December 2007(II): S173–S176
Inflammaging as a Major Characteristic of Old People: Can
It Be Prevented or Cured?
Claudio Franceschi, MD
Widespread aging at the population level is a recent
phenomenon that emerged in affluent societies. In-
flammation is necessary to cope with damaging agents
and is crucial for survival, particularly to cope with
acute inflammation during our reproductive years.
But chronic exposure to a variety of antigens, espe-
cially to some viruses such as cytomegalovirus, 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.
This condition carries the proposed name “inflam-
maging”. Centenarians are unique in that, despite
high levels of pro-inflammatory markers, they also
exhibit anti-inflammatory markers that may delay dis-
ease onset. The key to successful aging and longevity
is to decrease chronic inflammation without compro-
mising an acute response when exposed to pathogens.
Key words: inflammation, immunosenescence, lon-
gevity, hemopoiesis, cytomegalovirus, mitochondria,
© 2007 International Life Sciences Institute
Inflammation is a fundamental response to cope with
internal and external damaging agents. In younger indi-
viduals, such a response is positive and necessary to
protect against infectious diseases and other damaging
agents. In later life, however, it can be detrimental,
contributing to the development of a number of age-
related chronic diseases such as atherosclerosis,1,2type 2
diabetes,3,4Alzheimer’s disease,5and osteoporosis.6,7
Even major depression, a quite common condition in the
elderly, and frailty, an emerging clinical entity that oc-
curs late in life and is correlated with increased morbid-
ity and mortality within a few years, have a major
inflammatory component.8,9Centenarians, on the other
hand, manage to stave off these deleterious sequelae.
Despite signs of inflammation, such as high levels of
interleukin-6 (IL-6),10fibrinogen, and coagulation fac-
tors,11,12they are remarkably free of most age-related
diseases that have an inflammatory component.13Meta-
bolic syndrome and insulin resistance are extremely rare
among centenarians.14While both inflammation and
anti-inflammation are important for survival, centenari-
ans have achieved a peculiar compromise or trade-off
between the two.15
The human immune system has been molded by
evolution to defend against infection, thereby ensuring
the survival of young individuals of reproductive age.
With the recent dramatic increase in life expectancy,16,17
the immune system must now cope with chronic expo-
sure to antigens, lasting several decades more than in our
recent evolutionary past.18–20This continual antigenic
stress means the immune system can become overstim-
ulated over time21and inefficient with age, a process
carrying the proposed name “inflammaging”.22As a
result, chronic, low-grade inflammation develops, which
is a major contributor to age-associated frailty, morbid-
ity, and mortality.23This suggests that the propensity to
a strong inflammatory response may benefit the young
but may become detrimental at an older age, and indi-
viduals who achieve advanced age are those best
equipped to cope with chronic antigenic exposure.
It is important to stress that the concept of inflam-
maging stems from an evolutionary-based conceptualiza-
tion, and from experimental data in animals belonging to
several phyla and taxa, from invertebrates to vertebrates,
suggesting that not only the major characteristics of
Dr. Franceschi is with the Department of Experi-
mental Pathology and Interdepartmental Centre “L.
Galvani” at the University of Bologna, Bologna, Italy,
and the Department of Gerontology at the Italian Na-
tional Research Center on Aging (INRCA), Ancona,
Franceschi, Department of Experimental Pathology
and Interdepartmental Centre “L. Galvani,” Univer-
sity of Bologna, Via S. Giacomo 12, Bologna, Italy.
Phone: ?39-51-209-4743, Fax: ?39-51-209-4768,
S173Nutrition Reviews?, Vol. 65, No. 12
inflammation have been conserved throughout evolution
but also that inflammation is an integral part of an
integrated evolutionary-conserved network of defense
that includes stress response and natural immunity.24–26
Thus, inflammaging is a comprehensive concept that
stresses the fact that the most important network of
defense of the body is overstimulated as a whole during
aging, and that inflammation in the usual, more restricted
meaning, is only part of a more global phenomenon.
IMMUNOSENESCENCE AND ADAPTING TO
Within this context, immunosenescence can be con-
sidered the end result of an optimal immune function
aimed at maximizing early fitness throughout reproduc-
tive age, but also a major and dramatic example of
antagonistic pleiotropy, with the possible detrimental
effects of such “successful” immune and inflammatory
responses developing later in life.27Indeed, the pheno-
typic characteristics of old and very old people support
the concept that aging is a remodeling process whereby
the immune system progressively adapts to decades of
exposure to internal and external damaging agents,
changing the body’s micro-environment through altered
gene expression and changes in protein abundance, com-
position and interaction.
This remodeling, which changes the internal milieu
to which the cells are exposed, is so pervasive that its
effects can be detected at the stem cell level (e.g., at the
level of hemopoietic progenitors devoted to hemopoie-
sis). In centenarians, the number of circulating CD34?
cells, or undifferentiated hemopoietic stem cells, in pe-
ripheral blood is about half that found in young individ-
uals.28Production of granulocyte-macrophagic colony-
phytohemagglutinin (PHA)-stimulated peripheral blood
mononuclear cells (PBMC) also reduce with age, while
serum concentrations of stem cell factor (SCF) increase.
Interestingly, when CD34? cells from centenarians were
put in culture and exposed to optimal concentrations of
hemopoietic cytokines and growth factors, their response
(differentiated and formed colonies of erythrocytes,
granulocytes, and megakaryocytes) was indistinguish-
able (number and size of colonies) from that of young
subjects, demonstrating that hemopoietic potential is pre-
served, but the hemopoietic cytokine network (milieu)
undergoes a complex remodeling with age.28Similar
findings have been reported in aged mouse muscle:
Rejuvenation of progenitor cells, in this case satellite
cells, was possible by exposure to serum from young
mice, and vice versa, demonstrating that the age-related
decline in stem cell activity is, at least in part, the result
of an age-related remodeling process and the presence of
inhibitory factors (likely including cytokines involved in
inflammaging) accumulating in the body (serum) of old
animals, rather than an intrinsic loss of competency.29
Another aspect of immunosenescence is the accu-
mulation of megaclones of memory/effector cells di-
rected toward ubiquitary infectious agents that are resis-
tant to apoptosisand
molecules, and the exhaustion of the naı ¨ve T-cell
pool.30,31Cytomegalovirus (CMV) infection, character-
ized by the establishment of lifelong infection in humans,
is highly prevalent in the elderly,32with viral replication
thought to be tightly controlled by virus-specific CD8?
T-cells.33In a study of CMV-specific CD8? T-cell
frequency and phenotype from nonagenarians and cen-
tenarians, two epitopes, i.e., CMV1 (pp65, 495-503
NLVPMVATV, HLA-A2 restricted) and CMV2 (pp65,
417-427 TPRVTGGGAM, HLA-B7 restricted), were
found to be associated with highly variable increased
numbers of specific CD8? T-cells, which were largely
dysfunctional.34Another study reported an increased risk
for frailty in elderly women with chronic CMV infection.
This association was exacerbated by inflammation—
high levels of IL-6 in combination with CMV positivity
significantly increased the odds ratio for frailty.35
In centenarians, this chronic pro-inflammatory
state of aging is countered by increased expression of
growth factor-beta1 (TGF-?1) plasma levels were sig-
nificantly higher in elderly subjects when compared
with younger controls.36Although no relationship was
observed with TGF-?1 levels, the C allele and GC
genotype at the TGF-?1 ?915 polymorphism were
significantly less common in centenarians than in
younger controls, suggesting that variability in the
TGF-?1 gene also influences longevity.36Similarly,
the frequency of the IL-10 (-1082GG) genotype, as-
sociated with increased production of this anti-inflam-
matory cytokine, was higher in centenarians than in
younger controls. Patients with acute myocardial in-
farction showed the lowest frequency of this genotype,
while the (-1082AA) genotype was associated with
low production of IL-10 and was more prevalent in
patients with acute myocardial infarction.37IL-10
polymorphisms, related to high production of the cy-
tokine, also appear to be involved in longevity in
long-living subjects from Japan.38
These results, which should be extended and repli-
cated in different populations and cohorts, all support the
concept that aging is associated with adaptation and
remodeling of the immune system, but successful aging
and longevity require a balance between pro- and anti-
S174Nutrition Reviews?, Vol. 65, No. 12
INFLAMMATION AND MITOCHONDRIA
An emerging field is the role of mitochondria and
mitochondrial genome in aging and inflammaging. Mi-
tochondria are important for ATP synthesis, fatty acid
and steroid metabolism, and apoptosis, among other
functions, but they also produce a toxic by-product of
ATP synthesis, reactive oxygen species (ROS), that is
detrimental to the integrity of mitochondrial DNA
(mtDNA). As the function of mitochondria declines with
age, it is possible that accumulation of mutant mtDNA
molecules leads to dysfunction of age-related function,
which in turn might foster age-related diseases39,40
thereby impacting longevity.41A recent publication was
the first to provide evidence of such a relationship be-
tween mtDNA variability and an expression pattern of
stress responder nuclear genes in human cells.42A cybrid
model, whereby the original mtDNA is destroyed and
repopulated with foreign mtDNA of the desired geno-
type, was used to analyze cytokine and cytokine receptor
gene expression patterns in response to stress. Results
revealed mtDNA germ-line inherited (haplogroup) vari-
ant-specific effects for expression of IL-1?, TNFR2, and
IL-6 genes. While mitochondria and mtDNA variants
may play a role in inflammaging, further research is
needed to elucidate the mechanisms of such actions.
Inflammaging must be investigated and conceptual-
ized from an evolutionary perspective using the tools of
systems biology, in order to grasp its complexity and
systemic involvement.43A systematic search for chronic
infections, and the establishment of safe procedures to
eradicate them, would likely have a strong, beneficial
impact on health status, functional capability, overall
survival, and lifespan in the elderly. Particular attention
should be focused on identifying those at high risk for
developing high-level inflammaging (and corresponding
low-level anti-inflammaging) by determining polymor-
phic genetic markers associated with the propensity to
produce high levels of pro-inflammatory compounds.
This would allow intervention(s) to decrease inflammag-
ing in the elderly, without impairing their capability to
mount effective immune and inflammatory responses
towards those pathogens to which they are exposed in
everyday life. It is interesting to note that natural com-
pounds present in common foods have a variety of
beneficial effects, including anti-inflammatory and pos-
sibly anti-aging effects.44This promising field and soft
approach is worth exploring fully in the future. Mito-
chondria and mitochondrial DNA variants are likely
major players in inflammaging as well, and the cross-talk
between mitochondrial and nuclear genome is another
promising field of research.
1.Libby P. Inflammation in atherosclerosis. Nature.
Libby P. Inflammation and cardiovascular disease
mechanisms. Am J Clin Nutr. 2006;83(suppl):456–
Festa A, D’Agostino R, Jr., Tracy RP, Haffner SM.
Elevated levels of acute-phase proteins and plas-
minogen activator inhibitor-1 predict the develop-
ment of type 2 diabetes: the insulin resistance ath-
erosclerosis study. Diabetes. 2002;51:1131–1137.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker
PM. C-reactive protein, interleukin 6, and risk of
developing type 2 diabetes mellitus. JAMA. 2001;
Griffin WS. Inflammation and neurodegenerative
diseases. Am J Clin Nutr. 2006;83(suppl):470–474.
Lorenzo JA, Naprta A, Rao Y, et al. Mice lacking the
type I interleukin-1 receptor do not lose bone mass
after ovariectomy. Endocrinology. 1998;139:3022–
Kimble RB, Matayoshi AB, Vannice JL, Kung VT, Wil-
and tumor necrosis factor is required to completely
prevent bone loss in the early postovariectomy period.
De Martinis M, Franceschi C, Monti D, Ginaldi L.
Inflammation markers predicting frailty and mortality
in the elderly. Exp Mol Pathol. 2006;80:219–227.
Raison CL, Capuron L, Miller AH. Cytokines sing the
blues: inflammation and the pathogenesis of de-
pression. Trends Immunol. 2006;27:24–31.
Passeri G, Pini G, Troiano L, et al. Low vitamin D
status, high bone turnover, and bone fractures in
centenarians. J Clin Endocrinol Metab. 2003;88:
Coppola R, Mari D, Lattuada A, Franceschi C. Von
Willebrand factor in Italian centenarians. Haemato-
Mari D, Mannucci PM, Coppola R, Bottasso B,
Bauer KA, Rosenberg RD. Hypercoagulability in
centenarians: the paradox of successful aging.
Franceschi C, Bonafe M. Centenarians as a model
for healthy aging. Biochem Soc Trans. 2003;31:
Paolisso G, Barbieri M, Rizzo MR, et al. Low insulin
resistance and preserved beta-cell function contrib-
ute to human longevity but are not associated with
TH-INS genes. Exp Gerontol. 2001;37:149–156.
Franceschi C, Capri M, Monti D, et al. Inflammaging
and anti-inflammaging: a systemic perspective on
aging and longevity emerged from studies in hu-
mans. Mech Ageing Dev. 2007;128:92–105.
Oeppen J, Vaupel JW. Demography. Broken limits
to life expectancy. Science. 2002;296:1029–1031.
Rea IM. Ageing in the 21st century. Where to and
how will we get there? Report on the 10th congress
of the international association of biomedical ger-
ontology, the geriatrician’s view. Exp Gerontol.
De Martinis M, Franceschi C, Monti D, Ginaldi L.
Inflamm-ageing and lifelong antigenic load as major
S175 Nutrition Reviews?, Vol. 65, No. 12
determinants of ageing rate and longevity. FEBS
Franceschi C, Bonafe M, Valensin S. Human immu-
nosenescence: the prevailing of innate immunity,
the failing of clonotypic immunity, and the filling of
immunological space. Vaccine. 2000;18:1717–
Ginaldi L, De Martinis M, Monti D, Franceschi C.
Chronic antigenic load and apoptosis in immunose-
nescence. Trends Immunol. 2005;26:79–84.
Fagiolo U, Cossarizza A, Scala E, et al. Increased
cytokine production in mononuclear cells of healthy
elderly people. Eur J Immunol. 1993;23:2375–2378.
Franceschi C, Bonafe M, Valensin S, et al. Inflamm-
aging. An evolutionary perspective on immunose-
nescence. Ann N Y Acad Sci. 2000;908:244–254.
Franceschi C, Valensin S, Bonafe M, et al. The
network and the remodeling theories of aging: his-
torical background and new perspectives. Exp Ger-
Ottaviani E, Franceschi C. The neuroimmunology of
stress from invertebrates to man. Prog Neurobiol.
Ottaviani E, Franceschi C. The invertebrate phago-
cytic immunocyte: clues to a common evolution of
immune and neuroendocrine systems. Immunol To-
Ottaviani E, Franceschi C. A new theory on the
common evolutionary origin of natural immunity,
inflammation and stress response: the invertebrate
phagocytic immunocyte as an eye-witness. Domest
Anim Endocrinol. 1998;15:291–296.
Troen BR. The biology of aging. Mt Sinai J Med.
Bagnara GP, Bonsi L, Strippoli P, et al. Hemopoiesis
in healthy old people and centenarians: well-main-
tained responsiveness of CD34? cells to hemopoi-
etic growth factors and remodeling of cytokine net-
work. J Gerontol A Biol Sci Med Sci. 2000;55:B61–
66; discussion B67–70.
Conboy IM, Conboy MJ, Wagers AJ, Girma ER,
Weissman IL, Rando TA. Rejuvenation of aged pro-
genitor cells by exposure to a young systemic en-
vironment. Nature. 2005;433:760–764.
Fagnoni FF, Vescovini R, Passeri G, et al. Shortage
of circulating naive CD8(?) T cells provides new
insights on immunodeficiency in aging. Blood.
Nasi M, Troiano L, Lugli E, et al. Thymic output and
functionality of the IL-7/IL-7 receptor system in cen-
tenarians: implications for the neolymphogenesis at
the limit of human life. Aging Cell. 2006;5:167–175.
Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson
BO, Ferguson FG. Age-related change in peripheral
blood T-lymphocyte subpopulations and cytomeg-
alovirus infection in the very old: the Swedish lon-
gitudinal OCTO immune study. Mech Ageing Dev.
Appay V, Dunbar PR, Callan M, et al. Memory CD8?
T cells vary in differentiation phenotype in different
persistent virus infections. Nat Med. 2002;8:379–
Vescovini R, Telera A, Fagnoni FF, et al. Different
contribution of EBV and CMV infections in very
long-term carriers to age-related alterations of
CD8? T cells. Exp Gerontol. 2004;39:1233–1243.
Schmaltz HN, Fried LP, Xue QL, Walston J, Leng
SX, Semba RD. Chronic cytomegalovirus infection
and inflammation are associated with prevalent
frailty in community-dwelling older women. J Am
Geriatr Soc. 2005;53:747–754.
Carrieri G, Marzi E, Olivieri F, et al. The G/C915
polymorphism of transforming growth factor beta1
is associated with human longevity: a study in Italian
centenarians. Aging Cell. 2004;3:443–448.
Lio D, Candore G, Crivello A, et al. Opposite effects
of interleukin 10 common gene polymorphisms in
cardiovascular diseases and in successful ageing:
genetic background of male centenarians is protec-
tive against coronary heart disease. J Med Genet.
Okayama N, Hamanaka Y, Suehiro Y, Hasui Y,
Nakamura J, Hinoda Y. Association of interleu-
kin-10 promoter single nucleotide polymorphisms
–819 T/C and –592 A/C with aging. J Gerontol A
Biol Sci Med Sci. 2005;60:1525–1529.
Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mito-
chondrial DNA mutations as an important contribu-
tor to ageing and degenerative diseases. Lancet.
Wallace DC. A mitochondrial paradigm of metabolic
and degenerative diseases, aging, and cancer: a
dawn for evolutionary medicine. Annu Rev Genet.
Santoro A, Salvioli S, Raule N, et al. Mitochondrial
DNA involvement in human longevity. Biochim Bio-
phys Acta. 2006;1757:1388–1399.
Bellizzi D, Cavalcante P, Taverna D, et al. Gene
expression of cytokines and cytokine receptors is
modulated by the common variability of the mito-
chondrial DNA in cybrid cell lines. Genes Cells.
Salvioli S, Capri M, Valensin S, et al. Inflamm-aging,
cytokines and aging: state of the art, new hypothe-
ses on the role of mitochondria and new perspec-
tives from systems biology. Curr Pharm Des. 2006;
Salvioli S, Sikora E, Cooper EL, Franceschi C. Cur-
cumin in cell death processes: a challenge for CAM
of age-related pathologies. Evid Based Comple-
ment Alternat Med. 2007;4:181–190.
S176Nutrition Reviews?, Vol. 65, No. 12