Psychoneuroendocrine immunology (PNEI) and longevity

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Psychoneuroendocrineimmunology (PNEI)
and longevity
Cavezzi Attilio*, Ambrosini Lorenzo, Quinzi Valentina, Colucci Roberto, Colucci Enza
Psychoneuroendocrineimmunology (PNEI) is the science which studies the interactions between psychological, neural,
endocrine and immunological processes.
The concept of the PNEI system was developed in the seventies and eighties through the discoveries of the interaction
between immune system and molecules with neuroendocrine activity targeting multiple organs; the interdependence
between immunological, psychological and neuroendocrine mechanisms has been elucidated through several studies
subsequently.
PNEI system is a self-regulation network which is involved in the homeostasis of the organisms, in the maintenance of
chemical-physical-neuropsychological balance in response to stimuli of various nature.
The present review provides an overview of the fundamental scientic literature on PNEI and its interaction with chronic low
grade cellular inammation processes and consequently with longevity. Similarly literature data on the strict link between
hormetic processes and PNEI system are discussed, with reference to resilience as a key-factor in the natural/pathologic
evolution of aging.
Keywords: PNEI, Psychoneuroendocrineimmunology, Psychoneuroimmunology, Longevity, Hormesis, Inammation,
Polyphenols
the (patho-) physiological mechanisms proper of human psyche,
neurological system (limbic system and namely hypothalamus in
primis), endocrine system (e.g. hypophysis and receptor glands) and
immunitary system. These organs/circuits are part of an integrated
self-regulation network that aims at psycho-somatic homeostasis in
response to endogenous and exogenous stimuli of various nature
(Figure 1).
In this paper an overview of a few scientific evidences and of most
significant literature data about PNEI and longevity are presented.
In the latest years medicine is adapting the concept of illness
Sponsorships or competing interests that may be relevant to content are
disclosed at the end of this article.
Eurocenter Venalinfa, San Benedetto del Tronto (AP), Italy
*Corresponding Author. Address: Eurocenter Venalinfa, San Benedetto del
Tronto (AP), Italy. Tel: +390735500635. Email address: info@cavezzi.it (A.
Cavezzi).
Copyright © 2018 Cavezzi A et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Healthy Aging Research (2018) 7:12
Received 14 October 2018; Accepted 26 October 2018
Published online 03 November 2018
DOI: 10.12715/har.2018.7.12
Introduction
Psychoneuroendocrineimmunology (PNEI) is the scientific
discipline which studies the interactions between psychological,
neural, endocrine and immunological processes.
The concept of the PNEI system was born in the second half
of 20th century and developed mainly in the seventies and eighties
when different experiments confirmed the existence of a network
of immune-neuro-endocrine interactions [1]. In the nineties Ader [2]
diffused the main concepts of PNEI to a wider audience, following the
discovery that the lymphocytes (immunological cells) produce TSH
(hypophyseal hormone) and other molecules with neuroendocrine
activity. The scientific confirmation about the interdependent
relationship between immunological and neuroendocrine
mechanisms has progressively led to a new reappraisal of diagnostic
and therapeutic pathways in several medical fields and namely in
longevity medicine.
From the morpho-functional point of view PNEI system includes
NEURAL
SYSTEM
ENDOCRINE
SYSTEM
IMMUNE
SYSTEM
Figure 1. PNEI: Interconnections and signaling among psyche,
neural, endocrine and immune systems.

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and its modus operandi based on it. Emotions, mental attitude,
lifestyle, social support, nutrition are increasingly recognized as key
elements in the processes of diagnosis and treatment of any disease.
The functioning of the PNEI system highlights how psycho-social
elements are not only abstract expressions of a subjective experience;
their value is also expressed through concrete patho-physiological
clinical manifestations that depend on the individual-environment
relationship.
Literature evidence has highlighted how chronic low grade cellular
inflammation (CLGCI), neurodegenerative and cardiovascular
disorders, obesity, diabetes, cancer and, more generally, senescence
are all processes which are strictly linked to PNEI system activity.
More recently a fundamental link between hormetic processes and
PNEI system have been shown as well, referring to resilience as a key-
factor in the natural/pathologic process of aging [3].
In 2009 an editorial in the Lancet [4], titled “What is health?
The ability to adapt”, it is clearly stated that health is not a state of
complete physical, mental, and social well-being; and nor is it merely
the absence of disease or infirmity”. More properly the authors,
following Georges Canguilhem’s ideas, state that “health is the
ability to adapt to one’s environment. Health is not a fixed entity.
It varies for every individual, depending on their circumstances” and
they appreciate “the beauty of Canguilhem’s definition of health-of
normality-which includes the animate and inanimate environment,
as well as the physical, mental, and social dimensions of human
life”. According to this more comprehensive and modern view of
health, PNEI system in fact is recognized to play a significant role in
aging processes [5]. The imbalance between emotional and physical
stimuli is definitely connected to an ongoing series of phenomena
that include and affect biological, psychological and social aspects
within human life.
A literature search concerning PNEI system and longevity
has been performed through various biomedical databases, such
as pubmed/medline, google scholar, embase. The terms, PNEI,
Psychoneuroendocrineimmunology, psychoneuroimmunology,
psychosocial, resilience, mood, hormesis, together with the terms
longevity and aging were used for article search. As this paper was
not intended as a systematic review, after screening a few hundreds
of the resulting abstracts, the full texts of the most pertinent articles
have been collected, reviewed and lastly discussed and included as
references in the present text.
Our main aim was to highlight the main concepts and evidences
about the possible role of PNEI system in several medical fields,
namely in the inflammaging process, in the longevity mechanisms,
as well as in the “innovative” hormetic approach.
PNEI and Inammation
PNEI primarily provides the biological basis of bidirectional
communication between the endocrine, immune and
neuropsychological networks in physiological and pathological
conditions. Psycho-emotional and affective state of the individual
human being seem to influence or modify the course of a pathological
organic event [6].
The pivotal process through which the PNEI system intervenes in
most diseases is undoubtedly inflammation [7,8], in terms of interactions
with the CLGCI which accompanies human life. Table 1 summarizes
the main literature evidence regarding PNEI and inflammation, as
reported in this section.
Chronic stress, also called distress, basically represents the
persistent disequilibrium of the PNEI system pillars, and it acts
on the hypothalamus-hypophysis axis and the whole endocrine
system, which results finally in a modification of cortisol level.
Stress consequently favors inflammation of the tissues due to the
increase of cortisolemia and the increase of inflammatory cytokines
(i.e. IL-1, TNF, IL-6); they activate the immunitary system in a pro-
inflammatory sense. Extensive innervation of lymphoid organs
by neurovegetative fibers, releasing especially norepinephrine,
acetylcholine and neuropeptides has been widely documented [9].
An important role is played by the plexuses of sympathetic
nerve fibers that surround the arterial vessels which penetrate the
lymphoid organs. The interaction occurs by means of all immune
cells, especially those of innate immunity, which are typically involved
in inflammation processes. Among them mast cells are known
to be able to release large amounts of histamine and other active
substances that cause vasodilation and subsequently inflammation.
Of interest, these cells are present not only under the skin and the
mucous membranes of the body, but also in fundamental organs,
including the brain, where they can produce inflammation as well [10].
Mast cells can be activated in an inflammatory sense by the
main neuropeptides (Calcitonin-gene-related-peptide, substance P,
neuropeptide Y, nerve growth factor, vasoactive intestine peptide),
as well as by adrenaline, noradrenaline and other substances released
by nerve fibers [11]. It is clear how the vegetative nervous system is able
to modulate the inflammatory processes by interacting with the mast
cells and other relevant immune system components.
In the last half century inflammation has been recognized as one
of the main (if the not the main) causal processes in atherosclerosis
and in lipid profile alterations [12]. CLGCI and hyperdyslipidemia
may be connected to several causal and favoring factors and for
example the correlation between psychic depression, chronic stress
and alterations in the blood fat profile (dyslipidemia) has long been
known in medicine [13-16].
PNEI system science describes how all the compartments
influence and are influenced by the inflammatory processes: in
fact also the immune system is affected by the alterations related to
depression and dyslipidemia. Dantzer and coll. suggest that through
the release of cytokines in the brain an inflammatory condition
is established and it results in neuronal activity alteration which
causes depression and a procession of symptoms summarized in a
framework called "sickness behaviour" [17,18].
This close inter-relationship of inflammation, depression,
dyslipidemia and metabolic alterations is increasingly being
investigated to understand the pathogenesis of cardiovascular and
cerebrovascular diseases, but also to justify the differences recorded,
notwithstanding the same pharmacological treatment, in the post-
operative course of patients who have suffered myocardial or cerebral
infarction. An increasing number of studies [19] is equating the
weight of the risk factors related to psychosocial negative situations
(depression, anxiety, hostility, social isolation) to the classical biological
ones (smoking, hypercholesterolemia, hypertension, obesity, diabetes)
within the pathogenesis of cardiovascular diseases [20-22].
Chronic stress and inflammation are factors that can also
increase the risk of cancer and metastasis, particularly in the
lymphoglandular system. Dealing with the details of the molecular
mechanisms underlying this correlation is beyond the scope of
this work. The most reliable hypothesis is that an increase in the
production of neuropeptides and stress hormones can cause on one
hand an alteration in the signaling of cell proliferation (i.e. MTOR/
autophagy pathways), and on the other side the increase in cortisol,
with consequent dysregulation of immune response, insulin and
leptin.
Knowing the link between the neuroendocrine, the psychological

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and the immune system, it is not surprising that a meta-analysis
carried out on 165 controlled studies in oncology concludes that
psycho-social distress is related to an increase in the incidence of
cancer, a worse prognosis and an increase in mortality [23].
All these studies show how psychological emotions and stress can
translate into an inflammatory process that bidirectionally involves
the entire PNEI system and the target organs.
PNEI and Longevity
The PNEI approach is being investigated and proposed to
Table 1
PNEI and Inammation: Main literature data
Authors –
year Topic Outcomes
Vitetta et al. [6] Mind-body medicine: stress and its impact on
overall health and longevity
Adverse health outcomes such as coronary heart disease, gastrointestinal
distress, and cancer have been linked to unresolved lifestyle stresses,
expression of a negative impact on human life span.
Wirtz et al. [7] Psychological Stress, Inammation, and
Coronary Heart Disease
Chronic stress increases the risk of incident coronary heart disease and
poor cardiovascular prognosis; acute emotional stress can trigger acute
events in vulnerable patients. Stress also increases inammatory markers.
Alcocer-Gómez
et al. [8]
Stress-Induced NLRP3 Inammasome in
Human Diseases
Stress can trigger inappropriate activation of the NLRP3 inammasome
which contributes to the onset and progression of age-related diseases such
as metabolic disorders and metabolic syndrome.
Bellinger et
al. [9]
Sympathetic Modulation of Immunity:
Relevance to Disease
Sympathetic innervation of lymphoid tissues meets the criteria for
neurotransmission with immune cells as target cells
Rosa et al. [11] The role of histamine in neurogenic
inammation
The inammatory response evoked by the activation of the sensory nerve
bers is brought about by neuropeptides released from the peripheral
endings of sensory neurons upon their stimulation.
Capron [12] Inammation and atherosclerosis
Human atherosclerotic lesions share many features of an inammatory
reaction of arterial intima (increased penetration of plasma components,
proliferation of smooth muscle cells, inltration by monocytes/macrophages
and lymphocytes).
Yu et al. [13]
Psychological factors and subclinical
atherosclerosis in postmenopausal Chinese
women in Hong Kong
High perceived stress scores in postmenopausal women were associated
with an increased risk of elevated total cholesterol and elevated low-density
lipoprotein cholesterol.
Fan et al. [14]
Association between job stress and blood
lipids among university staff in Yunnan
province
Male staffs with higher job stress had higher risk of increased serum
triglycerides (3.5 folds) and increased serum low density lipoprotein-
cholesterol (2.9 folds). The risk of elevated serum triglycerides increased in
proportion to increasing job stress.
Xu et al. [15]
Association between job stress and newly
detected combined dyslipidemia among
Chinese workers: ndings from the SHISO
study
Effort, over-commitment, low reward and effort-reward imbalance increase
the risk of dyslipidemia, especially triglycerides and LDL-cholesterol.
Neves et al.
[16]
Chronic stress, but not hypercaloric diet,
impairs vascular function in rats
Stressed rats presented higher concentration of insulin, corticosterone,
lipids and higher atherogenic index values. Stress increased intima-media
thickness.
Dantzer et al.
[17]
From inammation to sickness and
depression: when the immune system
subjugates the brain
Conditions of chronic inammation exacerbate the sickness and depression-
like behaviors.
Dantzer et. Al.
[18]
Inammation-associated depression: from
serotonin to kynurenine
Inammation-associated depression: the degradation of tryptophan induces
the synthesis of kynurenine (neurotoxic compound).
Rozanski et al.
[19]
Impact of psychological factors on the
pathogenesis of cardiovascular disease and
implications for therapy
Chronic psychosocial stress can lead, probably via excessive
sympathetic nervous system activation, to exacerbation of coronary artery
atherosclerosis.
Rozanski et. al.
[20]
The epidemiology, pathophysiology, and
management of psychosocial risk factors
in cardiac practice: the emerging eld of
behavioral cardiology
Both exercise and multifactorial cardiac rehabilitation with psychosocial
interventions have demonstrated a reduction in cardiac events.
Psychopharmacologic interventions may also be effective.
Yusuf et al. [21]
Effect of potentially modiable risk factors
associated with myocardial infarction in 52
countries (the INTERHEART study): case-
control study
Smoking, raised ApoB/ApoA1 ratio, history of hypertension, diabetes,
abdominal obesity, psychosocial factors, lack of daily consumption of fruits
and, regular alcohol, lack of regular physical activity, were all signicantly
related to acute myocardial infarction.
Halaris [22] Inammation, heart disease, and depression
Morbidity and mortality of cardiovascular disease is possibly linked to mental
stress which leads to sustained sympathetic overdrive and diminished vagal
tone, contributing to a pro-inammatory status.
Chida et. al.
[23]
Do stress-related psychosocial factors
contribute to cancer incidence and survival?
Stress-prone personality or unfavorable coping styles and negative
emotional responses or poor quality of life were related to higher cancer
incidence, poorer cancer survival and higher cancer mortality.

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human relationships and, beyond a certain level, not on subjects’
intelligence, d) the human warmth of the relationship mother-child
positively influenced the rest of life, e) the higher warmth of the
relationship in childhood with fathers correlated with lower rates
of anxiety for adults and greater "satisfaction of life" at the age 75.
The fundamental conclusion of this study showed that the warmth
of human relationships has the greatest positive impact on 'life-span
and satisfaction'.
This confirmation of the significant role of PNEI system
in longevity has been regarded as a basic fact to be taken into
consideration in any medical/social approach towards healthy-aging.
Telomere length is another recognized important longevity
index and furthermore it is negatively influenced by chronic stress
and depression [31]. A clinical study [32] examined 58 young women
(38 years on average), of whom 39 were mothers of chronically ill
children (and therefore in a prolonged stress condition), while the
remaining ones served as a control group. All women were evaluated
with psychological tests of stress measurement and biological
tests, including telomere length measurement, telomerase activity,
and cellular oxidative stress. The resulting findings showed that
chronic stress in the mothers of sick children was associated with
lower telomerase activity, lower telomere length and greater cellular
oxidative stress. Conversely in the same study the subjects practicing
meditation (mindfulness) had greater telomerase activation and
longer telomeres.
Epigenetic changes related to chronic stress were highlighted
furthermore in a study on pregnant women suffering from chronic
stress; in this study the authors demonstrated that also the telomeres
of the offspring are affected, which will be statistically shorter both
for infants and adults [33].
Another study conducted on infants in early childhood, showed
a strong difference in telomere length linked to their psychological
and behavioral state [34]. The group of children characterized by
greater emotional reactivity, measured by psychological tests,
increased cortisol and heart rate, and also showed a reduction in
telomere length in cells [35].
Oxidative stress has been recognized at the base of many aging
processes and similarly the linkage between mood and neuronal
diseases, immunosenescence and oxidative stress has been shown in
different studies [36-38].
This growing evidence about the inter-relationship between
PNEI pathways, CLGCI and aging science (Table 2) highlights the
relevant correlation between the negative psycho-emotional factors
and social chronic stress and ultimately a worse longevity and a lower
quality of the aging processes.
address complex and multifactorial processes such as healthy aging
and longevity [5]. Chronic inflammation is considered the common
ground of many pathogenetic processes and in the early 2000s
Franceschi called "inflammaging" the combination of CLGCI, as
core pattern of any chronic degenerative process and senescence [24].
Inflammatory processes can originate and worsen due to multiple
causes, both of organic and of psychological/social nature, hence a
close interdependence and connection between inflammaging and
PNEI system dysregulation has been highlighted [25].
Looking at the interaction between PNEI and psycho-physical
aging several studies have been published. One study has shown
that a positive childhood from the psychosocial point of view may
guarantee a better cardiovascular function [26]; similarly a Korean
study on the psychosocial factors which interfere on healthy aging
showed that depression is the most relevant one, whereas conversely
the perceived health status, ego integrity, self-achievement, self-
esteem, participation at leisure activities were beneficial factors [27].
Another study has pointed out that senescence is a process that
can be improved by self-estimation and self-perception of own aging
with an increase of 7.5 years in the lifespan, in comparison to the
subjects who negatively interpret their aging process [28]; and this
result was achieved regardless of economic-social status, gender,
loneliness and disability.
Through a huge cohort of 3966 homozygous twins aged 70 years
or older, who were followed for a mean period of 9 years [29], other
authors showed that the individual level of feeling of well-being
predicted a greater longevity, regardless of family, genetic and shared
environment factors.
One of the most pertinent and relevant prospective investigation
on long-term aging and its connection with biological and psycho-
social factors was led by Vaillant and subsequently by Waldinger
(“The Harvard Grant study”) and it was extended for about 75 years
[30]. The great amount of collected data regarded 268 physically and
mentally healthy Harvard college students. These subjects were males
of American nationality with a high social status; the information
prospectively collected on a regular basis concerned: a) the physical
and mental state, b) several possible risk factors (i.e. smoke habit,
alcohol consumption), c) psycho-social features such as the enjoyment
of a career, the experience of retirement and the quality of family
life. The purpose of the study was to identify biological/psycho-social
predictive factors of healthy aging. The Harvard grant study, unique
for duration and typology of investigated subjects (“high social class”)
highlighted a few relevant findings: a) alcoholism was the factor with
the most destructive power, strongly correlating with neurosis and
depression, b) smoking was the second factor contributing to early
morbidity and death, c) financial success depended on warmth in
Table 2
PNEI and longevity: Pertinent literature
Authors - year Topics Outcomes
Guidi et al. [5] Psychoneuro-immunology and Aging
The neuroendocrine mechanisms of psychoimmune interaction: chronic
psychological distress and depression may worsen some immune functions
in the aging process.
Franceschi et
al. [24]
The network and the remodeling theories
of aging: historical background and new
perspectives
Two general theories on aging, as well as their experimental basis and
data, suggest that aging and longevity are related, in a complex way, to the
capability to cope with a variety of stressors.
Fougère et al.
[25]
Chronic Inammation: Accelerator of
Biological Aging
Biological aging is characterized by a chronic low-grade inammation level.
Inammaging effects include oxidative stress, mitochondrial dysfunction,
glycation, deregulation of the immune system, hormonal changes, epigenetic
modications, and dysfunction of telomeres.

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Therapeutic Approaches to Improve PNEI System
A lot of possible procedures which may positively act on the
PNEI system have been described and the main ones are related to
the techniques aimed at stress management such as: slow breathing
(i.e. 6 breaths/minute) [39,40], contra-resistance respiratory training [41],
meditation [42], prayer [43,44], autogenic training [45]. Table 3 reports a
few of the most validated methods and procedures which may have a
role in PNEI management within longevity medicine.
It has been shown that carotid baroceptors are influenced by
most of the stress management methods as to above [46], with a
particular reduction in blood pressure and heart rate, achieving the
cerebral alpha state of vigilant relaxation and basically a reduction
of excess cortisol. Other physical activities useful in PNEI system
adaptation are exercising, dance, Yoga and Tai-Chi.
Meditation, mindfulness and other spiritual/religious practices
have been documented as useful ways to improve PNEI system
functionality; studies on particularly long-lived subjects in Spain,
Italy and Greece have shown how the regular exercise of meditative/
spiritual practice correlates with a greater telomere length and a
decidedly long life expectancy [28,31]. In fact multiple biological factors
may have jeopardized the final results of these studies, hence a
multifactorial analysis would be of help in future similar studies.
PNEI-orientated approaches basically aim at increasing resilience,
which generally expresses the ability of a system to adapt to changes.
In psychology resilience is the ability to successfully adapt to life tasks
in the face of social disadvantage or other highly adverse conditions
[47].
All living beings may have a variable degree of self-repair (possibly
returning to the original condition) after a negative change of their
primary state. High level of personal resilience is a basic target in
longevity medicine [3] and improving PNEI mechanisms in the
elderly leads to an increase of their resilience, as well as to a higher
psycho-physical balance [48].
Autonomic neural system plays a major role in several aging
processes; heart rate variability, which is the result of vagus and
sympathetic nerve interaction, is a recognised expression of the
major (higher variability) or minor (lower variability) resilience and,
to some extent, of PNEI functionality [49,50].
The vagus nerve connects the brain to the internal organs and
it accounts for 75% of all parasympathetic nerve fibers. In 2002,
a large review showed for the first time the evidence on the anti-
inflammatory role of this nerve pathway [51]. In 2003, an Italian
study showed that stimulation of the vagus nerve has a powerful
anti-inflammatory effect, evidenced by the reduction of TNF-alpha,
Appleton et al.
[26]
A prospective study of positive early-
life psychosocial factors and favorable
cardiovascular risk in adulthood
Higher levels of childhood attention regulation capacity, cognitive ability and
positive home environment were associated with healthy levels of blood
pressure, cholesterol, and BMI.
Han et al. [27] Psychosocial factors for inuencing healthy
aging in adults in Korea
The factors that signicantly inuenced healthy aging were depression,
participation in leisure activities, perceived health status, ego integrity, self-
achievement and self-esteem.
Levy et al. [28] Longevity increased by positive self-
perceptions of aging
Self-perceptions of aging had a greater impact on survival than did gender,
socioeconomic status, loneliness, and functional health.
Sadler et al. [29] Subjective wellbeing and longevity: a co-twin
control study
The association between subjective well-being and longevity is independent
of familial factors such as shared genes and common environment: there is
a causal link between subjective well-being and longer lifespan.
Epel et al. [31] Can meditation slow rate of cellular aging?
Cognitive stress, mindfulness, and telomeres
Meditative practices appear to improve the endocrine balance (high DHEA,
lower cortisol) and decrease oxidative stress. Thus, meditation practices
may promote cell longevity and protect the telomeres.
Epel et al. [32] Accelerated telomere shortening in response
to life stress
In healthy women, psychological stress is associated with indicators of
accelerated cellular and organismal aging: oxidative stress, telomere length,
and telomerase activity.
Entringer et al.
[33]
Stress exposure in intrauterine life is
associated with shorter telomere length in
young adulthood
Exposure to maternal psychosocial stress during intrauterine life is
associated with signicantly shorter telomere length in young adulthood. The
prenatally stressed individuals also exhibited insulin and leptin resistance,
higher BMI, alterations in the regulation of the hypothalamic–pituitary–
adrenal axis.
Entringer et al.
[34]
Maternal psychosocial stress during
pregnancy is associated with newborn
leukocyte telomere length
As to the effects of potential determinants of newborn leukocyte telomere
length (gestational age at birth, weight, sex, and exposure to antepartum
obstetric complications), a signicant, independent, linear effect of
pregnancy-specic stress on newborn telomere length was shown.
Kroenke et al.
[35]
Autonomic and adrenocortical reactivity and
buccal cell telomere length in kindergarten
children
Children with the combination of higher sympathetic reactivity, greater
parasympathetic withdrawal, and higher cortisol response to an acute
stressor had the shortest telomere length.
Ng et al. [36] Oxidative stress in psychiatric disorders:
evidence base and therapeutic implications
Oxidative stress may be a common pathogenic mechanism underlying
many major psychiatric disorders. Multi-dimensional data support the role of
oxidative stress in schizophrenia, depression, bipolar disorder and anxiety
disorders.
De La Fuente
[37] Role of Neuroimmunomodulation in Aging
With aging, the immune cells show an increase in oxidant and inammatory
compounds and a decrease in antioxidant defenses, which is more evident
in phagocytic cells. The main mechanism is the activation of NF-kB in the
leukocytes.
Vida et al. [38]
Increase of Oxidation and Inammation in
Nervous and Immune Systems with Aging
and Anxiety
Animals with poor response to stress and high levels of anxiety had
high levels of oxidative stress in immune cells and showed premature
immunosenescence and shorter life expectancy.

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one of the most important inflammatory cytokines [52]. Further
studies [53,54] suggest that modulation of the whole neurovegetative
system is able to regulate peripheral inflammation. Manipulating
the vagus and the neurovegetative system (e.g. with neural therapy,
acupuncture, massages) [55] can therefore represent a key strategy to
be combined with more traditional treatments, in order to combat
inflammatory processes of various kinds.
In Okinawa, Japan, an important study was performed to
understand the reasons of the longer and healthier lifespan typical of
the local population. The main factors involved in subjects’ healthy
aging were: a) the diet rich omega 3 fatty acids and in polyphenols,
which are known to have a role in psycho-neural disorders [56-58],
b) the good level of physical activity, but also c) the positive and
compassionate way of thinking and of living one's aging [57].
Nutrition is another decisive factor in counteracting
inflammation, and it may represent one of the first therapeutic
interventions in PNEI system as well. The conventional western diet
that is being followed in recent decades, is leading to a worsening
of immune system, hence to the early development of a number of
diseases such as diabetes and autoimmune diseases, characterized
by chronic inflammation processes. Stress-diet-microbiota-mood
relationship has been widely investigated [59,60] and evidences
definitely point at the gut-brain axis as the core issue which links
nutrition to PNEI pathways.
As for the use of nutraceuticals/food supplements, scientific
data are increasingly demonstrating their contribution to body
successful aging and to PNEI system improved function [56-58,61,62].
Polyphenols represent the most interesting and well documented
natural antioxidants which help combating the excess of free radicals
and aging degenerative processes [62].
Polyphenols such as maqui, hydroxytyrosol, amla, curcumin,
all of them recognized as powerful antioxidants, have shown good
potential in several studies as to the decrease of oxidative stress.
Interestingly polyphenols’ role as hormetins [63] has been recognized
as well, hence they may stimulate a beneficial hormetic response
to their ingestion. Polyphenols work also as activators of vitagenes
and anti-inflammatory pathways, while their positive action in
mood alterations and PNEI system has been proven more recently
furthermore [56,64].
Omega 3 fatty acids may similarly be of interest in PNEI thanks
to their action on mood expressions, cognitive decay, resilience as a
whole [58,65].
With regards to other substances which have shown a positive
influence on PNEI system, melatonin has gained popularity in the
last decades, through several authoritative studies; melatonin is a
hormone produced mainly by the epiphysis at night, which acts as a
regulator for the complex mechanism of sleep-wake cycle, for cerebral
and immuno-endocrine metabolism and for the control of chronic
stress (cortisol). This multi-target hormone has been recognized as a
possible anti-aging agent as well [66].
In presence of melatonin release, cortisol levels decrease: this
is particularly important especially in elderly subjects, who have a
significantly reduced melatonin production [66,67]. Increasing the level
of melatonin through adequate sleep and (over the fifties) through
dietary supplements, can be therefore a further possible support
strategy which may improve mood, rebalance PNEI system and
control cortisol-mediated chronic stress [66-69].
PNEI: A Hormesis-Based System
The term hormesis comes from the Greek "stimulate" and it was
used for the first time in 1943 by Southam and Erhlich to indicate a
specific dose/response relationship. Hormesis is a highly conserved
phenomenon in the functioning evolution of animal/vegetal
organisms, characterized by a dose-dependent biphasic response. The
same hormetic stimulus (be it a biochemical substance, a physical
stress, or a psychological event) at low doses causes a beneficial
stimulation of metabolic pathways, whereas at high doses it generates
a negative effect on the metabolic processes [70].
PNEI system in fact responds to hormetic principles as a whole.
Resilience and adaptation capability play a major role in longevity,
as we discussed above, and both these features are significantly
influenced by the state of health of PNEI system. Any psychological,
physical or biological stressor positively or negatively interferes with
PNEI components and viceversa. Acute stressors at low doses and for
a short duration seem to play a role in longevity medicine, generating
a beneficial adaptation response which increases the tolerance level
to further exposure to stressors at higher doses (a typical form of
resilience) [71].
The most studied and proven stimuli which may induce a
Table 3
PNEI-targeting procedures and methods related to longevity medicine
Therapeutic treatment Physiological effects Related bibliography
Slow breathing Carotid baroceptors regulation; blood pressure and heart rate reduction;
excess cortisol reduction
39,40,41,45,46,49,50
Contra-resistance respiratory training Carotid baroceptors regulation; blood pressure and heart rate reduction;
resilience improvement
46,49,50
Meditation Carotid baroceptors regulation; blood pressure and heart rate reduction;
excess cortisol reduction; correlation with greater telomere length and
long life expectancy; resilience improvement
42,45,47,48,49,50
Prayer Carotid baroceptors regulation; blood pressure and heart rate reduction;
excess cortisol reduction; resilience improvement
43,44,47,48,49,50
Autogenic training Carotid baroceptors regulation; blood pressure and heart rate reduction;
excess cortisol reduction; resilience improvement
39,47,48,49,50
Vagus nerve stimulation (neural therapy,
acupuncture, massages)
Peripheral inammation regulation; TNF-alpha reduction 51,52,53,54,55
Nutrition and nutraceuticals (polyphenols,
omega 3 fatty acids)
Oxidative stress reduction; anti-inammatory pathways activation;
hormetic processes activators; protection against cognitive decay and
mood alterations
47,48,56,57,58,59,60,6
1,62,63,64,65
Melatonin supplementation Sleep-wake cycle regulation; cerebral and immuno-endocrine
metabolism support; chronic stress control (cortisol)
66,67,68

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Cavezzi A, et al. Healthy Aging Research (2018) 7:12 Healthy Aging Research
Table 4
PNEI and Hormesis
Authors - year Topics Outcomes
Calabrese et al. [70] Cellular stress responses, hormetic
phytochemicals and vitagenes in aging
and longevity
Dietary antioxidants, such as polyphenols and L-carnitine/acetyl-L-
carnitine, have a neuroprotective role through the activation of hormetic
pathways, including vitagenes, which encode for heat shock proteins
(Hsp) , the thioredoxin and the sirtuin protein systems.
Calabrese et al. [71] How does hormesis impact biology,
toxicology, and medicine?
Hormesis refers to adaptive responses of biological systems to
moderate environmental or self-imposed challenges through which
the system improves its functionality and/or tolerance to more severe
challenges.
Calabrese et al. [72] Preconditioning is hormesis. Part I:
Documentation, dose-response features
and mechanistic foundations
Hormetic doses of a variety of agents stimulated adaptive responses
that conditioned and protected cells against the subsequent toxicity
resulting from a second, higher dose of the same or different agents.
Calabrese et al. [73] Preconditioning is hormesis. Part II: How
the conditioning dose mediates protection:
Dose optimization within temporal and
mechanistic frameworks
The biological/biomedical effects induced by conditioning represent
a specic type of hormetic dose response and thereby contribute
signicantly to a generalization of the hormetic concept.
Calabrese et al. [74] Pre- and Post-conditioning hormesis in
elderly mice, rats, and humans; its loss
and restoration
Common rearing practices (i.e., no exercise; ad libitum feeding) are
strongly associated with the loss of preconditioning to prevent ischemic
reperfusion damage to the heart in old/elderly rodents. Substantial
restoration of preconditioning in old/elderly animal models is affected
via various types of exercise protocols, dietary interventions and
pharmacological means.
Hanisch [75] Microglia as a source and target of
cytokines
Dysregulation of microglial cytokine production could promote harmful
actions of the defense mechanisms, result in direct neurotoxicity, as
well as disturb neural cell functions
Chabot et al. [76] Mechanisms of IL-10 Production in
Human Microglia-T Cell Interaction
IL-10 generation is cell contact dependent between microglia T-cells
and lymphocytes
Ziv et al. [77] Immune-based regulation of adult
neurogenesis; Brain Behavior and
Immunity
Immune cells contribute to maintaining life-long hippocampal
neurogenesis. Too little immune activity (as in immune deciency
syndromes) or too much (as in severe inammatory diseases) can lead
to impaired hippocampal-dependent cognitive abilities.
Thanos et al. [78] Food Restriction Markedly Increases
Dopamine D2 Receptor (D2R) in a Rat
Model of Obesity as Assessed With In
vivo lPET Imaging ([11C] Raclopride) and
In vitro ([3 H] Spiperone)
Lack of a signicant difference between food restricted animals (obese
and lean) suggests that the differences in dopamine activity and D2
receptors levels between unrestricted obese and unrestricted lean rats
are modulated by access to food.
Katz et al. [79] Brain-Derived Neurotrophic Factor Is
Critically Involved in Thermal-Experience-
Dependent Developmental Plasticity
When BDNF in the hypothalamus was "knocked down" , thermal
establishment was impaired, reaction to thermal challenge was altered,
and the ability to maintain body temperature and body weight under
harsh conditions was reduced.
Kyriazis et al. [81] Nonlinear stimulation and hormesis in
human aging: practical examples and
action mechanisms
Any type of a hormetic dose-response phenomenon has an effect
that does not depend on the type of stressor and that it can affect
any biological model. Novel types of innovative, mild, repeated stress
or stimulation that challenge a biological system in a dose-response
manner are likely to have an effect to delay, prevent, or reverse age-
related changes in humans.
hormetic response in living organisms are: fasting, limited cold/
heat exposure, moderate exercising, resistance respiratory training,
polyphenols ingestion, oxygen deprivation or hyper-exposure,
radiations, spiritual/intellectual/social stimulation [71-74]. Table 4
summarizes a few studies and concepts regarding the hormesis
pathways.
In the therapeutic field, the concept of inflammation cannot be
separated from the one of hormesis; different levels and duration
of inflammation may represent beneficial, or harmful stimuli for
human health [74].
It has been shown that the three main proinflammatory
cytokines (IL-1, IL-6, TNF-a) are normally produced at low doses
from microglial cells and astrocytes in the brain (particularly in the
hypothalamus, hippocampus, thalamus and basal ganglia), as part
of the physiological processes of brain activation [75]. Even in the
presence of T cells, microglial cells assume a "protective" profile,
which stimulates neurogenesis, especially in the hippocampus. On
the contrary, in case of inflammatory activation with high doses
of cytokines, the microglial cells assume a distinguishable profile,
also from the morphological point of view, and the blocking of
neurogenesis occurs [76].
An experimental study has repeatedly documented in animals
that an immune deficiency is related to a blockage of hippocampal
neurogenesis [77]. In contrast, a stimulating environment or a
non-stressful physical activity causes a moderate release of a few
inflammatory mediators that however stimulate neurogenesis by
increasing the concentration of brain-derived neurotrophic factor
(BDNF), the most important neurotrophic substance targeting
neuronal growth and synapses development. On the contrary an
excessive inflammation can cause brain damage also as a consequence

8
Cavezzi A, et al. Healthy Aging Research (2018) 7:12 Healthy Aging Research
of the blockage of new neurons formation.
The limbic system, which is composed of hypothalamus, amygdala
and other neuronal structures, rules basic urges and desires together
with temperature and sleep regulation, hence it is strictly involved in
PNEI functionality. The possible primary hormetic stressors which
interact with limbic system are represented by caloric restriction,
fasting, cold/heat exposure and other forms of required adaptation;
these hormetic stimuli can significantly impact hypothalamus and
amygdala regulation.
In fact limbic system (N of PNEI) may respond less to
conventional medicine, drugs, intentional behaviours, especially
at long term; conversely hormetic pathways may influence limbic
system more stably, for example with fasting through increase of
dopamine receptors [78], or with high/low temperature exposure
through BDNF increase [79].
Other forms of hormesis and PNEI interaction regard
the possibility to have mental and social stimulation through
environmental enrichment, social and spiritual activities, technology
(i.e. internet) which are able to act in a hormetic fashion on the PNEI
components: a possible positive stimulation has been emphasized by
Kyriazis within this field [80].
Conclusion
Since the early seventies literature data have highlighted a relevant
role for PNEI in the aging process [1,81] and in any degenerative
disease; more recently a significant role has been attributed to
PNEI system in psychiatric diseases as well [82]. chronic stress and
psychological/social discomfort may result in pathophysiological
clinical manifestations and interfere with the immune system and
favour CLGCI and inflammaging. The latter process has a pivotal
role in disparate pathologies, from autoimmune diseases, diabetes,
atherosclerosis to neurodegeneration and cancer.
Literature data show that several measures aimed at improving
PNEI function, such as stress management, nutrition, nutraceuticals
(e.g. polyphenols, melatonin), may be beneficial in targeting CLGCI
and subsequently aging processes. Hormetic stressors may represent
a further potential mechanism to stimulate PNEI system, which
may ultimately result in an improvement in terms of resilience and
healthy aging.
Conict of Interest
The authors declare that they have no conflict of interest with
regard to the content of this article.
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