim, our survey (n = 1106) revealed that social media use made people less polarized in both partisan affect and vaccine hesitancy. In contrast, traditional media use made people more polarized in partisan affect. These findings corroborate the growing evidence that social media provide diverse viewpoints and incidental learning.

Keywords: Affective partisan polarization, COVID-19, polarization, social media, vaccine hesitancy


Negative affect decreases the weight that participants place on the health benefits and on the taste of food

Negative Affect, Affect Regulation, and Food Choice: A Value-Based Decision-Making Analysis. Daniel O’Leary et al. Social Psychological and Personality Science, June 13, 2022. https://doi.org/10.1177/19485506221079947

Abstract: Maladaptive eating is one of the greatest threats to health and well-being in the 21st century. Psychological factors that drive maladaptive eating are of interest as they may offer low-cost intervention targets. One such factor is negative affect. If negative affect does lead to maladaptive eating, interventions that reduce negative affect should lead to improved eating and food choice. One relevant class of techniques is affect regulation strategies. In the present research, we use survey data and a value-based decision-making task to demonstrate that negative affect is associated with maladaptive eating and food choice. We find that negative affect decreases the weight that participants place on the health benefits of food. We also show that teaching participants to use reappraisal to downregulate negative affect leads to healthier food choices. These findings indicate that reappraisal applied to incidental negative affect may be an effective method for improving eating and food choice.

Keywords: food, eating, affect, affect regulation, self-control, decision-making, value


Monday, June 13, 2022

Many taxa show substantial differences in lifespan between the sexes: however, these differences are not always in the same direction

The sex with the reduced sex chromosome dies earlier: a comparison across the tree of life. Zoe A. Xirocostas, Susan E. Everingham and Angela T. Moles. Biology Letters, March 4 2020. https://doi.org/10.1098/rsbl.2019.0867

Abstract: Many taxa show substantial differences in lifespan between the sexes. However, these differences are not always in the same direction. In mammals, females tend to live longer than males, while in birds, males tend to live longer than females. One possible explanation for these differences in lifespan is the unguarded X hypothesis, which suggests that the reduced or absent chromosome in the heterogametic sex (e.g. the Y chromosome in mammals and the W chromosome in birds) exposes recessive deleterious mutations on the other sex chromosome. While the unguarded X hypothesis is intuitively appealing, it had never been subject to a broad test. We compiled male and female longevity data for 229 species spanning 99 families, 38 orders and eight classes across the tree of life. Consistent with the unguarded X hypothesis, a meta-analysis showed that the homogametic sex, on average, lives 17.6% longer than the heterogametic sex. Surprisingly, we found substantial differences in lifespan dimorphism between female heterogametic species (in which the homogametic sex lives 7.1% longer) and male heterogametic species (in which the homogametic sex lives 20.9% longer). Our findings demonstrate the importance of considering chromosome morphology in addition to sexual selection and environment as potential drivers of sexual dimorphism, and advance our fundamental understanding of the mechanisms that shape an organism's lifespan.

4. Discussion

Our study provides evidence that, across multiple taxa, the heterogametic sex tends to have a considerably shorter lifespan than the homogametic sex. That is, an organism's chromosome morphology seems to have a substantial role in shaping this key life-history trait. The 17.6% difference between the lifespans of homogametic and heterogametic sexes revealed here is substantial enough to have major ecological and evolutionary implications. However, heterogametic sex chromosomes include everything from a complete absence of the second sex chromosome (X0 or Z0), to a highly reduced second sex chromosome (e.g. XY in humans), to X and Y or Z and W chromosomes of nearly equal length [5,32,33]. As not all heterogametic species have a degraded sex chromosome, our study likely represents a conservative test of the unguarded X hypothesis. A future direction will be to formally test the hypothesis that the difference in lifespan between sexes is proportional to the proportional difference in chromosome length between sexes. That is, to test the idea that species in which the second chromosome is absent or extremely reduced have a greater reduction in the lifespan of the heterogametic sex than do taxa in which the difference between sex chromosomes is relatively small. Ideally, this question should be addressed using a diverse range of taxa, both for generality, and to include species with as many different chromosome configurations, life histories and mating systems as possible. Another interesting direction for future research would be to begin to quantify the relative contributions of factors such as chromosome morphology, sexual selection, parental investment and exposure to predators.

Our second major finding was that when males are the heterogametic sex, they die 20.9% earlier than their female counterparts, but when females are the heterogametic sex, they die only 7.1% earlier than their male counterparts. Three possible explanations for this surprising trend include: (1) the degree of degradation of the Y chromosome, (2) telomere dynamics, and (3) side effects of sexual selection.

(1)

It is possible that the Y chromosome in male heterogametic species might tend to be more degraded than the W chromosome in female heterogametic species, potentially leading to a difference in heterogametic lifespan between XY and ZW systems. We know that many mammals (including humans) have highly reduced Y chromosomes [3335]. There is also evidence that the relative length of the W and Z chromosomes can vary substantially even within clades (e.g. birds, snakes; [6,3639]). However, a comparative analysis of the degradation of chromosomes across the tree of life has not yet been performed.

(2)

Telomeres are sections of non-coding DNA at the ends of chromosomes that protect coding DNA from deterioration during cell replication and other cellular processes [40,41]. Cell replication damages telomeres and studies suggest that the loss of telomere length over time causes the progression of ageing and shortening of lifespan [42]. However, oestrogen stimulates a promoter of the telomerase enzyme [43], which heals damaged telomeres by adding telomeric base pairs to its ends and indirectly activates other DNA repairing pathways [40]. Although we do not know whether oestrogen is important in all of our study species, it is possible that the effect of oestrogen on telomerase activation could help to explain the smaller decrease in lifespan when females are the heterogametic sex.

(3)

In many cases, males experience more intense sexual competition than females, as they are more reproductively efficient and so take more risks when pursuing a mating opportunity (e.g. males fighting for access to females or to establish their territory) [44,45]. Usually, females are not as efficient at reproducing, contribute more to their offspring than fathers, and so are predicted to engage in lower-risk behaviours [4446]. Higher mortality in males owing to side effects of sexual selection, in combination with the effect of sex chromosomes on longevity, could also explain why there is a smaller lifespan difference between ZW females and ZZ males in comparison with XY males and XX females [11,15,44].

Understanding the mechanisms underpinning the substantial difference in lifespan dimorphism in male versus female heterogametic species is an important direction for future research, as this may improve our understanding of the factors that affect ageing. There is a multibillion-dollar industry in extending human lifespan [47], however, there is a crucial knowledge gap and we have much to learn about the basic biology underpinning longevity and the drivers of lifespan differences across sexes and species. Here, we have provided the first evidence that the heterogametic sex does, on average, die earlier than its homogametic counterpart across a range of taxa. We also found that lifespan dimorphism between the sexes is greater in male heterogametic species in comparison with female heterogametic species. These findings are a crucial step in uncovering the underlying mechanisms affecting longevity, which could point to pathways for extending life. We can only hope that more answers are found in our lifetime.

Sunday, June 12, 2022

The human physiology of well-being: A systematic review on the association between neurotransmitters, hormones, inflammatory markers, the microbiome and well-being

The human physiology of well-being: A systematic review on the association between neurotransmitters, hormones, inflammatory markers, the microbiome and well-being. Lianne P.de Vries et al. Neuroscience & Biobehavioral Reviews, June 11 2022, 104733. https://doi.org/10.1016/j.neubiorev.2022.104733

Highlights

• Higher blood levels of serotonin could be related to higher well-being.

• Faster decrease of cortisol levels over the day is associated with higher well-being.

• The levels of different inflammatory markers are negatively related to well-being.

• An association between the microbiome composition and well-being is suggested.

• More research to the physiological factors underlying well-being is needed.

Abstract

To understand the pathways through which well-being contributes to health, we performed a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines on the association between well-being and physiological markers in four categories, neurotransmitters, hormones, inflammatory markers, and microbiome.

We identified 91 studies. Neurotransmitter studies (knumber of studies=9) reported only a possible positive association between serotonin and well-being. For the hormone studies (k=48), a lower momentary cortisol level was related to higher well-being (meta-analytic r=-.06), and a steeper diurnal slope of cortisol levels. Inflammatory marker studies (k=36) reported negative or non-significant relations with well-being, with meta-analytic estimates of respectively r=-.07 and r=-.05 for C-reactive protein and interleukin-6. Microbiome studies (k=4) reported inconsistent associations between different bacteria abundance and well-being.

The results indicate possible but small roles of serotonin, cortisol, and inflammatory markers in explaining differences in well-being. The inconsistent and limited results for other markers and microbiome require further research. Future directions for a complete picture of the physiological factors underlying well-being are proposed.

Keywords: well-beingphysiologyneurotransmittershormonesinflammatory markersmicrobiome

4. Discussion

To understand observed differences in well-being between people in more detail, and in order to enhance the development of future mental health prevention and intervention strategies, it is essential to identify physiological markers related to well-being. Therefore, the goal of this systematic review was to bring together the available literature on physiological markers related to well-being in four categories, namely neurotransmitters, hormones, inflammatory markers, and the microbiome. The systematic review resulted in respectively 48 and 36 studies on the association of hormones or inflammatory markers and well-being, whereas only 9 and 4 studies examined the relation between neurotransmitters or the microbiome and well-being. We first summarize and discuss the findings per category. Next, we propose directions for future research based on our current results.

4.1. Neurotransmitters

Nine studies investigated the association between levels of different neurotransmitters and well-being, mainly focusing on (nor)epinephrine and serotonin. In contrast to our expectations, we did not find studies that related dopamine levels to well-being and only a few studies related to (nor)epinephrine and serotonin. Levels of epinephrine and norepinephrine were mostly unrelated to measures of psychological well-being and positive affect. Only in a sample of older women (mean age=74), there was a moderate positive correlation between (nor)epinephrine and subscales of Ryff’s psychological well-being scale. More research on the moderating effects of well-being measure, age and sex is needed to confirm these findings.

Serotonin levels were more consistently positively related to the hedonic well-being measure positive affect, but the effect sizes were small. The relation between serotonin and other measures of hedonic well-being, e.g., life satisfaction, or eudaimonic well-being has not been investigated so far. In studies with larger sample sizes the moderation by age and sex should also be investigated.

The results should be interpreted in light of the difficulties of measuring neurotransmitters levels in humans due to their short term effects, low levels in the brain, and their mixture with other molecules (Niyonambaza et al., 2019). Furthermore there is an ongoing discussion whether urine or blood plasma measures of neurotransmitters reflect brain activity (Ailts et al., 2007Marc et al., 2011). The suggested positive correlation between neurotransmitter levels in the brain and the rest of the body, i.e., urine or blood (Marc et al., 2011) does suggest that the detected association between serotonin in the blood plasma and well-being indicates the involvement of serotonin resulting from brain activity in well-being.

Applying positron emission tomography (PET) and labeling neurotransmitters can help to identify the regional specificity in the brain of neurotransmitters associated with well-being. For example, in the field of anxiety, it has been found that neurotransmission in social anxiety disorder is characterized by an overactive serotonin system in the amygdala, caudate nucleus, putamen, hippocampus and anterior cingulate cortex (Frick et al., 2015). Similarly, PET studies can directly give insight in the association of well-being and functioning of neurotransmitters in specific brain regions.

Furthermore, there is a lot of development in new ways to assess serotonin in different tissues and with new techniques, such as real-time continuous monitoring (Si and Song, 2018Su et al., 2020). This might enable researchers to assess the level of different neurotransmitters more easily in the future and replicate the possible involvement of serotonin in complex traits like well-being.

4.2. Hormones

The association of different hormones with well-being has been investigated more often compared to the neurotransmitter research, as hormones are currently easier to assess via, for example, saliva samples. Of the 48 hormone studies, 39 studies included one or more measures of cortisol. The meta-analysis on the association between the level of momentary cortisol and well-being resulted in a small negative effect, r=-.06, indicating that lower cortisol levels are related to higher levels of well-being. In addition, although a meta-analysis could not be performed, another relatively consistent finding was the association of a faster decrease of cortisol levels over the day (i.e., steeper slope) with higher well-being. The results of the relation between the cortisol awakening response and total cortisol secretion and well-being were less consistent. However, as reported by Smyth et al. (2015), the timing of cortisol sampling is important. In their study, only when the participants strictly adhered to the sampling protocol, lower cortisol awakening response was associated with higher well-being. Furthermore, as indicated by Booij et al. (2016), large individual differences in the relation between different measures of cortisol and well-being were present in their sample. This makes it difficult, if not impossible, to find consistent associations when averaging the relation within a large sample. In an earlier review, the inconsistency of findings regarding hormones and positive affects is also suggested to be due to the variability in samples, age, measures of well-being and timing (Dockray and Steptoe, 2010). Furthermore, as cortisol is “the stress hormone” and there is a clear negative association between stress and well-being (e.g., Schiffrin et al., 2009), stress might mediate the relation between diurnal cortisol and well-being and controlling for stress is needed in future studies.

Cortisol can be sampled in saliva, urine, or hair and the levels in the different samples reflect different processes. Whereas salivary and urinary cortisol reflect the real-time levels of cortisol, hair cortisol reflects the cortisol exposure over longer periods of time and is related to chronic stress (Russell et al., 2012). Cortisol measured in cortisol and urine versus hair is therefore not directly comparable. We identified two studies using a hair sample of cortisol and only one (Smyth et al., 2016) reported a small negative association with well-being in elderly participants. Research in larger samples is needed to examine the relation of hair cortisol (i.e., long-term cortisol exposure) and well-being.

To summarize, most measures of cortisol were not consistently related to well-being and individual differences could play a large role in the association. However, the small associations between momentary levels of cortisol and the slope of the cortisol decrease over the day and well-being were consistent. This effect was not different for hedonic and eudaimonic well-being. In future research, researchers need to be stricter on the timing of the cortisol sample and avoid variability, e.g., by using tube caps with time recording and strict instructions to the participants. In addition, focusing on the individual patterns instead of the average cortisol response or level across individuals is necessary to understand the relation between cortisol and well-being in more detail.

The association of other hormones with well-being were investigated in only a few studies and most of these studies did not report a (consistent) significant association, limiting the ability to draw conclusions. DHEA-S and testosterone were not related to different measures of well-being in respectively 5 of the 6 studies and 3 of the 4 studies. This might reflect a power issue, as most sample sizes of the discussed studies are small (n<100) or the absence of a detectable association between the levels of these hormones and well-being. More promising is the positive relation between vitamin-D in the blood and well-being. However, since this is based on only two studies, more research is needed to confirm this association.

Whereas oxytocin has mainly been investigated in relation to positive social behaviour, oxytocin is also suggested to play a role in different behaviors and traits related to well-being, such as emotional processing, trust and depressive behaviors (IsHak et al., 2011). However, surprisingly, the direct relation between oxytocin and well-being has only been investigated in a single study (Barraza et al., 2013). In a small sample (noxytocin=21) of older adults (Mage=80) no association could be reported. Future direct and powerful studies should shed more light on the hypothesized association between well-being and oxytocin.

Finally, most studies on the different hormone levels included relatively older samples (average age: 53.1, and in 6 of the 14 studies the average age is above 65). Since hormone production and levels are affected by age (Sternbach, 1998Van Cauter et al., 1996), more research is needed to study the effects of age on the association between hormones and well-being in age diverse samples.

4.3. Inflammatory markers

The results of the 36 studies on the inflammatory markers and well-being showed more consistent results compared to the previous categories. CRP was negatively associated with well-being in 14 of the 26 studies and IL-6 was negatively associated with well-being in 11 of the 25 studies, whereas the other studies did not find a significant effect. Additionally, both CRP (r=-.07) and IL-6 (r=-.05) showed small but significant negative relations with well-being in a meta-analysis. Based on the available studies, the well-being measure was not a significant moderator, suggesting that the inflammatory markers have an influence on overall well-being and not on specific aspects of hedonic or eudaimonic well-being.

Besides CRP and IL-6, fibrinogen was negatively related to well-being in three of the seven studies, and other inflammatory markers such as other interleukins or white blood cell count were either negatively related with well-being or non-significantly. Based on these results, a consistent pattern of negative associations between different inflammatory markers and well-being emerges. Lower levels of baseline inflammatory markers, i.e., reflecting less activation of the immune system, is linked to higher well-being. The non-significant findings can either be due to weaker designs or smaller samples, leading to lower power.

Similar to the hormone studies, the reviewed inflammatory marker studies included relatively older samples. The average age of the samples is 52.6 (SD=13.7) and in 17 of the 36 studies the average age is above 50, while only two studies the average age is below 30 years. As some studies suggested moderation by age (e.g., Fancourt and Steptoe, 2020), more research is needed into the effects of age on the association between inflammation and well-being in younger and age diverse samples.

A next step in the research on inflammation and well-being is the direction of effect. The direction of effect between inflammation and mental ill-being, i.e., depression, appears to be bidirectional. Patients with inflammatory diseases have a higher likelihood to develop major depressive disorder and often individuals with major depression show increased inflammatory markers, and the levels decrease with the recovery from depression (e.g., Amodeo et al., 2018Dahl et al., 2014). As well-being and mental ill-being are related but have independent effects on health and other outcomes, the direction of effect between inflammation and well-being should be investigated. Some longitudinal studies in this review showed significant associations between inflammatory markers and well-being a few years later, indicating a possible causal effect from inflammation to well-being.

4.4. Microbiome

Lastly, the composition and diversity of the gut microbiome in relation to well-being is a relatively new and fast developing research field. We could only identify four studies that related the gut microbiome diversity or composition to well-being. All studies reported significant results with the abundance of different bacteria or the diversity of the microbiome associated with higher hedonic well-being, i.e., positive affect or quality of life, indicating that it is likely that the microbiome plays a role in well-being. However, more research is needed to be confident about the specific associations between the microbiome composition and well-being, because one study only included 3 participants, different effects of different bacteria have been studied, and there might be a publication bias in that only studies with significant effects are published in this upcoming field.

Microbiome research is further complicated by the possible effects of variation in dietary habits and geography on the composition of the gut microbiota. Ideally, when investigating the microbiome, participants should be in a stable environment, keep a constant diet and living habit, and maintain a certain activity level. As this can be difficult in daily life, Li et al. (2016) minimized the possible confounding by other factors by investigating three participants that stayed 105 days in a closed human life support system with minimal interference, i.e., a laboratory that simulates a lunar-like environment. This study gave the first insights in the unconfounded relation between the gut microbiome and well-being. In future studies outside such a system, the possible confounding by diet, environment and activity should be taken into account.

Another point of discussion is the current sampling methods for gut microbiome. Tang et al. (2020) reviewed the methods and concluded that more precise sampling methods for the composition and diversity of the gut microbiome are needed. Current measures from fecal samples (and other non-invasive methods) are just a proxy for the composition of the gut microbiome. More precise sampling methods are needed to increase the reliability of the microbiome research and to replicate findings.

4.5. Future directions

In different categories consistent relationships between physiological markers and well-being (e.g., the hormone cortisol, and inflammatory markers CRP and IL-6) were reported. With respect to these effects, further research should be conducted to investigate the direction of the effect or possible moderators or confounders on the effect, as suggested above. In other categories, such as neurotransmitters and the microbiome, additional research is needed to get a complete picture of the role of these physiological markers in relation to well-being. Besides further research into the association of physiological markers related to well-being in the single categories, promising fields for future research include the integration or combination of multiple physiological categories in relation to well-being, the direction of causality, and innovative ways to measure and analyze physiological data.

4.5.1. Integration

A first observation based on the reviewed studies is that the findings of the different studies are diverse and not connected. Most studies investigated the relation between one physiological marker and well-being. Similar to the criticized candidate gene literature (i.e., investigating the association of a single or a few candidate genes with well-being, depression or other genetically complex phenotypes) in which results are mixed and do not seem to replicate (e.g., Border et al., 2019Johnson et al., 2017; van de Weijer, in press), the pick-and-choose strategy for physiological markers might have led to similar inconsistent results. Where the genome-wide association approach has been introduced to systematically search for genetic variants for complex traits, a similar data-driven approach should be used for future research into the physiology of well-being. Combining multiple physiological markers across the different categories, aka an multi-omics approach, could result in a more complete picture of the physiology underlying well-being.

Combining multiple physiological markers across the different categories could result in a more complete picture of the physiology underlying well-being. An example of combining data is multi-omics approaches, that combine and integrate multiple types of omics data, such as genomics, proteomics, transcriptomics, epigenomics, metabolomics, and microbiomics (Hasin et al., 2017). All the different processes influence each other and by combining these data, researchers can get a broader picture and a more comprehensive insight in the physiological markers and human biology underlying traits or diseases. To learn more about multi-omics, Wörheide et al. (2021) and Subramanian et al. (2020) provide helpful overviews and different applications of this approach within the domain of mental ill-being, e.g., for aggressive behavior and psychiatric disorders, can be found (Hagenbeek et al., 2021Korologou-Linden et al., 2021).

To understand the physiology underlying well-being, multi-omics approaches can also be applied to the combination of hormones, neurotransmitters, inflammatory markers, and the microbiome. For example, the stress hormone cortisol, and inflammation, the reaction of the immune system, are strongly linked (e.g., Adam et al., 2017Morey et al., 2015). Furthermore, recent research reported an influence of the gut microbiome on mental health via the level of neurotransmitters (Liu et al., 2020). The gut microbiome can alter the levels of different neurotransmitter and this alteration of neurotransmitters influences mental health. Similarly, an interaction between three categories, namely the gut microbiome, the stress response, including cortisol, and immune system is suggested to play a role in depression, and anxiety (Peirce and Alviña, 2019). As we have shown that cortisol, different immune factors and possibly the microbiome are associated with well-being, investigating these factors at the same time might lead to a clearer picture about the relation between the human physiology and well-being. To conclude, for a complete overview of the physiological markers underlying well-being, combining measures of multiple physiological markers into a large well-being study is needed.

4.5.2. Direction of effect

As we reported consistent associations of (diurnal) cortisol and different inflammatory markers with well-being, a next step is to investigate the direction of the effect between the physiological marker and well-being. Can the association be explained by a causal relationship from the physiological marker to well-being, vice versa, in both directions or is the association explained by another factor? If the direction of causation is known, this can help to design interventions to enhance well-being or prevent poorer mental health. The reported associations in this review are only correlational and it is impossible to determine causality in cross-sectional observational studies. Causality analyses, such as longitudinal (intervention) studies and Mendelian Randomization can enable future researchers to investigate the direction of causality in this field.

Longitudinal studies in which either well-being or the level of physiological factors, such as hormones or neurotransmitters are observed over time, or manipulated (e.g., by triggering their response or substitution) can allow for causal interferences to be made. For example, in the experimental design of Barraza et al. (2013) half of the participants received oxytocin for 10 days and the other half a placebo. The levels of well-being were compared before and after the treatment. There was no effect of the treatment on well-being in both groups. However, if an increase in well-being the oxytocin group, but not the placebo group had been reported, this would be evidence for a causal relation between oxytocin and well-being. Similarly, the other way around, interventions that increase well-being can be used to investigate if well-being has a causal effect on various physiological factors. For example, a meta-analysis across 20 randomized control trials (RCT) reported that mindfulness mediation is associated with immune system processes involved in inflammation, and biological aging, i.e., meditation resulted in a decrease in CRP levels (Black and Slavich, 2016). Similarly, a recent meta-analysis on the effects of meditation interventions on cortisol levels reported that such interventions resulted in reduced cortisol levels, but only when assessed in blood compared to saliva and in people at risk for somatic illnesses (Koncz et al., 2021). As mindfulness and meditation have also been linked to increased well-being, these findings could indicate a causal link between well-being and different physiological factors. Future randomized control studies specific to well-being interventions or physiological manipulations are needed to confirm these hypotheses and investigate the direction of causation.

Another approach to study the direction of causation, that does not need longitudinal data or any intervention, is Mendelian Randomization (MR), which uses genetic variants to test the causal relationships between an exposure variable and outcome. MR relies on the natural, random assortment of genetic variants resulting in a random distribution of genetic variants in a population (Smith and Ebrahim, 2003). In short, if the assumptions are met and a genetic variant is associated both with the exposure (e.g., inflammatory marker levels) and the outcome (e.g., well-being), this would provide supportive evidence for a causal effect of the immune response on well-being. To learn more about Mendelian Randomization, see Gagliano Taliun and Evans, (2021) and Smith and Ebrahim (2003) for an overview and guidelines. Different applications of this approach within the domain of mental ill-being with physiological factors can be found as well (for example (Kappelmann et al., 2021Perry et al., 2021).

Finally, results of animal studies can indicate possible causal effects of well-being and physiological factors. Although there are limitations in generalizing results from animal studies to human well-being, these results can be the starting point for research in humans and provide clues about the mechanisms and causality. Animal research has been helpful in health-related research areas, but is rare in the well-being field, largely because of the subjective nature of well-being. In the field of depression and stress, animal research on physiological factors has reported different causal mechanisms. For example, in rats, a microbiome transplantation from severely depressed patients to the rats induced depression-like behaviors, like anhedonia and anxiety-like behaviours (Kelly et al., 2016). Similarly, rodents that experienced more induced stress showed higher levels of inflammatory markers (Powell et al., 2013). These results could indicate a possible causal effect between well-being and different physiological factors and future animal research to well-being can be used to investigate causality and confirm these hypotheses.

4.5.3. Innovations and data-driven research

Related to innovations in the methods to measure physiological markers, e.g., real-time continuous monitoring (Si and Song, 2018Su et al., 2020), there are also rapid developments in the approaches to collect and analyse (big) data. Using the developments in the artificial intelligence and machine learning fields, patterns can be detected in physiological data that we would not predict. These approaches enable us to focus more on data-driven research instead of hypothesis driven research (Scheel et al., 2020). For example, using a data driving approach, and applying machine learning, Poletti et al. (2021) could distinguish between unipolar and bipolar depression based on the plasma levels of 54 cytokines, chemokines and growth factors (i.e., the immune-inflammatory signature) of the participants. For more information about artificial intelligence and machine learning, see overview articles, e.g., Jordan and Mitchell, 2015Yann LeCun, Yoshua Bengio, 2015). Different applications of this approach within the domain of mental ill-being with physiological factors can be found as well (for example (Poletti et al., 2021Wardenaar et al., 2021).

4.6. Limitations

The low number of studies in some categories of this systematic review limits our ability to draw more firm conclusions about the association between the physiological factors and well-being and this highlights the need for more studies investigating the physiology of well-being. Furthermore, the low number of studies could indicate a possible publication bias, especially in the newer fields, if studies with non-significant findings are not published.

Another limitation, touched upon briefly in the results of the different categories, is that only a limited number of studies controlled for negative affect and depressive symptoms when investigating physiological factors in relation to well-being. Since well-being and ill-being are related (Baselmans et al., 2018Okbay et al., 2016), controlling for ill-being when investigating the relation between physiological factors and well-being can help to disentangle the independent associations of physiological factors with well-being and ill-being.

A similar approach of controlling for confounding effects could be interesting for hedonic and eudaimonic well-being measures. Although hedonic and eudaimonic well-being measures are strongly correlated, they also capture slightly different parts of well-being. As proposed by Ryff et al. (2004) hedonic and eudaimonic well-being could have partly different neurobiological and physiological correlates. To learn more about the distinction between hedonic and eudaimonic well-being, future studies should include both measures and when examining the effects of hedonic well-being control for eudaimonic well-being and vice versa.

A quantitative meta-analysis on the association between cortisol levels, two inflammatory markers (CRP and IL-6), and well-being was possible due to a substantial number of homogenous study designs and reported effects. We only included studies that reported bivariate correlations, not including standardized regression coefficients and other effect sizes, since in many regression different covariates are added, leading to biased estimates when including the partial correlations between the markers and well-being. As a result, for the other categories and factors, a meta-analysis was not possible, since the studies were too heterogeneous in study methods, analysis techniques, and reported statistics. Furthermore, even though we performed a detailed literature search according to the PRISMA guidelines, it is possible we missed some papers.

Finally, in all included studies, well-being is measured with self-report measures. While self-report has its limitations, i.e., recall and reporting biases, well-being is conceptually a subjective experience and currently it is not possible to reliably measure well-being objectively.

4.7. Conclusion

[...]