Mechanisms of Ageing and Development 130 (2009) 40–45

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Mechanisms of Ageing and Development

journal homepage: www.elsevier.com/locate/mechagedev

Review

Inflammation, ageing and cancer

Sonya Vasto a,c, Giuseppe Carruba a,b, Domenico Lio a, Giuseppina Colonna-Romano a,
Danilo Di Bona a,c,d, Giuseppina Candore a, Calogero Caruso a,c,*
a
Gruppo di Studio sull’Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Palermo, Italy
b
Oncologia Sperimentale, Dipartimento di Oncologia, ARNAS-Ospedale Civico, Palermo, Italy
c
Medicina Trasfusionale ed Immunoematologia, Ospedale Universitario, Palermo, Italy
d
Istituto di Biomedicina ed Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Palermo, Italy

A R T I C L E I N F O A B S T R A C T

Article history: Cancer is generally recognized as an age-related disease. In fact, incidence and mortality rates of most
Available online 10 July 2008 human cancers increase consistently with age up to 90 years, but they plateau and decline thereafter. A
low-grade systemic inflammation characterizes ageing and this pro-inflammatory status underlies
Keywords: biological mechanisms responsible for age-related inflammatory diseases. On the other hand, clinical and
Ageing epidemiological studies show a strong association between chronic infection, inflammation and cancer
Cancer and indicate that even in tumours not directly linked to pathogens, the microenvironment is
Genetics characterized by the presence of a smouldering inflammation, fuelled primarily by stromal leukocytes. In
Inflammation
this review, we have briefly mentioned inflammatory mediators involved in cancer although we decided
Longevity
to choose the ones which show a strict association with ageing and longevity. Inflammation is necessary
to manage with damaging agents and is crucial for survival. But, in our opinion, the pro-inflammatory
status of ageing might be one of the mechanisms which relate cancer to ageing. The most appropriate
inflammatory genes have been selected to survive and to reproduce. Paradoxically, inflammatory age-
related diseases (including cancer) are the marks of the same evolutionistic trait. Centenarians are
characterized by a higher frequency of genetic markers associated with better control of inflammation.
The reduced capacity of centenarians to mount inflammatory responses appears to exert a protective
effect towards the development of those age-related pathologies having a strong inflammatory
pathogenetic component, including cancer. All in all, centenarians seem to carry a genetic background
with a peculiar resistance to cancer which is also an anti-inflammatory profile.
ß 2008 Elsevier Ireland Ltd. All rights reserved.

1. Introduction: ageing and cancer
Nowadays, people are living much longer than they used to do,
however they are not free from ageing. Ageing is a relentless
process that affects all cells, tissues, organs, and organisms,
diminishing homeostasis and increasing organism vulnerability
(Franceschi et al., 2008). Ageing progression causes a reduction of
the response to environmental stimuli and, in general, is associated
with an increased predisposition to illness and death (Troen, 2003;
Candore et al., 2006a). In the Western countries, if we compare the
mortality rate in people over 65 years, versus individuals in the age
range between 25 and 44 years, it increases to 100-fold for stroke,
* Corresponding author at: Dipartimento di Biopatologia e Metodologie
Biomediche, Università di Palermo, Corso Tukory 211, 90134 Palermo, Italy.
Tel.: +39 0916555911; fax: +39 0916555933.
E-mail address: marcoc@unipa.it (C. Caruso).
and chronic lung disease, 92-fold for heart disease, 89-fold for
pneumonia and influenza and 43-fold by cancer (Troen, 2003).
Ageing in good condition seems directly correlated with a good
functioning of the immune system, suggesting that genes
regulating the immune inflammatory responses are involved in
longevity (Candore et al., 2006b; Franceschi et al., 2008).
The high incidence of death due to infectious, cardiovascular
and cancer diseases underlies a common feature in these
pathologies that is represented by dysregulation of both instructive
and innate immunity (Licastro et al., 2005; Candore et al., 2006b).
Several studies show that a low-grade systemic inflammation
characterizes ageing and that inflammatory markers are significant
predictors of mortality in old humans (Krabbe et al., 2004;
Bruunsgaard, 2006). This pro-inflammatory status of the elderly
underlies biological mechanisms responsible for physical function
decline and age-related diseases such as Alzheimer’s disease and
atherosclerosis are initiated or worsened by systemic inflamma-
tion (reviewed by Bruunsgaard, 2006; Vasto et al., 2007, 2008).

0047-6374/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.mad.2008.06.003
 S. Vasto et al. / Mechanisms of Ageing and Development 130 (2009) 40–45
A wide range of factors, including smoking, infections, obesity,
genetics and declining of sex hormone levels may contribute to
systemic low-grade inflammatory activity in older individuals
(Krabbe et al., 2004). However, increased levels of circulating
inflammatory mediators may mostly result from a constant, low-
grade activation of immune system by lifetime chronic exposure to
a variety of pathogens (De Martinis et al., 2005). Some studies have
linked a lifelong individual’s exposure towards infections both to
inflammatory status and to increased risk of heart attack, stroke,
and cancer; in particular, the risk of heart attack, dementia and
cancer is correlated with serum levels of c-reactive protein (CRP)
(Schmidt et al., 2002; Trichopoulos et al., 2006; Ridker, 2007).
Among individuals, CRP levels correlate with the number of
seropositivities to common pathogens, suggestive of infection
history (Zhu et al., 2000). Hence, there are numerous studies
pointing out a strong relationship among inflammatory mediators,
ageing and age-related diseases as cardiovascular and Alzheimer’s
diseases showing that people genetically predisposed to weak
inflammatory activity have a reduced chance of developing age-
related inflammatory diseases and an increased chance of
becoming centenarians (reviewed by Candore et al., 2006a; Capri
et al., 2008; Vasto et al., 2007, 2008).
All kinds of malignant neoplasms (here referred as cancer)
involve morphological cellular transformation, dysregulation of
apoptosis, uncontrolled cellular proliferation, invasion, angiogen-
esis, and metastasis. Cancer is the second leading cause of death in
both United States and Europe. Nearly 560,000 Americans and over
1,700,000 Europeans died from cancer in 2007 and 2001,
respectively, accounting for 22.9% of all deaths (American Cancer
Society, 2007; IARC, 2002). Epidemiological studies have demon-
strated that mortality due to cancer increases with age up to age
ninety at which point it plateaus and then declines (Smith, 1996).
Cancer deaths account for 40% from age 50 to 70 and less then 4%
for centenarian people (Smith, 1996; Bonafè et al., 2002).
Centenarians, i.e. people that live longer than 100 years, their
children and siblings have better chances to escape major age
related disease including cancer (Terry et al., 2004). Accordingly,
autoptic studies of a group of Japanese centenarians clearly
showed that, in centenarians, the cause of death by cancer and
metastatic spread were lower than expected (Miyaishi et al., 2000).
Autopsies performed on Italian centenarians also showed that
cancer prevalence was decreasing in individuals over 99 years
compared to younger individuals (Franceschi et al., 2008).
Hence, advancing age is the most potent of all carcinogens
(DePinho, 2000). What underlies this intimate link between cancer
and advanced age is not clear yet. An increase in somatic mutations
has been documented in aged cells, and presumably relates to
cumulative lifetime exposure to endogenous and exogenous DNA
damaging agents, as well as to an accumulation of mutations
during DNA replication (reviewed by DePinho, 2000). However, as
previously stated, in oldest old individuals cancer prevalence does
not increase despite the longer exposure to exogenous and
endogenous factors causing cancer but declines, why? We will
try to suggest a possible explanation in the last paragraph, after
having briefly reviewed the relationship between cancer and
inflammation.
2. Cancer and inflammation
Clinical and epidemiological studies have suggested a strong
association between chronic infection, inflammation and cancer
(Coussens and Werb, 2002; Shacter and Weitzman, 2002), as for
example in alcohol abuse leading to liver and pancreas inflamma-
tion, smoking leading to air-way inflammation, sexual transmitted
disease as human papiloma virus or hepatitis C virus leading to
41
cervical and liver cancer, respectively (Lin and Karin, 2007).
Furthermore, Helicobacter pylori is associated with gastric carci-
noma (Fox and Wang, 2007) whereas infection with Epstein Barr
virus is associated with Burkitt lymphoma and nasopharyngeal
carcinoma (Deyrup, 2008). Free radicals, released at the site of
inflammation, are involved in carcinogenesis, not only damaging
DNA, but also modifying cancer related proteins and regulating
transcription (Perwez Hussain et al., 2003).
Furthermore, several lines of evidence indicate that even in
tumours not directly linked to pathogens, the microenvironment is
characterized by the presence of a smouldering inflammation,
fuelled primarily by stromal leukocytes and by hypoxic conditions
(Allavena et al., 2008; Mantovani et al., 2008). Tumour-associated
macrophages are a major player in the inflammatory response and
produce a multitude of growth factors for epithelial and
endothelial cells, as well as inflammatory cytokines and chemo-
kines that that affect angiogenesis and may enhance cell
proliferation, promotion and eventually progression of a popula-
tion of cancer cell. In addition, immunosuppressive mediators
released by local inflammatory or tumour cells extinguish host-
mediated anti-tumour responses and facilitate tumour progression
(Mantovani et al., 2008; Sica et al., 2008).
Following, we will mention inflammatory mediators involved
in cancer although we decided to choose the ones which show a
strict association with ageing and longevity (see Caruso et al.,
2007).
Interleukin-6 (IL-6) plays a major role in the response to injury
or infection and is involved in the immune response, inflammation,
and hematopoiesis (Ershler and Keller, 2000). Emphasis has put on
a central role for IL-6 in governing inflammation and on the
therapeutic potential of targeting IL-6 as a strategy for the
treatment of chronic inflammatory diseases, including cancer
(Heinrich et al., 2003; Hong et al., 2007). Overproduction of IL-6
contributes, through its roles as a growth factor or an anti-
apoptotic factor, to the development of malignant diseases and
elevated serum IL-6 levels have been correlated with an adverse
prognosis in patients with several different types of cancer (Culig
et al., 2005; Hong et al., 2007). Circulating IL-6 is, in fact, associated
with some cancers but, despite the abundance of published
studies, it is not clear if IL-6 is useful in the diagnosis of cancer or
relevant to its aetiology (Heikkilä et al., 2008). Several findings
suggest that IL-6 acts as a potent stimulator of metastasis by up-
regulating the expression on endothelial cells of adhesion
molecules and by stimulating the production of angiogenic factors
(Hutchins and Steel, 1994; Cohen et al., 1996). The status of a
common functional G/C single nucleotide polymorphism (SNP)
located at 174 bp upstream from the start site of transcription has
been reported to influence IL-6 levels in vitro and in vivo, the
highest IL-6 levels in blood being found in subjects homozygous for
the G allele (reviewed by Caruso et al., 2007). This SNP is involved
in several chronic conditions, including age-related inflammatory
diseases and it is detrimental for longevity (Mocchegiani et al.,
2008; reviewed by Caruso et al., 2007). The frequency of G/C-174
IL-6 SNP was investigated in several cancers with contrasting
results (Deans et al., 2007; Litovkin et al., 2007; Slattery et al.,
2007; Upadhyay et al., 2008; Vairaktaris et al., 2006; reviewed by
Caruso et al., 2004). To understand these discrepant results, it has
to take into account that IL-6 can simultaneously generate
functionally distinct or sometimes contradictory signals through
its receptor complex (Kamimura et al., 2003). The final physio-
logical output can be thought of as a consequence of the
orchestration of the diverse signalling pathways. This might
explain how IL-6 can elicit both pro-inflammatory and anti-
inflammatory effects, depending on the in vivo environmental
circumstances (Kamimura et al., 2003).
42 S. Vasto et al. / Mechanisms of Ageing and Development 130 (2009) 40–45
The pleiotropic pro-inflammatory cytokine tumour necrosis
factor(TNF)-a is an important mediator of the inflammatory
responses with multiple biologic activities. Several polymorphic
areas are documented within the TNF gene cluster and the -308A
SNP located in the promoter region is associated with stronger
transcriptional activation than the G allele (reviewed by Candore
et al., 2004). It is reported to have an increased frequency in
autoimmune and inflammatory diseases, including the age-related
ones and it does not appear to favour longevity (reviewed by
Caruso et al., 2007; Cardelli et al., 2008). TNF-a has been
implicated in the pathogenesis of cancer, mainly in the context
of chronic inflammation, because it triggers DNA damage,
angiogenesis, invasion and metastasis and in experimental models,
most evidence supports the potential enhancement of neoplasia by
TNF-a (Szlosarek and Balkwill, 2003). There is increasing evidence
that TNF-a is also produced by cancer and acts as an endogenous
cancer promoter: levels of TNF-a protein and mRNA expressed by
epithelial cancer cells and macrophages within the cancer islands
excised from malignant biopsies, correlate with grade of malig-
nancy (Naylor et al., 1993; Szlosarek and Balkwill, 2003). However,
it has recently been reported an increased risk of lymphoma in
rheumatoid arthritis patients treated with immunomodulatory
TNF-a blockers (reviewed by Williams, 2008). That might reflect
the severity of the disease, associated with greater TNF-a activity,
stimulating anti-tumour activity (reviewed by Williams, 2008). In
fact, depending of the levels, TNF-a produces a variety of cellular
responses which could either facilitate or inhibit tumourigenesis
(Mocellin and Nitti, 2008). So it is not surprising that contrasting
results have been obtained in case control studies to examine the
role of TNF-a polymorphism in cancer (Danforth et al., 2008;
Garrity-Park et al., 2008; Zhang et al., 2008).
IL-10 plays a critical role in limiting the intensity and duration
of immune and inflammatory responses. IL-10 production is
tightly regulated and several SNPs controlling its productions have
been described. IL-10 low-producer genotypes seem to play a
particular role in the susceptibility to inflammatory diseases,
together with the age-related ones, where IL-10 high producer
genotypes are involved in the attainment of longevity (reviewed by
Caruso et al., 2007). Tumour biopsies from patients with different
kinds of cancers have demonstrated an increase in IL-10 compared
with healthy tissue controls (Salazar-Onfray et al., 2007),
suggesting a role for IL-10 in the evasion of the anti-tumour
immune response. Furthermore, the demonstration of a higher
expression of IL-10 in metastatic than in primary tumours has led
to the proposal that IL-10 increases tumour metastasis (Dummer
et al., 1995). In fact, IL-10 has been considered to promote tumour
evasion, decreasing histocompatibility class I antigen expression
and sensitivity to tumour-specific cytotoxic lymphocytes (CTL)
(Matsuda et al., 1994) and activating immunosuppressive reg-
ulatory T cells that may suppress anti-tumour CTL activity in vivo
(Salazar-Onfray et al., 2007). In contrast, IL-10 has been reported to
possess anti-angiogenic properties (Stearns et al., 1999), which
may help inhibit tumour growth. So, it is not surprising that taking
into account the double-edged role of IL-10, current case–control
data on IL-10 genotype and cancer are seemingly confusing and
contradictory (reviewed in Caruso et al., 2004; Vairaktaris et al.,
2008; Michaud et al., 2006).
As previously stated, chronic inflammation caused by persistent
infection by parasites, bacteria, or viruses may be a driving force in
cancer development. The Toll like receptor (TLR) family of proteins
recognizes pathogen-associated molecular patterns and is
involved in pathogen-mediated inflammation. Engagement of
the ligands to TLRs results in the production of various pro-
inflammatory cytokines and effector molecules (Balistreri et al.,
2007). In cancer cells, TLRs may act as surface sensors initiating
pathways involved in proliferation as well as inducing mediators
able to regulate the infiltrating inflammatory cells (Chen et al.,
2008). Hence, TLR signalling in cancer cells can mediate tumour
escape and tumour progression, being regarded as one of the
mechanisms for chronic inflammation in carcinogenesis and
progression (Sun et al., 2008). TLR polymorphisms known to
regulate the inflammatory response have been described in age-
related diseases and, reciprocally, in longevity (Balistreri et al.,
2004) and some of them have been associated with increased risk
of cancer, in particular prostate cancer (Zheng et al., 2004; Chen
et al., 2007; Sun et al., 2006; Achyut et al., 2007).
Cyclooxygenase (COX) is a key enzyme in the formation of
inflammatory mediator prostaglandins, and an inducible isoform
of COX, COX-2, has been implicated in age-related diseases,
including cancer (reviewed by Subbaramaiah and Dannenberg,
2003; Caruso et al., 2007). Through the production of prosta-
glandins, COX-2 is hypothesised to influence carcinogenesis by
promoting cell proliferation, inhibiting apoptosis, stimulating
angiogenesis, and mediating immune suppression (Fosslien,
2001). Increased amounts of COX-2 are found commonly in
both premalignant and malignant tissues (Edwards et al., 2004;
Turini and DuBois, 2002). Overexpression of COX-2 appears to be
a consequence of transcription by oncogenes, growth factors,
gytokines and tumour promoters (Smith et al., 2006). On the
other hand, epidemiological studies show that use of non-
steroidal anti-inflammatory drugs (NSAIDs), prototypic inhibi-
tors of COX, is associated with a reduced risk of several
malignancies, including colorectal cancer (reviewed by Subbar-
amaiah and Dannenberg, 2003). Moreover, tumour formation
and growth are reduced in animals that are either engineered to
be COX-2 deficient or treated with a selective COX-2 inhibitor
and treatment with a COX-2 inhibitor, reduced the number of
colorectal polyps in patients with familial adenomatous poly-
posis. (reviewed by Subbaramaiah and Dannenberg, 2003).
However, it is possible that the anti-cancer activity of these
compounds might also reflect COX-independent effects, since
high concentrations of NSAIDs suppress the growth of cells in
culture that do not express COX-2 (reviewed by Subbaramaiah
and Dannenberg, 2003). In our hands the pro-inflammatory
alleles of COX-2 were under-represented in centenarians and
over-represented in many age-related diseases (Vasto et al.,
2007, 2008) and pro-inflammatory COX-2 alleles have been
shown to be associated with cancer in most studies (Shen et al.,
2006; Cheng et al., 2007; Hou et al., 2007; Moons et al., 2007;
Ueda et al., 2008).
However, we have to conclude this paragraph pointing out that
there is a ‘yin–yang’ relationship between inflammation and
cancer progression. Cancers that release little or no cytokines or
chemokines show limited inflammation that appears to be
accompanied by restricted vascularization and cancer growth.
Production of some inflammatory stimuli can lead to a level of
inflammation associated with vessel formation and growth factor
release, favouring cancer growth. High levels of inflammation with
strong monocyte infiltration are associated with cytotoxicity and
cancer regression and elimination (Allavena et al., 2008; Witz,
2008).
3. Conclusions: ageing, cancer and inflammation
Cancer is generally recognized as an age-related disease
(DePinho, 2000), but the exact relationship between the two
processes remains still not completely clear. Doubtlessly, inci-
dence and mortality rates of most human cancers increase
consistently with age up to 90 years, but they plateau and decline
thereafter. Cancer deaths account for 40% of all deaths in subjects
 S. Vasto et al. / Mechanisms of Ageing and Development 130 (2009) 40–45
aged 50–69 years but account for only 4% of deaths in centenarians
(Smith, 1996).
The steady increase of incidence and mortality of cancer with
age has been also interpreted as a consequence of both the
exploitation of large-scale population screening programs and the
worldwide improvement of diagnostic capacities (reviewed by
Caruso et al., 2004). However, as previously stated, there is
convincing evidence that cancer and ageing remain associated
until around 90 years of age but they diverge substantially
thereafter (Smith, 1996; Bonafè et al., 2002). Therefore, a central
question remains: are cancer and ageing interdependent or their
association represents merely the parallel evolution of two
unrelated processes?
Recent studies have indicated that both ‘‘convergent’’ and
‘‘divergent’’ mechanisms may relate cancer and ageing to each
other (Serrano and Blasco, 2007). In the former, molecular
pathways simultaneously provide protection against cancer and
ageing resistance by acting on specific causal events shared by the
two phenomena, notably the generation and accumulation of
cellular, genetic or epigenetic, damage. In the latter, some process
may exert opposing effects on cancer and ageing; specifically,
protecting from cancer but promoting ageing. This includes the
shortening of telomeres and the derepression of the INK4a/ARF
locus that encodes p14(ARF) which plays an important role in the
p53 pathway (Kirkwood, 2002; Campisi, 2005; Badal et al., 2008).
Both these mechanisms may result in a restraint of cell
proliferation, eventually leading to conflicting effects on cancer
and ageing: while they favour cancer protection, long-term
regeneration and longevity are in some way impaired. In contrast,
distinct mechanisms may also be implicated to reconcile a
prolongation of lifespan with an increased cancer risk, thus
implying that cancer is a downside of evolution. Ideally, a subtle
balance between convergent and divergent mechanisms could
result in the promotion of a healthy, non-ageing and cancer-free
lifetime during youth and adulthood. In theory, the possibility to
potentiate convergent mechanisms and, therefore, to foster anti-
ageing, anti-cancer effects could be used to promote a healthier,
enduring life (Serrano and Blasco, 2001; Finkel et al., 2007).
As briefly discussed in the present paper, there is a link between
inflammation and cancer. Inflammation is necessary to manage
with damaging agents and is crucial for survival, particularly to
cope with acute inflammation during our reproductive years
(Licastro et al., 2005). But chronic exposure to a variety of antigens,
for a period much longer than that predicted by evolution, induces
a chronic low-grade inflammatory status that contributes to age-
associated morbidity and mortality (reviewed by De Martinis et al.,
2006; Vasto et al., 2007). So, in our opinion, the pro-inflammatory
status of ageing might be one of the both ‘‘convergent’’ and
‘‘divergent’’ mechanisms which relate cancer to ageing. The most
appropriate inflammatory genes have been selected to survive and
to reproduce. Paradoxically, inflammatory age-related diseases
(including cancer) are the marks of the same evolutionistic trait
(Caruso et al., 2005).
Surprisingly, centenarians are unique in that, despite high
levels of pro-inflammatory markers, they also exhibit anti-
inflammatory markers that may delay disease onset. In fact,
centenarians were quite able of mounting effective inflammatory
responses, thus becoming more robust (Franceschi et al., 2007).
However, in centenarians such an inflammatory status was
compensated by the concomitant development of strong and
effective anti-inflammatory responses and by a higher frequency of
genetic markers associated with better control of inflammation
(i.e. anti-inflammatory IL-6, TNF-a, IL-10, TLR-4, COX-2 genotypes)
(Caruso et al., 2007; Franceschi et al., 2007, 2008). The net result of
such a complex scenario is a slower and more limited and balanced
43
development of pro-inflammatory status in centenarians, a process
that in ‘‘normal’’ people is either faster or inadequately counter-
acted by anti-inflammatory responses. The reduced capacity of
centenarians to mount inflammatory responses appears to exert a
protective effect towards the development of those age-related
pathologies having a strong inflammatory pathogenetic compo-
nent, including cancer (reviewed by Caruso et al., 2004; Candore
et al., 2006a; Capri et al., 2008; Franceschi et al., 2007, 2008; Vasto
et al., 2007).
All in all, associations between inflammatory gene polymorph-
isms and cancer are not conclusive although centenarians seem to
carry a genetic background with a peculiar resistance to cancer
which is also an anti-inflammatory profile.
Acknowledgement
This work was supported by Italian Ministry of Health grant
(Molecular mechanisms of stem cancer cell survival control) to G.C.
and C.C.
References
Achyut, B.R., Ghoshal, U.C., Moorchung, N., Mittal, B., 2007. Association of Toll-like
receptor-4 (Asp299Gly and Thr399Ileu) gene polymorphisms with gastritis and
precancerous lesions. Hum. Immunol. 68, 901–907.
Allavena, P., Garlanda, C., Borrello, M.G., Sica, A., Mantovani, A., 2008. Pathways
connecting inflammation and cancer. Curr. Opin. Genet. Dev. 18, 3–10.
American Cancer Society, 2007. Cancer Facts and Figures 2007. American Cancer
Society, Atlanta.
Badal, V., Menendez, S., Coomber, D., Lane, D.P., 2008. Regulation of the p14ARF
promoter by DNA methylation. Cell Cycle 1, 112–119.
Balistreri, C.R., Candore, G., Colonna-Romano, G., Lio, D., Caruso, M., Hoffmann, E.,
Franceschi, C., Caruso, C., 2004. Role of Toll-like receptor 4 in acute myocardial
infarction and longevity. JAMA 292, 2339–2340.
Balistreri, C.R., Candore, G., Listı̀, F., Fazio, T., Gangi, S., Incalcaterra, E., Caruso, M.,
Vecchi, M.L., Lio, D., Caruso, C., 2007. Role of TLR4 polymorphisms in inflam-
matory responses: implications for unsuccessful aging. Ann. N. Y. Acad. Sci.
1119, 203–207.
Bonafè, M., Barbi, C., Storci, G., Salvioli, S., Capri, M., Olivieri, F., Valensin, S., Monti,
D., Gonos, E.S., De Benedictis, G., Franceschi, C., 2002. What studies on human
longevity tell us about the risk for cancer in the oldest old: data and hypotheses
on the genetics and immunology of centenarians. Exp. Gerontol. 37, 1263–1271.
Bruunsgaard, H., 2006. The clinical impact of systemic low-level inflammation in
elderly populations. With special reference to cardiovascular disease, dementia
and mortality. Dan. Med. Bull. 53, 285–309.
Campisi, J., 2005. Suppressing cancer: the importance of being senescent. Science
309, 886–887.
Candore, G., Balistreri, C.R., Colonna-Romano, G., Lio, D., Caruso, C., 2004. Major
histocompatibility complex and sporadic Alzheimer’s disease: a critical reap-
praisal. Exp. Gerontol. 39, 645–652.
Candore, G., Colonna-Romano, G., Balistreri, C.R., Di Carlo, D., Grimaldi, M.P., Listi, F.,
Nuzzo, D., Vasto, S., Lio, D., Caruso, C., 2006a. Biology of longevity: role of the
innate immune system. Rejuvenation Res. 9, 1.
Candore, G., Balistreri, C.R., Listı̀, F., Grimaldi, M.P., Vasto, S., Colonna-Romano, G.,
Franceschi, C., Lio, D., Caselli, G., Caruso, C., 2006b. Immunogenetics, gender, and
longevity. Ann. N. Y. Acad. Sci. 1089, 516–537.
Capri, M., Salvioli, S., Monti, D., Caruso, C., Candore, G., Vasto, S., Olivieri, F.,
Marchegiani, F., Sansoni, P., Baggio, G., Mari, D., Passarino, G., De Benedictis,
G., Franceschi, C., 2008. Human longevity within an evolutionary perspective:
the peculiar paradigm of a post-reproductive genetics. Exp. Gerontol. 43, 53–60.
Cardelli, M., Cavallone, L., Marchegiani, F., Oliveri, F., Dato, S., Montesanto, A., Lescai,
F., Lisa, R., De Benedictis, G., Franceschi, C., 2008. A genetic-demographic
approach reveals male-specific association between survival and tumor necro-
sis factor (a/g)-308 polymorphism. J. Gerontol. A Biol. Sci. Med. Sci. 63, 454–460.
Caruso, C., Lio, D., Cavallone, L., Franceschi, C., 2004. Aging, longevity, inflammation,
and cancer. Ann. N. Y. Acad. Sci. 1028, 1–13.
Caruso, C., Candore, G., Colonna-Romano, G., Lio, D., Franceschi, C., 2005. Inflam-
mation and life-span. Science 307, 208–209.
Caruso, C., Balistreri, C.R., Crivello, A., Forte, G.I., GrimaldiI, M.P., Listı̀, F., Scola, L.,
Vasto, S., Candore, G., 2007. The genetics of innate immunity and inflammation
in ageing, age-related diseases and longevity. In: Pawelec G. Immunosenes-
cence, Landes Bioscience and Springer Science, Austin, TX 78701, United States,
ISBN: 978-0-387-76840-3, pp. 154–173.
Chen, Y.C., Giovannucci, E., Kraft, P., Lazarus, R., Hunter, D.J., 2007. Association
between Toll-like receptor gene cluster (TLR6, TLR1, and TLR10) and prostate
cancer. Cancer Epidemiol. Biomarkers Prev. 16, 1982–1989.
44 S. Vasto et al. / Mechanisms of Ageing and Development 130 (2009) 40–45
Chen, R., Alvero, A.B., Silasi, D.A., Steffensen, K.D., Mor, G., 2008. Cancers take their
Toll—the function and regulation of Toll-like receptors in cancer cells. Oncogene
27, 225–233.
Cheng, I., Liu, X., Plummer, S.J., Krumroy, L.M., Casey, G., Witte, J.S., 2007. COX2
genetic variation, NSAIDs, and advanced prostate cancer risk. Br. J. Cancer 97,
557–561.
Cohen, T., Nahari, D., Cerem, L.W., Neufeld, G., Levi, B.Z., 1996. Interleukin 6 induces
the expression of vascular endothelial growth factor. J. Biol. Chem. 271, 736–
741.
Coussens, L.M., Werb, Z., 2002. Inflammation and cancer. Nature 420, 860–867.
Culig, Z., Steiner, H., Bartsch, G., Hobisch, A., 2005. Interleukin-6 regulation of
prostate cancer cell growth. J. Cell Biochem. 95, 497–505.
Danforth, K.N., Rodriguez, C., Hayes, R.B., Sakoda, L.C., Huang, W.Y., Yu, K., Calle, E.E.,
Jacobs, E.J., Chen, B.E., Andriole, G.L., Figueroa, J.D., Yeager, M., Platz, E.A.,
Michaud, D.S., Chanock, S.J., Thun, M.J., Hsing, A.W., 2008. TNF polymorphisms
and prostate cancer risk. Prostate 68, 400–407.
Deans, C., Rose-Zerilli, M., Wigmore, S., Ross, J., Howell, M., Jackson, A., Grimble, R.,
Fearon, K., 2007. Host cytokine genotype is related to adverse prognosis and
systemic inflammation in gastro-oesophageal cancer. Ann. Surg. Oncol. 14,
329–339.
De Martinis, M., Franceschi, C., Monti, D., Ginaldi, L., 2005. Inflamm-ageing and
lifelong antigenic load as major determinants of ageing rate and longevity. FEBS
Lett. 579, 2035–2039.
De Martinis, M., Franceschi, C., Monti, D., Ginaldi, L., 2006. Inflammation markers
predicting frailty and mortality in the elderly. Exp. Mol. Pathol. 80, 219–227.
DePinho, R.A., 2000. The age of cancer. Nature 408, 248–254.
Deyrup, A.T., 2008. Epstein-Barr virus-associated epithelial and mesenchymal
neoplasms. Hum. Pathol. 39, 473–483.
Dummer, W., Becker, J.C., Schwaaf, A., Leverkus, M., Moll, T., Bröcker, E.B., 1995.
Elevated serum levels of interleukin-10 in patients with metastatic malignant
melanoma. Melanoma Res. 5, 67–68.
Edwards, J., Mukherjee, R., Munro, A.F., Wells, A.C., Almushatat, A., Bartlett, J.M.,
2004. Her2 and COX2 expression in human prostate cancer. Eur. J. Cancer 40,
50–55.
Ershler, W.B., Keller, E.T., 2000. Age-associated increased interleukin-6 gene expres-
sion, late-life diseases, and frailty. Annu. Rev. Med. 51, 245–270.
Finkel, T., Serrano, M., Blasco, M.A., 2007. The common biology of cancer and ageing.
Nature 448, 767–774.
Fosslien, E., 2001. Review: molecular pathology of cyclooxygenase-2 in cancer-
induced angiogenesis. Ann. Clin. Lab. Sci. 31, 325.
Fox, J.G., Wang, T.C., 2007. Inflammation, atrophy, and gastric cancer. J. Clin. Invest.
117, 60–69.
Franceschi, C., Capri, M., Monti, D., Giunta, S., Olivieri, F., Sevini, F., Panourgia, M.P.,
Invidia, L., Celani, L., Scurti, M., Cevenini, E., Castellani, G.C., Salvioli, S., 2007.
Inflammaging and anti-inflammaging: a systemic perspective on aging and
longevity emerged from studies in humans. Mech. Ageing Dev. 128, 92–105.
Franceschi, C., Motta, L., Motta, M., Malaguarnera, M., Capri, M., Vasto, S., Candore,
G., Caruso, C., 2008. IMUSCE. The extreme longevity: the state of the art in Italy.
Exp. Gerontol. 43, 45–52.
Garrity-Park, M.M., Loftus Jr., E.V., Bryant, S.C., Sandborn, W.J., Smyrk, T.C., 2008.
Tumor necrosis factor-alpha polymorphisms in ulcerative colitis-associated
colorectal cancer. Am. J. Gastroenterol. 103, 407–415.
Heikkilä, K., Ebrahim, S., Lawlor, D.A., 2008. Systematic review of the association
between circulating interleukin-6 (IL-6) and cancer. Eur. J. Cancer 44, 937–945.
Heinrich, P.C., Behrmann, I., Haan, S., Hermanns, H.M., Müller-Newen, G., Schaper,
F., 2003. Principles of interleukin (IL)-6-type cytokine signalling and its regula-
tion. Biochem. J. 374, 1–20.
Hong, D.S., Angelo, L.S., Kurzrock, R., 2007. Interleukin-6 and its receptor in cancer:
implications for translational therapeutics. Cancer 110, 1911–1928.
Hou, L., Grillo, P., Zhu, Z.Z., Lissowska, J., Yeager, M., Zatonski, W., Zhu, G., Baccarelli,
A., Chanock, S.J., Fraumeni Jr., J.F., Chow, W.H., 2007. COX1 and COX2 poly-
morphisms and gastric cancer risk in a Polish population. Anticancer Res. 27,
4243–4247.
Hutchins, D., Steel, C.M., 1994. Regulation of ICAM-1 (CD54) expression in human
breast cancer cell lines by interleukin 6 and fibroblast-derived factors. Int. J.
Cancer 58, 80–84.
International Agency for Research on Cancer. Globocan 2000. IARC 2002.
Kamimura, D., Ishihara, K., Hirano, T., 2003. IL-6 signal transduction and its
physiological roles: the signal orchestration model. Rev. Physiol. Biochem.
Pharmacol. 149, 1–38.
Kirkwood, T.B., 2002. p53 and ageing: too much of a good thing? Bioessays 24, 577–
579.
Krabbe, K.S., Pedersen, M., Bruunsgaard, H., 2004. Inflammatory mediators in the
elderly. Exp. Gerontol. 39, 687–699.
Licastro, F., Candore, G., Lio, D., Porcellini, E., Colonna-Romano, G., Franceschi, C.,
Caruso, C., 2005. Innate immunity and inflammation in ageing: a key for
understanding age-related diseases. Immun. Ageing 2, 8.
Lin, W.W., Karin, M., 2007. A cytokine-mediated link between innate immunity,
inflammation, and cancer. J. Clin. Invest. 117, 1175–1183.
Litovkin, K.V., Domenyuk, V.P., Bubnov, V.V., Zaporozhan, V.N., 2007. Interleukin-6-
174G/C polymorphism in breast cancer and uterine leiomyoma patients: a
population-based case control study. Exp. Oncol. 29, 295–298.
Mantovani, A., Romero, P., Palucka, A.K., Marincola, F.M., 2008. Tumour immunity:
effector response to tumour and role of the microenvironment. Lancet 371,
771–783.
Matsuda, M., Salazar, F., Petersson, M., Masucci, G., Hansson, J., Pisa, P., Zhang, Q.J.,
Masucci, M.G., Kiessling, R., 1994. Interleukin 10 pretreatment protects target
cells from tumor- and allo-specific cytotoxic T cells and downregulates HLA
class I expression. J. Exp. Med. 180, 2371–2376.
Michaud, D.S., Daugherty, S.E., Berndt, S.I., Platz, E.A., Yeager, M., Crawford, E.D.,
Hsing, A., Huang, W.Y., Hayes, R.B., 2006. Genetic polymorphisms of interleu-
kin-1B (IL-1B), IL-6, IL-8, and IL-10 and risk of prostate cancer. Cancer Res. 66,
4525–4530.
Miyaishi, O., Ando, F., Matsuzawa, K., Kanawa, R., Isobe, K., 2000. Cancer incidence in
old age. Mech. Ageing Dev. 117, 47–55.
Mocchegiani, E., Giacconi, R., Costarelli, L., Muti, E., Cipriano, C., Tesei, S., Pierpaoli, S.,
Giuli, C., Papa, R., Marcellini, F., Gasparini, N., Pierandrei, R., Piacenza, F., Mariani,
E., Monti, D., Dedoussis, G., Kanoni, S., Herbein, G., Fulop, T., Rink, L., Jajte, J.,
Malavolta, M., 2008. Zinc deficiency and IL-6-174G/C polymorphism in old
people from different European countries: effect of zinc supplementation.
ZINCAGE study. Exp. Gerontol. 43, 433–444.
Mocellin, S., Nitti, D., 2008. TNF and cancer: the two sides of the coin. Front Biosci.
13, 2774–2783.
Moons, L.M., Kuipers, E.J., Rygiel, A.M., Groothuismink, A.Z., Geldof, H., Bode, W.A.,
Krishnadath, K.K., Bergman, J.J., van Vliet, A.H., Siersema, P.D., Kusters, J.G.,
2007. COX-2 CA-haplotype is a risk factor for the development of esophageal
adenocarcinoma. Am. J. Gastroenterol. 102, 2373–2379.
Naylor, M.S., Stamp, G.W.H., Foulkes, W.D., Eccles, D., Balkwill, F.R., 1993. Tumor
necrosis factor and its receptors in human ovarian cancer: potential role in
disease progression. J. Clin. Invest. 91, 2194–2206.
Perwez Hussain, S., Hofseth, L.J., Harris, C.C., 2003. Radical causes of cancer. Nat. Rev.
Cancer 3, 276–285.
Ridker, P.M., 2007. Inflammatory biomarkers and risks of myocardial infarction,
stroke, diabetes, and total mortality: implications for longevity. Nutr. Rev. 65,
S253–S259.
Salazar-Onfray, F., Lopez, M.N., Mendoza-Naranjo, A., 2007. Paradoxical effects of
cytokines in tumor immune surveillance and tumor immune escape. Cytokine
Growth Factor Rev. 18, 171–182.
Schmidt, R., Schmidt, H., Curb, J.D., Masaki, K., White, L.R., Launer, L.J., 2002. Early
inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging
Study. Ann. Neurol. 52, 168–174.
Serrano, M., Blasco, M.A., 2001. Putting the stress on senescence. Curr. Opin. Cell
Biol. 13, 748–753.
Serrano, M., Blasco, M.A., 2007. Cancer and ageing: convergent and divergent
mechanisms. Nat. Rev. Mol. Cell Biol. 8, 715–722.
Shacter, E., Weitzman, S.A., 2002. Chronic inflammation and cancer. Oncology 16,
217–226.
Shen, J., Gammon, M.D., Terry, M.B., Teitelbaum, S.L., Neugut, A.I., Santella, R.M.,
2006. Genetic polymorphisms in the cyclooxygenase-2 gene, use of nonster-
oidal anti-inflammatory drugs, and breast cancer risk. Breast Cancer Res. 8,
R71.
Sica, A., Allavena, P., Mantovani, A., 2008. Cancer related inflammation: the macro-
phage connection. Cancer Lett. (Epub ahead of print).
Slattery, M.L., Wolff, R.K., Herrick, J.S., Caan, B.J., Potter, J.D., 2007. IL6 genotypes and
colon and rectal cancer. Cancer Causes Control 18, 1095–1105.
Smith, D.W., 1996. Cancer mortality at very old age. Cancer 77, 1367–1372.
Smith, W.I., Dewitt, D.I., Garavito, R.M., 2006. Cyclooxygenases: structural, cellular
and molecular biology. Annu. Rev. Biochem. 69, 145–182.
Stearns, M.E., Rhim, J., Wang, M., 1999. Interleukin 10 (IL-10) inhibition of primary
human prostate cell-induced angiogenesis: IL-10 stimulation of tissue inhibitor
of metalloproteinase-1 and inhibition of matrix metalloproteinase (MMP)-2/
MMP-9 secretion. Clin. Cancer Res. 5, 189–196.
Subbaramaiah, K., Dannenberg, A.J., 2003. Cyclooxygenase 2: a molecular target for
cancer prevention and treatment. Trends Pharmacol. Sci. 24, 96–102.
Sun, Q., Liu, Q., Zheng, Y., Cao, X., 2008. Rapamycin suppresses TLR4-triggered IL-6
and PGE(2) production of colon cancer cells by inhibiting TLR4 expression and
NF-kappaB activation. Mol. Immunol. 45, 2929–2936.
Sun, J., Wiklund, F., Hsu, F.C., Bälter, K., Zheng, S.L., Johansson, J.E., Chang, B., Liu, W.,
Li, T., Turner, A.R., Li, L., Li, G., Adami, H.O., Isaacs, W.B., Xu, J., Grönberg, H., 2006.
Interactions of sequence variants in interleukin-1 receptor-associated kinase 4
and the toll-like receptor 6-1-10 gene cluster increase prostate cancer risk.
Cancer Epidemiol. Biomarkers Prev. 15, 480–485.
Szlosarek, P.W., Balkwill, F.R., 2003. Tumor necrosis factor a: a potential target for
the therapy of solid tumors. Lancet Oncol. 4, 565–573.
Terry, D.F., Wilcox, M.A., McCormick, M.A., Pennington, J.Y., Schoenhofen, E.A.,
Andersen, S.L., Perls, T.T., 2004. Lower all-cause, cardiovascular, and cancer
mortality in centenarians’ offspring. J. Am. Geriatr. Soc. 52, 2074–2076.
Trichopoulos, D., Psaltopoulou, T., Orfanos, P., Trichopoulou, A., Boffetta, P., 2006.
Plasma C-reactive protein and risk of cancer: a prospective study from Greece.
Cancer Epidemiol. Biomarkers Prev. 15, 381–384.
Troen, B.R., 2003. The biology of aging. Mt. Sinai J. Med. 70, 3–22.
Turini, M.E., DuBois, R.N., 2002. Cyclooxygenase-2: a therapeutic target. Annu. Rev.
Med. 53, 35–57.
Upadhyay, R., Jain, M., Kumar, S., Ghoshal, U.C., Mittal, B., 2008. Association of
interleukin-6 (-174G>C) promoter polymorphism with risk of squamous cell
esophageal cancer and tumor location: an exploratory study. Clin. Immunol.
(Epub ahead of print).
Ueda, N., Maehara, Y., Tajima, O., Tabata, S., Wakabayashi, K., Kono, S., 2008. Genetic
polymorphisms of cyclooxygenase-2 and colorectal adenoma risk: the Self
Defense Forces Health Study. Cancer Sci. 99, 576–581.
 S. Vasto et al. / Mechanisms of Ageing and Development 130 (2009) 40–45
Vairaktaris, E., Yapijakis, C., Serefoglou, Z., Derka, S., Vassiliou, S., Nkenke, E.,
Vylliotis, A., Spyridonidou, S., Neukam, F.W., Schlegel, K.A., Patsouris, E.,
2008. The interleukin-10 (-1082A/G) polymorphism is strongly associated with
increased risk for oral squamous cell carcinoma. Anticancer Res. 28, 309–314.
Vairaktaris, E., Yiannopoulos, A., Vylliotis, A., Yapijakis, C., Derka, S., Vassiliou, S.,
Nkenke, E., Serefoglou, Z., Ragos, V., Tsigris, C., Vorris, E., Critselis, E., Avgoustidis,
D., Neukam, F.W., Patsouris, E., 2006. Strong association of interleukin-6-174
G>C promoter polymorphism with increased risk of oral cancer. Int. J. Biol.
Markers 21, 246–250.
Vasto, S., Candore, G., Balistreri, C.R., Caruso, M., Colonna-Romano, G., Grimaldi,
M.P., Listi, F., Nuzzo, D., Lio, D., Caruso, C., 2007. Inflammatory networks in
ageing, age-related diseases and longevity. Mech. Ageing Dev. 128, 83–91.
Vasto, S., Candore, G., Listı̀, F., Balistreri, C.R., Colonna-Romano, G., Malavolta, M., Lio,
D., Nuzzo, D., Mocchegiani, E., Di Bona, D., Caruso, C., 2008. Inflammation, genes
and zinc in Alzheimer’s disease. Brain Res. Rev. (Epub ahead of print).
45
Williams, G.M., 2008. Antitumor necrosis factor-alpha therapy and potential cancer
inhibition. Eur. J. Cancer Prev. 17, 169–177.
Witz, I.P., 2008. Yin-yang activities and vicious cycles in the tumor microenviron-
ment. Cancer Res. 68, 9–13.
Zhang, J., Dou, C., Song, Y., Ji, C., Gu, S., Xie, Y., Mao, Y., 2008. Polymorphisms of tumor
necrosis factor-alpha are associated with increased susceptibility to gastric
cancer: a meta-analysis. J. Hum. Genet. 53, 479–489.
Zheng, S.L., Augustsson-Balter, K., Chang, B., Hedelin, M., Li, L., Adami, H.O., Bensen,
J., Li, G., Johnasson, J.E., Turner, A.R., Adams, T.S., Meyers, D.A., Isaacs, W.B., Xu, J.,
Grönberg, H., 2004. Sequence variants of toll-like receptor 4 are associated with
prostate cancer risk: results from the Cancer Prostate in Sweden Study. Cancer
Res. 64, 2918–2922.
Zhu, J., Quyyumi, A.A., Norman, J.E., Csako, G., Waclawiw, M.A., Shearer, G.M.,
Epstein, S.E., 2000. Effects of total pathogen burden on coronary artery disease
risk and C-reactive protein levels. Am. J. Cardiol. 85, 140–146.