main topic

Wien Med Wochenschr (2018) 168:76–84

DOI 10.1007/s10354-017-0574-2

Psychoneuroimmunology—developments in stress
research
Rainer H Straub · Maurizio Cutolo

Received: 8 February 2017 / Accepted: 19 May 2017 / Published online: 9 June 2017
© Springer-Verlag Wien 2017

Summary Links between the central nervous stress multicenter randomized controlled trials to influence
system and peripheral immune cells in lymphoid or- stress responses and outcome in chronic illness.
gans have been detailed through 50 years of intensive
research. The brain can interfere with the immune Keywords Stress research · Brain · Immune system ·
system, where chronic psychological stress inhibits Rheumatic disease · Psychoneuroimmunology
many functions of the immune system. On the other
hand, chronic peripheral inflammation—whether Introduction
mild (during aging and psychological stress) or severe
(chronic inflammatory diseases)—clearly interferes For centuries, stressful life experiences and an indi-
with brain function, leading to disease sequelae like vidual’s psychological state have been known to in-
fatigue but also to overt psychiatric illness. In recent fluence manifestation and course of diseases. In the
years, it has been observed that psychological stress 1960s, studies were initiated to discover links between
can be disease permissive, as in chronic inflammatory psychological stress (brain) and the immune system
diseases, cancer, cardiovascular diseases, acute and (periphery) [2, 4, 66, 68, 69]. At the time, it remained
chronic viral infections, sepsis, asthma, and others. obscure how the brain can exert influence on periph-
We recognized that stress reactivity is programmed eral immune function. While many studies started as
for a lifetime during a critical period between fetal black box experiments, where the connecting path-
life and early childhood, which then influences stress ways remained unknown, more than 50 years of in-
behavior and stress responses in adulthood. First tensive investigation uncovered important physiolog-
phase II clinical studies, e.g., on cognitive behavioral ical pathways that connect the brain and the immune
therapy and mind–body therapies (e. g., mindfulness- system.
based stress reduction), are available that show some The important role of the hypothalamic–pituitary–
benefits in stressful human diseases such as breast adrenal axis (HPA axis) was stressed very early af-
cancer and others. The field of psychoneuroimmunol- ter discovery of the anti-inflammatory role of cortisol
ogy has reached a firm ground and invites therapeutic (and, later, adrenal androgens) [7, 34, 66, 76]. This was
approaches based on Good Clinical Practice phase III supported by studies showing that defects of the HPA
axis can even induce chronic inflammatory diseases in
animal models [63, 71]. Soon it became clear that the
R. H. Straub () HPA axis played a role in human chronic rheumatic
Laboratory of Experimental Rheumatology and
diseases such as rheumatoid arthritis [21, 23].
Neuroendocrine Immunology, Department of
Internal Medicine I, University Hospital Regensburg,
A second pathway was related to the sympathetic
93042 Regensburg, Germany nervous system (SNS), with the two branches of the
rainer.straub@ukr.de adrenal medullary system (adrenaline) and sympa-
thetic nerve fibers (noradrenaline), which reach nearly
M. Cutolo
Research Laboratories and Academic Division of Clinical
every site in the body [9, 32, 36, 40]. Sympathetic, anti-
Rheumatology, Postgraduate School of Rheumatology, and proinflammatory effects were observed.
Department of Internal Medicine, University of Genova, During the 1980s and 1990s, the roles of many
IRCCS San Martino, Genova, Italy more non-adrenal stress hormones, such as growth

76 Psychoneuroimmunology—developments in stress research K

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hormone, thyroid gland hormones, hormones of the other proinflammatory factor was called the “two hit
renin–angiotensin–aldosterone system, and others model” of stress-induced inflammation in chronic in-
have been added to the concept of stress-induced flammatory diseases [73]. Additionally, recent stud-
immunomodulation [6, 26, 43]. Finally, the parasym- ies demonstrate that the four major downstream hor-
pathetic nervous system (PSNS) with its major neu- monal and neuronal pathways described above show
rotransmitter acetylcholine was observed to play an signs of dysfunction in these patients, leading to in-
anti-inflammatory and immunosuppressive role via complete stress responses and, consequently, proin-
alpha7 subunit nicotinergic receptors [11, 62]. While flammatory sequelae [74].
the SNS is up-regulated during the stress response, It was demonstrated that stress influences the de-
the PSNS is downregulated, so that the anti-inflam- velopment and progression of cancer, which was first
matory response of the PSNS is probably missing. confirmed in defined experimental models, where the
Similarly, the hypothalamic–pituitary–gonadal axis immunosuppressive influence of stress was strong
is downregulated during stress, which similarly re- [5]. The major immune cells suppressed were nat-
moves anti-inflammatory influences of androgens on ural killer cells, cytotoxic T cells, T helper type 1
immune responses. cells, and macrophages [54]. In the last 10–20 years,
While psychological stress mainly starts in the brain researchers tried to carry out studies in humans to
to influence these four major downstream hormonal reveal an influence of stress on cancer and immune
and neuronal pathways and, thereby, the immune sys- response. Epidemiological and clinical studies have
tem, the immune system can itself influence the brain now provided evidence for links between chronic
and the four downstream operators. These recipro- stress, depression, and social isolation on one side
cal influences were described as immune-neuro-en- and cancer progression on the other [44, 49].
docrine feedback circuits with short (local in the organ The influence of stress on the cardiovascular system
or tissue) and long loops (between organs) [8]. These is another important aspect of psychoneuroimmunol-
cybernetic concepts were mainly derived from physio- ogy, because stress-induced inflammation is linked to
logical considerations of a normally functioning body cardiovascular disease. Furthermore, many other in-
challenged for a short period of time (such as during flammation-related diseases such as obesity, type 2
infection or wounding). However, peripheral inflam- diabetes mellitus, hypertension, the metabolic syn-
matory influence directed towards the central ner- drome, pain, and others have been linked to chronic
vous system can be highly unfavorable when it is long stress and are accompanied by an increase in inflam-
standing (chronic). Repeated cytokine injections into matory factors [18, 45].
humans over weeks induced marked changes of stress Another important concept came from stressful
responses and behavior [52, 60]. The last 20 years events in fetal, perinatal, postnatal, and childhood life,
have linked peripheral inflammation with develop- which can have long-term detrimental effects on
ment of major depression and other neurological dis- stress responsivity and disease in later life [67]. In
eases such as Alzheimer dementia, diseases which are humans, maternal deprivation was linked to later
experienced as chronically stressful [25, 59]. development of cardiovascular disease [51], fetal
Another important concept builds on acute stress stressful constraints were linked to the metabolic
versus chronic stress, which changed the understand- syndrome and obesity [37], and childhood trauma
ing of stress-induced immunomodulation by the brain was positively linked to later appearance of autoim-
[27]. While long-term stress is generally harmful and mune diseases [28, 55, 70]. Traumatic events can even
immunosuppressive, short-term stress can be protec- lead to transgenerational transmission of physiolog-
tive and immunsupportive, as it prepares the organ- ical, behavioral, and cognitive problems, as well as
ism to deal with challenges [27]. This interpretation psychopathology based on changes of the neuroen-
is based on the threats posed to animals and humans docrine crosstalk, epigenetic signatures in relevant
during evolutionary history, where short—not long or pathways, alterations in neuroanatomical develop-
chronic—psychological stress was a normal factor in ment, and set-point changes of the immune system
daily life. [13].
Based on research performed in the past decades, it Finally, stress theories were presented to explain the
seems that psychological stress can influence pathogen- influence of acute or chronic stress on health in ani-
esis and exacerbation of chronic autoimmune-inflam- mals and humans (homeostasis as the basis; [15]). The
matory rheumatic diseases such as rheumatoid arthri- first theory of Hans Selye mentions the acute stressor
tis, systemic lupus erythematosus, juvenile idiopathic that leads to an acute stress response (alarm reac-
arthritis, and many others [22, 39, 47, 75, 79]. This in- tion), which is usually adaptive (stage of resistance)
fluence can occur many years before outbreak, shortly but may, over time, lead to a maladaptive response
before, and during the disease. Most stressful events and breakdown of the HPA axis (stage of exhaus-
stimulate the inflammatory process in these chronic tion) [65]. Similarly, the “stress response–allostasis
inflammatory diseases. One or two concomitant fac- response–allostatic load theory” says that allostatic
tors can aggravate stress-induced disease flares. The load can accumulate, and the overexposure to me-
parallel appearance of psychological stress and an- diators of neural, endocrine, and immune stress can

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have adverse effects on various organs leading to dis- tion prior to a psychological stress can influence, for
ease. Allostatic load over a lifetime may cause the example, the risk of developing posttraumatic stress
allostatic systems to wear out or become exhausted, disorder (PTSD). In cross-sectional studies, PTSD and
which then leads to chronic disease [48]. inflammation were associated, but it is not known
The cognitive activation theory of stress is based whether this observed association is the result of
on coping concepts, where chronic activation in the PTSD predisposing to inflammation or to inflam-
absence of coping can lead to stress-related diseases mation predisposing to PTSD [30]. In the Marine
(summarized in [77]). This theory also links recur- Resiliency Study, 2600 war zone-deployed Marines
ring subjective health complaints and repetitive ex- were investigated for symptoms of PTSD, psycholog-
tensive activation of cognitive networks related to ill- ical parameters, and laboratory parameters (C-reac-
ness and pain, called psychobiological sensitization tive protein, CRP) before deployment and at 3 and
(similar to sensitization of pain pathways as an aggra- 6 months following a 7-month deployment. The main
vating process) [77]. A similar approach was demon- outcome parameter was the Clinician-Administered
strated as perseverative cognition hypothesis mani- PTSD Scale (CAPS). Adjusting for the baseline CAPS
fested in worry, rumination, and anticipatory stress score, trauma exposure, and other relevant covariates,
that are linked to illness [14, 64]. Worry, rumination, baseline plasma CRP concentration was a highly sig-
and anticipatory stress are associated with enhanced nificant overall predictor of post-deployment PTSD
cardiovascular, endocrinological, immunological, and [30]. This demonstrates that an existing inflammatory
neurovisceral activity [14]. condition, albeit mild, can predispose to PTSD. Since
Another stress theory explains homeostatic effect inflammation can trigger depressive symptoms or
(y-axis) as a U-shaped function over stress system ac- even major depression [25], these findings once more
tivity (x-axis), where healthy homeostasis (or eustasis) demonstrate the crosstalk directed from the periphery
is achieved in the middle, optimal range of the curve, (immune system and inflammatory condition) to the
with a maximum beneficial homeostatic effect [18]. central nervous system (brain).
Suboptimal effects left and right of the optimum range
may occur as cacostasis or distress (either excessive/ Stress induces inflammation and is disease per-
prolonged or deficient/shortish activity) [18]. missive
Based on the different models, several therapeu-
tic approaches were suggested to balance or cope The examples of how psychological stress influences
with stressful events. For example, cognitive behav- chronic inflammatory diseases, cancer, and cardiovas-
ioral therapy, mind–body therapies (including Tai cular disease were reported in the Introduction. Here
Chi, Qigong, yoga, meditation, mindfulness medita- are some new studies that confirm the permissive ef-
tion, mindfulness-based stress reduction), physical fect of psychological stress on chronic diseases.
exercise, healing touch, music therapy, therapeutic People with a high body mass index (BMI) demon-
massage, and health education among others can, strate an increased inflammatory state and somewhat
to some extent, deal with distress and, importantly, increased plasma glucocorticoid levels. However, it is
they also beneficially affect readout parameters of the not known whether higher glucocorticoids in people
immune system (summarized in [12]). with a high BMI elicit anti-inflammatory effects due to
The research field is highly active, adding innumer- immunosuppressive effects of glucocorticoids. In ad-
able publications to the body of information. A recent dition, it is not known whether short-term stress that
named series of publications with the title “Twenty stimulates glucocorticoid release has a stronger im-
Years of Brain, Behavior, and Immunity (1987–2007)” munosuppressive effect in people with a high BMI. In
summarized some of these ideas in the abovemen- a study on 42 healthy men with a BMI of 21–34 kg/m2,
tioned different fields of psychoneuroimmunology re- glucocorticoid sensitivity of monocytes were tested
search [3, 10, 19, 24, 35, 41–43, 50, 53, 72]. Compre- in vitro using increasing doses of dexamethasone as
hensive textbooks presented further details which be- an immunosuppressant and lipopolysaccharide-stim-
came available up until approximately 2007 [1]. Since ulated tumor necrosis factor (TNF) as readout param-
this time, many aspects have been absorbed by the eter [80]. A higher BMI was associated with a lower
various clinical fields by demonstrating the multiplex glucocorticoid sensitivity of monocyte TNF produc-
influence of stress on immune-mediated disease. This tion after stress (main effect of BMI: p < 0.001) and
review is written to highlight specific aspects of clini- with more pronounced decreases of glucocorticoid
cal psychoneuroimmunology since the year 2007. sensitivity following stress (interaction of stress-by-
BMI: p = 0.002). The data suggest that with increas-
Reciprocal influence of inflammation on the brain ing BMI, glucocorticoids are less able to inhibit TNF
production following stress. This might suggest a new
The reciprocal influence of inflammation on the brain mechanism linking BMI with an elevated risk for ad-
has been shortly mentioned in the Introduction (in verse cardiovascular, metabolic, and central nervous
the context of depression and dementia). However, it outcomes following stress [80].
remained unclear whether a proinflammatory situa-

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Another study demonstrated a similar stress-in- symptoms [56]. This study is another indication of
duced deficient glucocorticoid effect, which was a detectable link between psychological stress and in-
coined glucocorticoid receptor resistance (GCR) [20]. flammation/dysregulation of the immune response.
The authors determined stressful life events, GCR, For a long time now, the link between psychologi-
and control variables in 276 otherwise healthy adult cal stress and asthma has been intensively discussed.
subjects. These people were then quarantined, ex- Psychological stress can affect airway inflammatory
posed to one of two rhinoviruses, and followed for responses to irritants and allergens [61], but the im-
5 days with nasal washes for viral isolation and assess- portance of stress in the etiology of adult-onset res-
ment of signs/symptoms of a common cold. Those piratory and dermatologic allergic disorders remains
subjects with recent exposure to a long-term threat- unclear. A total of 9785 subjects from the Copenhagen
ening stressful experience demonstrated GCR—and City Heart Study, Denmark, were included. At base-
those with GCR were at a higher risk of subsequently line (1981–1983), these subjects were free of atopic
developing a cold [20]. disorders and they were asked for stress intensity and
In a second study, the authors studied 79 sub- frequency. The subjects were followed until 2010.
jects who were subsequently exposed to a rhinovirus Perceived stress was associated with atopic disorders
and monitored at baseline and for 5 days after viral in a dose-dependent manner: High versus low stress
challenge for the production of proinflammatory cy- was associated with a higher risk of self-reported
tokines (interleukin [IL]-1β, TNF, and IL-6) locally in asthma incidence (odds ratio, OR = 2.32; 95% confi-
nasal secretions [20]. Now, greater GCR predicted the dence interval, CI: 1.47–3.65), daily intake of asthma/
production of more local proinflammatory cytokines bronchitis medication (OR = 2.26; 1.42–3.58), first-
among infected subjects. They concluded that these time asthma hospitalization (OR = 2.01; 1.41–2.86),
data provide support for a model suggesting that allergic rhinitis (OR = 1.64; 0.99–2.72), and atopic
prolonged stressors result in GCR, which, in turn, in- dermatitis (OR = 1.75; 1.11–2.77), which was indepen-
terferes with appropriate regulation of inflammation. dent of smoking status [61]. This study shows another
Since inflammation plays an important role in the on- pathway by which chronic distress can influence sys-
set and progression of a wide range of diseases, this temic inflammation.
model may have broad implications for understand- Intestinal permeability for bacteria is increased
ing the role of stress under normal healthy conditions due to psychological stress, as studied in animals. In
[20]. a recent investigation in human subjects, the authors
Another investigation turned to the recurrence quantified small intestinal permeability by a 2-hour
of herpes simplex virus disease upon psychosocial lactulose-mannitol urinary excretion test [78]. Public
stress [17]. The authors performed a meta-analysis speech—a paradigmatic test of acute psychological
on 11 eligible studies on herpes simplex virus recur- stress—increased intestinal permeability. This effect
rence. They confirmed a robust positive association was only present in those subjects with an elevated
between psychosocial stress and symptomatic herpes saliva cortisol. Additional corticotropin releasing
simplex virus recurrence. Sensitivity analyses demon- hormone stimulation even increased permeability,
strated that psychological distress was more strongly which was blocked by administration of a mast cell
associated with symptomatic herpes simplex virus stabilizer [78]. Although psychological stress clearly
recurrence than stress stimuli per se, and that psy- increased intestinal permeability, the authors have
chosocial stress tended to be more strongly associated not investigated a possible increase of lipopolysac-
with oral than genital herpes recurrence. Similar to charide in the circulating blood, which would support
the rhinovirus study, the herpes simplex virus study animal studies. Nevertheless, this study can be seen
shows a clear relationship between psychological as a forerunner for similar studies with a focus on
stress and a viral stimulus of inflammation. Repeti- inflammation and bacterial translocation.
tive or continuous psychological stress perceived as In a study in mice, it was demonstrated that
distress can, thus, lead to a more proinflammatory chronic psychological stress activates hematopoietic
situation over longer time [17]. stem cell activity leading to stress-induced mono-
Psychological stress might be a forerunner of overt cytosis and neutrophilia. This depended on nora-
sepsis. In a cohort of 30,183 subjects within the Rea- drenaline-induced increase of hematopoietic stem
sons for Geographic and Racial Differences in Stroke cell proliferation [38]. The authors also examined
Study, the investigators determined the level of per- atherosclerosis-prone Apoe(–/–) mice, where acceler-
ceived stress and followed these people for 1–10 years ated hematopoiesis promoted dangerous plaque for-
[56]. In 2003 to 2012, 1500 participants experienced mation associated with vulnerable lesions that cause
an episode of sepsis. Increased stress was associ- myocardial infarction and stroke in humans [38].
ated with a higher 1-year adjusted incidence of sepsis, Such a stress-induced pathway may additionally lead
even after accounting for depressive symptoms. The to cardiovascular sequelae and a higher inflammatory
association between stress and the 10-year adjusted load.
incidence of sepsis was also significant, but this as- In another study in mice, the authors investigated
sociation was reduced when adjusting for depressive the link between chronic stress and cancer progres-

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sion [46]. Chronic stress restructured lymphatic net- Therapeutic approaches to balance or cope with
works within and around tumors to provide pathways stressful events
for tumor cell escape. Pharmacological inhibition of
the sympathetic nervous system blocks the effect of With all the information gathered through more than
chronic stress on lymphatic remodeling in vivo and re- 30 years of intensive research, the first therapeutic ap-
duces lymphatic metastasis in preclinical cancer mod- proaches were expected to treat subjects with exagger-
els and in patients with breast cancer [46]. This can be ated stress responses. The different theories provided
a novel route for how the activation of the sympathetic a platform to tackle stress behavior.
nervous system can stimulate cancer outcomes. One approach is mindfulness based stress reduc-
In conclusion, this section clearly shows the per- tion (MBSR), which was applied in a non-randomized
missive effects of psychological stress on chronic dis- controlled study in patients with early-stage breast
ease and inflammation. cancer [81]. Early-stage breast cancer patients who
did not receive chemotherapy self-selected into an
Stressful events in fetal, perinatal, postnatal, and 8-week MBSR program or an assessment only, con-
childhood life trol group. The first assessment was at least 10 days
after surgery and prior to adjuvant therapy, as well as
In the Introduction, we already linked early life stress before the MBSR start-up. Further assessments were
and later disease outcomes. Two important stud- mid-MBSR, at completion of MBSR, and at 4 weeks
ies—one in humans and one in mice—support the post-MBSR completion [81]. At the first visit before
enormous impact of early life events and later disease. MBSR start, reductions in peripheral blood mononu-
Disasters provide natural experiments that can sim- clear cell natural killer (NK) cell activity (NKCA) and
ulate prenatal stress. Five months after the 1998 Que- interferon (IFN)-γ production and increases in IL-4,
bec ice storm, women were recruited who had been IL-6, and IL-10 production and plasma cortisol lev-
pregnant during the disaster [16]. The authors as- els were observed for both groups of breast cancer
sessed the degrees of objective hardship and subjec- patients. Over time, women in the MBSR group re-
tive distress. Thirteen years later, they investigated established their NKCA and cytokine production lev-
DNA methylation profiling in T cells obtained from els. In contrast, breast cancer patients in the control
36 of the children [16]. Prenatal maternal objective group exhibited continued reductions in NKCA and
hardship was correlated with DNA methylation levels IFN-γ production, with increased IL-4, IL-6, and IL-10
at 1675 CpG (cytosine-p-guanine) sites affiliated with production [81]. MBSR women had reduced cortisol
957 genes predominantly related to immune function levels, improved quality of life, and increased coping
[16]. Changes in DNA methylation in the genes of se- effectiveness compared to controls [81]. These results
cretogranin V and lymphotoxin alpha both highly cor- provide preliminary evidence that MBSR can be favor-
related with maternal objective stress, and were com- able in breast cancer.
parable in T cells and peripheral blood mononuclear In another study with compassion meditation,
cells (PBMCs). These data provide first evidence in the influence on physiological pathways was stud-
humans supporting the conclusion that prenatal ma- ied in more detail [57]. Much attention has been
ternal stress results in a lasting, broad, and function- paid to meditation practices that emphasize calming
ally organized DNA methylation signature in several the mind, improving focused attention, or develop-
tissues in offspring [16]. ing mindfulness, but less is known about meditation
Prenatal infection and exposure to traumatizing practices that foster compassion. The presented
experiences during peripuberty have each been as- study examined the effect of compassion meditation
sociated with an increased risk for neuropsychiatric on innate immune, neuroendocrine, and behavioral
disorders [33]. Evidence is lacking for the cumulative responses to psychosocial stress and evaluated the
impact of such prenatal and postnatal environmental degree to which engagement in meditation practice
challenges on brain functions and vulnerability to psy- influenced stress reactivity [57]. Sixty-one healthy
chiatric disease. In a translational mouse model that adults were randomized to 6 weeks of training in
combined exposure to prenatal immune challenge compassion meditation (n = 33) or participation in
and peripubertal stress, the authors demonstrated a health discussion control group (n = 28), followed
synergistic pathological effects on adult behavioral by exposure to a standardized laboratory stressor
functions and neurochemistry [33]. The prenatal (Trier social stress test [TSST]) [57]. Physiologic and
insult markedly increases the vulnerability of the behavioral responses to the TSST were determined
pubescent offspring to brain immune changes in re- by repeated assessments of plasma concentrations of
sponse to stress [33]. The findings reveal interactions IL-6 and cortisol, as well as total distress scores on
between two adverse environmental factors that have the Profile of Mood States (POMS). No main effect
individually been associated with neuropsychiatric of group assignment on TSST responses was found
disease (another “two hit model of stress”). This for IL-6, cortisol, or POMS scores [57]. However,
supports theories that mental illnesses with delayed within the meditation group, increased meditation
onsets involve multiple environmental hits. practice was correlated with decreased TSST-induced

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cate [31]. These genomic regions include telomeres,

which contain repetitive DNA and telomere-binding
proteins. If not properly regulated, replication of such
genomic regions can result in DNA damage, leading
to genomic instability [31]. Thus, the length of the
telomere is a marker of genomic stability and it de-
creases with cellular aging. Telomerase activity plays
an essential role in cell survival, by lengthening telom-
eres and promoting cell growth and longevity. It is
now possible to quantify the low levels of telomerase
activity in human leukocytes.
In a recent study, the authors tested whether leuko-
cyte telomerase activity changes under acute psy-
chological stress [29]. A total of 44 elderly women,
including 22 high-stress dementia caregivers and
22 matched low-stress controls were subjected to
a brief laboratory psychological stressor. At base-
line, caregivers had lower telomerase activity levels
than controls, but during stress, telomerase activity
increased similarly in both groups [29]. Across the en-
tire sample, subsequent telomerase activity increased
by 18% 1 h after the end of the stressor [29]. The
increase in telomerase activity was independent of
changes in numbers or percentages of monocytes,
lymphocytes, and specific T cell types. Telomerase
activity increases were associated with greater cortisol
increases in response to the stressor [29]. The authors
conclude that telomerase activity is dynamic with
exposure to an acute stressor.
In another study, global sleep quality, measured by
the Pittsburgh Sleep Quality Index (PSQI), and diary-
Fig. 1 Psychoneuroimmunology crosstalk. The brain commu-
reported sleep duration were linked to telomere length
nicates with the immune system, thereby influencing immune
function (red lines: stimulating; green lines: inhibiting). The im- in different immune cell subsets [58]. A sample of
mune system communicates with the brain by reciprocal path- 87 obese men and women were investigated. Poorer
ways. Both directions are linked to the development of diseases. PSQI global sleep quality was associated with statisti-
This is mainly relevant when either psychological stress lasts too cally significantly shorter telomere length in lympho-
long or immune system activation is chronic. In both situations, cytes but not granulocytes, and in particular in CD8+
physical and mental activity are low, which can lead to illness. T cells and CD4+ T cells [58]. Poorer global sleep qual-
RAA renin–angiotensin–aldosterone system, T3 triiodothyro-
nine (active thyroid gland hormone)
ity predicted shorter telomere length in CD8+ T cells
among those with high perceived stress but not in
low-stress participants [58]. These findings provide
IL-6 and POMS distress scores. Moreover, individuals preliminary evidence that poorer global sleep quality
with meditation practice times above the median ex- is related to telomere length in several immune cell
hibited lower TSST-induced IL-6 and POMS distress types, which may serve as a pathway linking sleep
scores compared to individuals below the median, and disease risk in obese individuals.
who did not differ from controls [57]. These data Since the cellular aging process can be proinflam-
suggest that engagement in compassion meditation matory per se, stress-induced changes in telomerase
may reduce stress-induced immune and behavioral activity and telomere length might stimulate a more
responses. Future studies are required to determine proinflammatory situation.
whether individuals who engage in compassion med-
itation techniques are more likely to exhibit reduced Conclusions
stress reactivity [57].
Studies before 2007 defined the physical pathways be-
Stress and telomere length tween the brain and the immune system, i.e., the HPA
axis, sympathetic nervous system, and non-adrenal
A new field of investigation links stress with a cellular stress hormones (e. g., angiotensin). With psycholog-
aging marker, i. e., telomere length. The DNA repli- ical stress, the parasympathetic nervous system and
cation machinery encounters problems at numerous the hypothalamic–pituitary–gonadal axis are down-
genomic regions that are inherently difficult to repli- regulated so that their anti-inflammatory influence is

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