Approaches to Aging Control. Vol 21.
october 2017
PEY could control neuroflammation and aging.
Joan Cunill Aixelà1, Clara Babot Marquillas1, Beatriz Almolda2, Manuel Portero-Otín3, José Serrano3
1Ovivity Group. 2Unit of Histology. Dept Cell Biology, Physiology and Immunology, Faculty of Medicine, Autonomous
University of Barcelona. 3Nutren Nutrigenomics, URL
ABSTRACT
Neuroprotection is essential to combat the aging
process caused by inflammaging, which produces
an impairment of the blood-brain barrier. The
hypothalamus is one of the most sensitive parts of
the brain to ageing, and is of vital importance as it
controls the hypothalamus-pituitary-adrenal axis
that influences the immune, nervous and endocrine
systems (especially controls of the adrenal gland
and growth levels of hormone secreted by the
pituitary gland). Animals with a performant pathway
transection lesion in the hippocampus were treated
orally with a compound extracted from a heat-
processed fertilized egg yolk named Processed
Egg Yolk (PEY), and a significant decrease in pro-
inflammatory cytokines was observed, demonstrating
its action neuroprotective. PEY over-expresses
growth factors, lipids, vitamins and several compounds
with neurotrophic activity. These results can have a
significant impact on neuroprotection and on the
aging prevention.
INTRODUCTION
Ageing is a complex physiological process
characterized by a progressive degeneration of cells
and loss of regenerative capacity. In the recent years,
some theories have been developed to explain
how ageing is happening, describing processes like
oxidative stress [1], telomeres shortening [2], protein
homeostasis loose [3], senescence-associated secretory
phenotype (SASP) [4], inflammaging [5] or stem cell
niches exhaustion [6]. One of the most recognized
cause of ageing is the dysregulation of the immune
system as a result of defects in both initiation and
resolution of immune responses (immunosenescence)
[7], which also affects the central nervous system
(CNS).
The effect of the immune response on the CNS is
regulated in part by the hypothalamus-hypophysis-
adrenal axis, existing a bidirectional communication
between the immune and the neuroendocrine
systems. In this context, inflammatory cytokines
play a fundamental role in the maintenance of the
immune response homeostasis.
57

Figure 1. Cytokines activate the HPA axis at different levels.
Adrenal glands secrete glucocorticoid hormones, producing an
anti-inflammatory effect (negative feed-back).
The presence of inflammation, specifically the
release of cytokines, including IL-1, TNF-α and
IL-6, provides a direct stimulus to the activity of
the hypothalamus and pituitary gland (even directly
into the adrenal glands), resulting in the production
of adrenal glucocorticoids [8], which have an anti-
inflammatory effect, constituting a negative feed-
back control loop. With ageing, a deregulation of
this equilibrium is established, breaking this negative
feed-back and thus accelerating the ageing process
and contributing to the decreased longevity [9].
Cytokines are also implied in the ageing process
through other mechanisms, since they are activators
of NF-κB complexes. Zhang et al [10] demonstrated
that ageing development is characterized by chronic
activation of NF-κB-directed innate immune
pathway predominantly in the hypothalamus, and
identified that IKKβ/NF-κB negatively regulated
gonadotrophin-releasing hormone (GnRH). The
same authors observed that the direct injection of
GnRh into the hypothalamus increased neurogenesis,
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muscle endurance, and memory capacity of aged
mice. 
Finally, an age-dependent progressive loss of BBB
integrity in the hippocampus (an area directly
related with the memory processes) is described
in the literature [11]. This loss can promote the
accumulation of inflammatory cytokines in the CNS,
thus participating in the loss of the homeostasis and
promoting further accumulation of inflammatory
molecules.
All these data establish a clear relation between the
presence of cytokines in the CNS and the ageing
process, and lead us to hypothesize that promoting
neuroprotection by reducing the inflammaging into
the CNS could avoid or at least slow down this ageing
It exists process.
RESULTS
A new way to avoid the inflammaging and to
recover protein homeostasis has been discovered
and evidenced through clinical application in both
animals and humans (data not shown in this work).
Specifically, in this article, we introduce a new
ingredient, denominated PEY (Processed Egg Yolk).
We summarize the most important molecules in
its composition, as well as its cytokine regulatory
effects in the hippocampus, which confers PEY
neuroprotective and neuroregenerative properties.
PEY composition
PEY is a characteristic bulk of molecules extracted
from a fertilized and heat-treated egg yolk (process
patented), which mainly over-express more than 800
molecules. The studies in its composition, carried out
by Nutren Nutrigenomics, have revealed the presence
of various compounds with neurotrophic activity,
including several growth factors, neurotrophic lipids,
proteins and vitamins, among others. We list some of
the most relevant for this work in Table 1.
Approaches to Aging Control. Vol 21. october 2017

Table 1. Some important compounds found in DISCUSSION

PEY composition
It is not an easy work to relate the composition of
Growth PEY with its observed effects, since it’s a very complex
Lipidomics Proteomics Metabolomics
factors naturally occurring composition, and probably the
NGF Cerebrosides
α-tocopherol compounds are acting by synergies and not as a single
VEGF Gangliosides Apolipoprotein
Docosahexaenoic
IGF-1 Sphingolipids -A
acid
active ingredient. Also, the mechanisms that promote
TGF-β Sphingomielins
ageing are really complex, which makes even harder
to establish direct correlations. Much more research is
PEY effects in the CNS needed to establish relationships between composition
and effects.
In a study carried out by the Unit of Medical
Histology from the Dept. Cell Biology, Physiology What can be said about the composition of PEY,
and Immunology of the Autonomous University of is that we found in it molecules with important
Barcelona (UAB), we recently found that PEY is able activities related to the CNS. For example, VEGF
to control the inflammation caused by the performant and IGF-1 are known to be trophic factors with
pathway transection lesion in the hippocampus, that neuroprotective and neuroregenerative effects, as well
is in a part of the brain very near to the hypothalamus as NGF [12]; docosahexaenoic acid (DHA) has been
and easily accessible to study. shown to have potent anti-inflammation activity and
to be neuroprotective by suppressing both Aβ40 and
As detailed in Table 2, a significant decrease in Aβ42 peptide release (both stimulated by the pro-
inflammatory cyto kines IL-1α, IL-1β, IL-2 and IL-6, inflammatory cytokine interleukin (IL)-1ß) [13];
at 3 days post-injury, as well as an important increase Apolipoprotein A plays a role in the cholesterol
in the anti-inflammatory cytokine IL-10, at 7 days, transport in the brain [14]; Gangliosides and
was observed in the hippocampus of PEY-treated sphingolipids are known to be important modulators
animals, of membrane receptors, and be involved in cell
adhesion/recognition and myelin–axon interaction,
Table 2. Changes found in the hippocampus of and to have pharmacological for neuroprotection.
PEY-treated animals vs non-treated animals after
the perforant pathway transection (n= 4-7 per In the study carried out by the UAB, a decrease in
experimental group). The amount of the specified the inflammatory cytokines IL-1α, IL-1β, IL-2, IL-6,
cytokines was measured in the hippocampus using MCP-1, MIP-1α, MIP-1β, CXCL-10 and an increase
the Luminex technology (protein microarray to of the anti-inflammatory cytokine IL-10 was observed.
quantify multiple molecules at the same time). IL-1α is a pro-inflammatory cytokine whose main
functions include regulation of the immune system’s
3 days post-injury 7 days post-injury response by inducing an increase in the inflammation;
Decreased cytokines
Increased decreased Increased IL-1β induces release of COX2 in the CNS, and its
cytokines cytokines cytokines
expression is linked to neurodegenerative processes
IL-1α, IL-1β, IL-2, IL-6,
- CXCL-10 IL-10
MCP-1, MIP-1α, MIP-1β [15]; IL-2 promotes the differentiation of naïve T
lymphocytes into effector T lymphocytes; IL-6 plays
an important role modulating the neuroinflammatory

59

process [16]; MCP-1, MIP-1α and MIP-1β are
related to the attraction of neutrophils, monocytes,
eosinophils, T lymphocytes, NK cells, and other
leukocytes to sites of inflammation, as well as CXCL-
10 [17]. With opposite effects, IL-10 is considered to
be an important anti-inflammatory cytokine exerting
suppressive effects on the immune response and in the
neuroinflammatory processes that affect to the CNS,
its late expression coincides with stages of recovery
and regeneration [18].
As we have reviewed in the introduction, ageing is
related to a chronic inflammation which occurs as a
consequence of the loss of the necessary equilibrium
in the HPA axis signalization, and by a loose in the
homeostasis in the CNS. In view of the results obtained,
it can be said that PEY is acting as a neuroprotective
agent by decreasing the pro-inflammatory and
increasing the anti-inflammatory cytokines in the
CNS in an induced injury model. This demonstrates
that PEY may be a potent anti-aging ingredient that
acts by reducing the inflammaging in the brain.
CONCLUSION
A direct relation between the chronical presence
of cytokines in the CNS and the process of ageing
exists. Recently discovered, PEY is a promising active
ingredient that have been shown a high potential as an
anti-aging treatment by reducing the inflammaging.
Different pre-clinical and clinical studies are
being carried out simultaneously to discover new
applications and to help understand the mechanisms
of action the different effects observed.
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