| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 24, 2006
Contents
The Wide Roles of Cytokines During Evolution
Executive Editors: M. de Eguileor and E. Ottaviani
Editorial Pp. 2993-2995
Phylogeny and Genetic Code: Evolution and Conservation
Pp. 2997-3013
G. Lanzavecchia
[Abstract]
The Cell Type-Specific Signal Proteins (Pheromones)
of Protozoan Ciliates Pp. 3015-3024
P. Luporini, A. Vallesi, C. Alimenti and C. Ortenzi
[Abstract]
Cytokines and Invertebrates: TGF-β
and PDGF Pp. 3025-3031
A. Franchini, D. Malagoli and E. Ottaviani
[Abstract]
Hematopoietic Cell Formation in Leech Wound Healing
Pp. 3033-3041
A. Grimaldi, G. Tettamanti, G. Perletti, R. Valvassori
and M. de Eguileor
[Abstract]
Innate Immunity in Lophotrochozoans: The Annelids
Pp. 3043-3050
M. Salzet, A. Tasiemski and E. Cooper
[Abstract]
Advances in Fish Cytokine Biology Give Clues to
the Evolution of a Complex Network Pp. 3051-3069
S. Bird, J. Zou and C. Secombes
[Abstract]
Biological Activity of Cytokines: An Evolutionary
Perspective Pp. 3071-3081
G. Scapigliati, F. Buonocore and M. Mazzini
[Abstract]
Avian Cytokines - An Overview Pp. 3083-3099
F. Giansanti, M.F. Giardi and D. Botti
[Abstract]
Cytokines and Chemokines as Regulators of Angiogenesis
in Health and Disease Pp. 3101-3115
R. Benelli, G. Lorusso, A. Albini and D.M. Noonan
[Abstract]
Distinctive Cellular Roles for Novel Protein Kinase
C Isoenzymes Pp. 3117-3133
G. Perletti and D.M. Terrian
[Abstract]
Cannabinoids, Immune System and Cytokine Network
Pp. 3135-3146
P. Massi, A.Vaccani and D. Parolaro
[Abstract]
Frailty of Elderly Age: The Role of the Endocrine
- Immune Interaction Pp. 3147-3159
R. Paganelli, A. Di Iorio, A. Cherubini, F. Lauretani,
C. Mussi, S. Volpato, M. Abate, G. Abate and L. Ferrucci
[Abstract]
Inflamm-Aging, Cytokines and Aging: State of the
Art New Hypotheses on the Role of Mitochondria and New Perspectives
from System Biology Pp. 3161-3171
S. Salvioli, M. Capri, S. Valensin, P. Tieri, D. Monti,
E. Ottaviani and C. Franceschi
[Abstract]
Abstracts
[Back
to top]
Editorial
The Wide Roles of Cytokines During Evolution
In recent years, the knowledge on cytokines has advanced and
even if new data are continuously added, we would contribute
throwing light upon the multiple functions that these molecules
can accomplish. As documented by the contributions here reported,
these molecules are described as cytokine-like and cytokines
in invertebrates and vertebrates, respectively. Actually,
fish represent the first group in which cytokine genes are
found.
The collected reviews regarding protozoa, invertebrates, vertebrates
including man, report on biological activities of these versatile
molecules that range over many fields. Cytokine-like and cytokines
play several important roles such as chemical secretion (pheromones),
development, immune and neuroendocrine responses, wound repair,
aging, longevity and so on. Taken together, the reviewed data
confirm the surprising similarity between molecules and processes
in invertebrates and vertebrates and suggest that basic common
features of fundamental biological events are conserved and
extended across diverse species, tissues and developmental
phases, supporting the general idea that an increasing number
of early acquisitions during metazoan evolution are also common
in higher vertebrates. In accordance with these concepts we
propose as first review of the issue a speculation about phylogeny
that could be useful to set the general problem of conservation
of molecules and their functioning in the evolutional background.
Lanzavecchia’s paper [1], starting from historical data,
underlines that on the whole biological evolution appears
as a series of modulations more or less accentuated by a grouping
of genetic information that are maintained rather constant
along all the branches of the phylogenetic tree. The studies
on the genomes of diverse animals confirm the existence of
a relevant molecular conservation and this fundamental conservation
of the general genetic patrimony of the living organisms justifies
the use of diverse animal forms for the study and comprehension
of general biological phenomena, potentially relevant for
human health.
In the second article, Luporini and coworkers [2] provide
data on structure of the Euplotes raikovi, Euplotes
octocarinatus, and Euplotes nobilii pheromone
family members. These studies have expanded the knowledge
of the biological and evolutionary significance of these ancient,
cell type-specific signal proteins. Identified and for a long
time studied only for their paracrine mating inducing activity,
pheromones have now revealed a more universal and primordial
function such as autocrine cell stimulation for the vegetative
growth revealing intriguing similarities of structure and
cross-reactions with members of cytokines evolved by more
advanced multicellular organisms.
The paper of Franchini et al. [3] outlines the presence
and function of TGF-β
and PDGF family members in invertebrates, stressing
the early appearance of these molecules in evolution. These
molecules play an important role in development, in immune
and neuroendocrine responses and in wound repair by activating
classical transduction pathways.
Grimaldi and coworkers’ paper [4] focuses on the comparison
of angiogenic process in vertebrates and hirudineans subjected
to surgical explant or cytokine treatment. The reviewed data
confirm the surprising similarities between leech and vertebrate
processes in wound healing and suggest that basic common events
such as antigenic expressions of endothelial and hemopoietic
cells, cytokine secretion and regulation as well as extracellular
matrix interactions, are conserved and extended across diverse
species, tissues and developmental phases.
The article of Salzet et al. [5] emphasizes the different
immunodefense strategies that adaptation undertakes during
the course of evolution of two classes of annelids i.e.
oligochaetes and achaetes. Innate immunity plays a major role
as a first defense against microbes. Effectors of the innate
response include pattern recognition receptors (PRR), phagocytic
cells, proteolytic cascades and peptides/proteins with antimicrobial
properties. Each element of these events has been well studied
in vertebrates and in some invertebrates such as annelids.
From these different researches, it appears that mammalian
innate immunity could be considered as a mosaic of invertebrate
immune responses. Annelids belonging to the lophotrochozoans'
group are primitive coelomates that possess specially developed
cellular immunity against pathogens including phagocytosis,
encapsulation and spontaneous cytotoxicity of coelomocytes
against allogenic or xenogenic cells. They have also developed
an important humoral immunity that is based on antimicrobial,
hemolytic and clotting properties of their body fluid.
The paper of Bird and coworkers [6] underlines that it is
now clear from the number of cytokine genes that have been
isolated within teleosts that a complex cytokine network is
present to regulate the innate and adaptive immune responses
of fish. In particular, the authors consider which components
of this network potentially evolved later (after the fish-tetrapod
divergence), leading to unique cytokine genes in particular
vertebrate groups.
From the Scapigliati and coworkers’ review [7], it emerges
that cytokines investigated to date are well conserved in
jawed vertebrates and their biological activities are superimposable
among evolutionary distant species. Vertebrates seem a homogeneous
group with respect to the biological activities exerted by
cytokines on target cells. However, despite the clear homologies
in bioactivities, no antibody cross-reactivity is evident
between mammalian and cold-blooded vertebrates, suggesting
independent evolutionary pathways inside families. It also
clearly emerges that the knowledge on the biological activity
of vertebrate cytokines does not follow evolution, since two
classes of vertebrates, namely amphibians and reptiles have
been almost neglected at present.
The article of Giansanti et al. [8] provides exhaustive
data on avian cytokines. Most of the studies are focused on
chicken, and even if comparative aspects with other avian
groups are limited, the existence of T1 and T3 avian cytokines
was assessed long ago and the recent relevant demonstration
of the existence of T2 cytokines in birds is a further step
in depicting a more complete view on avian immunology. The
progressive knowledge of avian cytokines can hopefully help
in developing new strategies in prophylaxis and therapy of
avian diseases, not always completely controlled due to the
emergence of more pathogenic strains.
The study reviewed of Benelli et al. [9] focuses
on modulatory cytokines and chemokines that are critical regulators
of angiogenesis. Due to the fact that angiogenesis is not
only a physiological condition but also an important component
of numerous pathological states, the actions of principal
cytokines and chemokines on the angiogenic process have been
considered. In addition, it has been discussed how both can
be considered potential pharmaceutical targets or pharmaceuticals
for modulation of angiogenesis in chronic inflammation associated
with cancer, rheumatoid,arthritis and other inflammatory diseases.
The article of Perletti and Terrian [10] is well included
in the panorama of the multiple functions that cytokines can
perform. Since a number of in vitro studies have
implicated protein kinase Cδ
(PKCδ)
and PKCε
in the regulation of the immune system, it is important to
compare and contrast the structures of these two nPKC isoenzymes
and their respective roles in the modulation of cytokine production
and various other cellular processes, such as growth, differentiation,
apoptosis, and tumor suppression.
Massi and coworkers’ review [11] underlines that marijuana,
natural and endogenous cannabinoid compounds are immunomodulators.
Numerous evidences exist to suggest that the cannabinoids
significantly affect almost every component of the immune
response machinery and impact the also functioning of the
cytokine network. The evaluation of the biological consequences
of these drug-induced cytokine changes has also dramatically
become important considering not only the impact of cytokines
on immune system per se but also envisaging their
influence on cancer, inflammation, autoimmune disease, brain
injury, hematopoietic colony formation where cannabinoids
have demonstrated a clear role as important modulators.
The paper of Paganelli et al. [12] analyzes in detail
that the so-called demographic transition has changed the
age structure of the population worldwide, with profound effects
on societal organization. The growing number and percentage
of old and very old people has compelled the scientific community
to focus on age related diseases and peculiar consequences
of aging itself such as disability and frailty. Understanding
the pathophysiology of frailty, a syndrome characterized by
a reduced functional reserve and impaired adaptive capacity
that results from cumulative declines of multiple subsystems,
and causes increased vulnerability to adverse outcomes, is
a major topic in aging research. Aging processes induce multiple
changes in the hormones network, in the immune system, and
can modulate their efficiency and effectiveness in determining
a response to stressors. These triggering events can unmask
frailty (i.e. at risk) in older people. Starting from these
assumptions, the relationship of the endocrine and immune
networks has been analyzed in aging and in the different domains
that are characteristically associated with the frailty syndrome,
such as disability and sarcopenia, as well as in aging-related
diseases such as Alzheimer’s dementia and Congestive
Heart Failure.
Finally, the paper of Salvioli and coworkers [13] summarizes
the present knowledge on the role of pro-inflammatory cytokines
on chronic inflammation leading to organismal aging, a phenomenon
called "inflamm-aging". In particular, authors review
genetic data regarding polymorphisms of genes encoding for
cytokines and proteins involved in natural immunity (such
as Toll-like Receptors and Heat Shock Proteins) obtained from
large population studies including young, old and very old
people in good health status or affected by age-related diseases
such as Alzheimer's Disease and Type II Diabetes. The available
data are in favor of the hypothesis that pro-inflammatory
cytokines play an important role in aging and longevity. In
addition, here a possible hypothesis to reconcile energetic
dysfunction, including mitochondria, and inflammaging has
been presented. New perspectives for future studies, including
phylogenetic studies in animal models and in silico
studies on mathematical and bioinformatic models inspired
by the system biology approach, are also proposed.
References
[1] Lanzavecchia G. Phylogeny and genetic code: evolution
and conservation. Curr Pharm Design 2006; 12(24): 2997-3013.
[2] Luporini P, Vallesi A, Alimenti C, Ortenzi C. The cell
type-specific signal proteins (pheromones) of protozoan ciliates.
Curr Pharm Design 2006; 12(24): 3015-3024.
[3] Franchini A, Malagoli D, Ottaviani E. Cytokines and invertebrates:
TGF-β
and PDGF. Curr Pharm Design 2006; 12(24): 3025-3031.
[4] Grimaldi A, Tettamanti G, Perletti G, Valvassori R de
Eguileor M. Hematopoietic cell formation in leech wound healing.
Curr Pharm Design 2006; 12(24): 3033-3041.
[5] Salzet M, Tasiemski A, Cooper E. Innate immunity in lophotrochozoans:
the annelids. Curr Pharm Design 2006; 12(24): 3043-3050.
[6] Bird S, Zou J, Secombes C. Advances in fish cytokine biology
give clues to the evolution of a complex network. Curr Pharm
Design 2006; 12(24): 3051-3069.
[7] Scapigliati G, Buonocore F, Mazzini M. Biological activity
of cytokines: an evolutionary perspective. Curr Pharm Design
2006; 12(24): 3071-3081.
[8] Giansanti F, Giardi MF Botti D. Avian Cytokines - An Overview.
Curr Pharm Design 2006; 12(24): 3083-3099.
[9] Benelli R, Lorusso G, Albini A, Noonan DM. Cytokines and
chemokines as regulators of angiogenesis in health and disease.
Curr Pharm Design 2006; 12(24): 3101-3115.
[10] Perletti G, Terrian DM. Distinctive cellular roles for
novel protein kinase C isoenzymes. Curr Pharm Design 2006;
12(24): 3117-3133.
[11] Massi P, Vaccani A, Parolaro D. Cannabinoids, immune
system and cytokine network. Curr Pharm Design 2006; 12(24):
3135-3146.
[12] Paganelli R, Di Iorio A, Cherubini A, Lauretani F, Mussi
C, Volpato S, et al. Frailty of elderly age: the
role of the endocrine - immune interaction. Curr Pharm Design
2006; 12(24): 3147-3159.
[13] Salvioli S, Capri M, Valensin S, Tieri P, Monti D, Ottavini
E, et al. Inflamm-aging, Cytokines and Aging: state
of the art new hypotheses on the role of mitochondria and
new perspectives from system biology. Curr Pharm Design 2006;
12(24): 3161-3171.
Magda de Eguileor
Department of Structural and Functional Biology
University of Insubria
Via J. H. Dunant 3, 21100 Varese
Italy
E-mail: magda.deeguileor@uninsubria.it
Enzo Ottaviani
Department of Animal Biology
University of Modena and Reggio Emilia
via Campi 213/D, 41100 Modena
Italy
E-mail: ottaviani.enzo@unimore.it
[Back to top]
Phylogeny and Genetic Code: Evolution and Conservation
G. Lanzavecchia
After a general view of the actual situation of the phylogenetic
relationships between the diverse animals and thus having
traced the fundamental elements of an essentially phylogenetic
classification, several themes that emerge from this initial
analysis have been developed. For instance one of the fundamental
problems is about homologous genes shared by the protostomes
and deuterostomes and attributed back to that hypothetical
group of the primitive bilaterians, the Urbilateria, “reconstructed”
from genetic analysis. The analyzed genes are essentially
of a regulatory type, thus a remarkable conservation of functions
seems to exist. This fundamental conservation of the general
genetic patrimony of the living organisms, within an overall
picture which includes an infinite gamma of structural and
functional modulations of the single genes, and a vast gamma
of temporal and spatial modulations of regulation of the genic
activity, justifies the use of diverse animal forms for the
study and comprehension of general biological phenomena, potentially
relevant for human health.
[Back to top]
The Cell Type-Specific Signal Proteins (Pheromones)
of Protozoan Ciliates
P. Luporini, A. Vallesi, C. Alimenti and C. Ortenzi
In association with their mechanisms of self/non-self
recognition (known as mating type systems), ciliates synthesize
and constitutively secrete cell type-specific proteins into
their extracellular medium. These proteins, designated as
pheromones, have been isolated from species of Euplotes
and shown to be members of families of structurally homologous
molecules, all rich in intra-chain disulfide bonds and organized
exclusively in helical conformation. Due to their similar
architectures, they can interact with their membrane receptors
in competition with one another and bind effectively to their
cells of origin in autocrine fashion, or to other co-specific
cells in paracrine fashion. In the former case, they promote
the vegetative cell growth; in the latter, they induce cells
to temporarily arrest their growth stage and shift to a mating
(sexual) stage. These varied, context-dependent activities
of ciliate pheromones imply an early evolution of basic properties
of animal growth factors and cytokines in the unicellular
eukaryotes.
[Back to top]
Cytokines and Invertebrates: TGF-β
and PDGF
A. Franchini, D. Malagoli and E. Ottaviani
The review outlines the presence and function of TGFβ
and PDGF family members in invertebrates. TGF-β
and PDGF play an important role in development, in immune
and neuroendocrine responses and in the wound repair by activating
the classical transduction pathways. Generally speaking, these
cytokines appear very early in evolution and conserve their
functions.
[Back to top]
Hematopoietic Cell Formation in Leech Wound Healing
A. Grimaldi, G. Tettamanti, G. Perletti, R. Valvassori
and M. de Eguileor
The angiogenic process in vertebrates and hirudineans
has been compared. The leech Hirudo medicinalis,
subjected to an angiogenic stimulus (surgical explant or cytokine
treatment) responds, as a vertebrate, with the formation of
an extensive network of new vessels accompanied by the production
of circulating cells.
The reviewed data confirm the surprising similarity between
hirudinean and vertebrate processes in wound healing, and
suggest that basic common events such as antigenic expressions
of endothelial and hemopoietic cells, cytokine secretion and
regulation as well as extracellular matrix interactions, are
conserved and extended across diverse species, tissues and
developmental phases.
[Back to top]
Innate Immunity in Lophotrochozoans: The Annelids
M. Salzet, A. Tasiemski and E. Cooper
Innate immunity plays a major role as a first defense
against microbes. Effectors of the innate response include
pattern recognition receptors (PRR), phagocytic cells, proteolytic
cascades and peptides/proteins with antimicrobial properties.
Each element of these events has been well studied in vertebrates
and in some invertebrates such as annelids. From these different
researches, it appears that mammalian innate immunity could
be considered as a mosaic of invertebrate immune responses.
Annelids belonging to the lophotrochozoans' group are primitive
coelomates that possess specially developed cellular immunity
against pathogens including phagocytosis, encapsulation and
spontaneous cytotoxicity of coelomocytes against allogenic
or xenogenic cells. They have also developed an important
humoral immunity that is based on antimicrobial, hemolytic
and clotting properties of their body fluid. In the present
review, we will emphasize the different immunodefense strategies
that adaptation has taken during the course of evolution of
two classes of annelids i.e. oligochaetes and achaetes.
[Back to top]
Advances in Fish Cytokine Biology Give Clues to
the Evolution of a Complex Network
S. Bird, J. Zou and C. Secombes
Complex immune systems require complex regulatory mechanisms.
Whilst the control of innate and inflammatory responses is
likely to be ancient in origin, and potentially ubiquitous
in the animal kingdom, clearly the evolution of an adaptive
immune system in vertebrates is likely to coincide with new
regulatory mechanisms and molecules. Key amongst these is
the cytokine network, well characterised in mammals and becoming
increasingly well characterised in fish and birds. This article
will review our current understanding of which components
of this network are crucial for adaptive immunity and evolved
early, being present from fish to mammals. It will also consider
which components of this network potentially evolved later
(after the fish-tetrapod divergence) leading to unique cytokine
genes in particular vertebrate groups.
[Back to top]
Biological Activity of Cytokines: An Evolutionary
Perspective
G. Scapigliati, F. Buonocore and M. Mazzini
It appears evident that teleost fish are at present the vertebrate
group in which, excluding mammals, most information on the
immune system is available. However, despite the great impetus
on the discovery of genes homologous to mammalian immunomodulatory
molecules, the knowledge on biological activities exerted
by cytokines is meager. This review reports the present knowledge
on the biological activities of cytokine-like and cytokines
in invertebrates and cold-blooded vertebrates.
[Back to top]
Avian Cytokines - An Overview
F. Giansanti, M.F. Giardi and D. Botti
In recent years the knowledge of avian cytokines has
advanced and new data are continuously added. Nevertheless,
some discontinuities persist and the correlations between
molecular and functional levels are not completely clear.
Most of the studies are focused on chicken, and comparative
aspects with other avian groups are limited. The existence
of T1 and T3 avian cytokines was assessed long ago and the
recent relevant demonstration of the existence of T2 cytokines
in birds is a further step in depicting a more complete view
on avian immunology. The progressive knowledge of avian cytokines
can hopefully help in developing new strategies in prophylaxis
and therapy of avian diseases, not always completely controlled
due to the emergence of more pathogenic strains.
[Back to top]
Cytokines and Chemokines as Regulators of Angiogenesis
in Health and Disease
R. Benelli, G. Lorusso, A. Albini and D.M. Noonan
The intricate interplay between the endothelium and immune
cells has been well recognized in the context of immune responses.
However, the fact that this inter-relation extends well beyond
immune regulation is becoming increasingly recognized, with
particular regards to the influence of the immune system on
the essential endothelial process of angiogenesis, where the
contribution of cytokines drives the angiogenic process. As
angiogenesis is an important component of numerous pathological
states, among these chronic inflammatory conditions and cancer,
understanding the role of cytokines and chemokines in guiding
new vessel formation provides key insight into novel therapeutic
modalities. Here we review the actions of principal cytokines
and chemokines on the angiogenic process and discuss how both
can be considered potential pharmaceutical targets or pharmaceuticals
themselves for modulation of angiogenesis in chronic inflammation
associated with cancer, rheumatoid arthritis and other inflammatory
diseases.
[Back to top]
Distinctive Cellular Roles for Novel Protein Kinase
C Isoenzymes
G. Perletti and D.M. Terrian
A number of in vitro studies have implicated
protein kinase Cδ
(PKCδ)
and PKCε
in the regulation of the immune system. In recent years, this
has been convincingly demonstrated in mice deficient for PKCδ
and PKCε.
The reported phenotypes for these transgenic mice indicate
that PKCδ
suppresses immunoresponsiveness and inhibits the proliferation
of B-lymphocytes, while PKCε
is required for macrophages to mount an effective immune response
to bacterial pathogens. In either case, these isoenzymes appear
to cooperate in fine-tuning certain immunoreactions by either
suppressing (PKCδ)
or stimulating (PKCε)
the transcription of various cytokines. This review will compare
and contrast the structures of these two nPKC isoenzymes and
their respective roles in the modulation of cytokine production
and various other cellular processes, such as growth, differentiation,
apoptosis, and tumor suppression.
[Back to top]
Cannabinoids, Immune System and Cytokine Network
P. Massi, A.Vaccani and D. Parolaro
How cannabinoids influence immune function has been examined
extensively in the last 30 years. Studies on drug-abusing
humans and animals, as well as in vitro models employing
immune cell cultures, have shown that marijuana, natural and
endogenous cannabinoid compounds are immunomodulators. These
substances modulate host resistance to bacterial, protozoan
and viral infections as well as they can profoundly affect
the Th1/Th2 response. Recently, two types of cannabinoid receptor,
CB1 and CB2, have been discovered. While CB1 is expressed
primarily in the brain, CB2 is peculiar of the immune cells.
Cannabinoid receptors have been shown to be involved in some
but not all of immune effects. Nevertheless, their identification
provides a specific mechanism of action in the attempting
to find out how exogenous cannabinoids and endogenous cannabinoid
system affect the immune apparatus, strengthen the hypothesis
of cannabinoids as immunomodulators. As support to this theory,
enough evidence exists to suggest that the cannabinoid system
significantly affects almost every component of the immune
response machinery and impacts the functioning also of the
cytokine network. The evaluation of the biological consequences
of these drug-induced cytokine changes has also dramatically
become important considering not only the impact of cytokines
on immune system per se but also envisaging their
influence in cancer, inflammation, autoimmune disease, brain
injury, hematopoietic colony formation in which cannabinoids
have demonstrated a clear role as important modulators.
[Back to top]
Frailty of Elderly Age: The Role of the Endocrine
- Immune Interaction
R. Paganelli, A. Di Iorio, A. Cherubini, F. Lauretani,
C. Mussi, S. Volpato, M. Abate, G. Abate and L. Ferrucci
The so-called demographic transition has changed the age structure
of the population worldwide, with profound effects on societal
organization. The growing number and percentage of old and
very old people has compelled the scientific community to
focus on age related diseases and peculiar consequences of
aging itself such as disability and frailty. Understanding
the pathophysiology of frailty, a syndrome characterized by
a reduced functional reserve and impaired adaptive capacity
that results from cumulative declines of multiple subsystems,
and causes increased vulnerability to adverse outcomes, is
a major topic in aging research. Aging processes induce multiple
changes in the hormones network (menopause, andropause, somatopause
and adrenopause), in the immune system, and can modulate their
efficiency and effectiveness in determining a response to
stressors. These triggering events can unmask frailty in older
people. Starting from these assumptions, we analyzed the relationship
of the endocrine and immune networks in aging and in the different
domains that are characteristically associated with the frailty
syndrome, such as disability and sarcopenia, as well as in
diseases related to aging such as Alzheimer’s dementia
and Congestive Heart Failure.
[Back to top]
Inflamm-Aging, Cytokines and Aging: State of the
Art New Hypotheses on the Role of Mitochondria and New Perspectives
from System Biology
S. Salvioli, M. Capri, S. Valensin, P. Tieri, D. Monti,
E. Ottaviani and C. Franceschi
In this article we summarise present knowledge on the
role of pro-inflammatory cytokines on chronic inflammation
leading to organismal aging, a phenomenon we proposed to call
"inflamm-aging". In particular, we review genetic
data regarding polymorphisms of genes encoding for cytokines
and proteins involved in natural immunity (such as Toll-like
Receptors and Heat Shock Proteins) obtained from large population
studies including young, old and very old people in good health
status or affected by age-related diseases such as Alzheimer's
Disease and Type II Diabetes. On the whole, despite some controversial
results, the available data are in favour of the hypothesis
that pro-inflammatory cytokines play an important role in
aging and longevity. Further, we present a possible hypothesis
to reconcile energetic dysfunction, including mitochondria,
and inflamm-aging. New perspectives for future studies, including
phylogenetic studies in animal models and in silico
studies on mathematical and bioinformatic models inspired
by the systems biology approach, are also proposed.
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