C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

Experimental Gerontology 35 (2000) 879±896

879

www.elsevier.nl/locate/expgero

The network and the remodeling theories of aging:
historical background and new perspectives
Á
C. Franceschi a,b,* ,1, S. Valensin a,1, M. Bonafe a,1, G. Paolisso c,
d
e
A.I. Yashin , D. Monti , G. De Benedictis f
b

a
Department of Experimental Pathology, University of Bologna, Bologna, Italy
Department of Gerontological Research, Italian National Research Center on Aging (INRCA), Ancona, Italy
c
Department of Geriatric Medicine and Metabolic Diseases, Second University of Naples, Naples, Italy
d
Max Plank Institute for Demographic Research, Rostock, Germany
e
Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy
f
Department of Cell Biology, University of Calabria, Cosenza, Italy

Received 30 June 2000; accepted 4 July 2000

Abstract
Two general theories, i.e. ªthe network theory of agingº (1989) and ªthe remodeling theory of
agingº (1995), as well as their implications, new developments, and perspectives are reviewed and
discussed. Particular attention has been paid to illustrate: (i) how the network theory of aging ®ts
with recent data on aging and longevity in unicellular organisms (yeast), multicellular organisms
(worms), and mammals (mice and humans); (ii) the evolutionary and experimental basis of the
remodeling theory of aging (immunological, genetic, and metabolic data in healthy centenarians,
and studies on the evolution of the immune response, stress and in¯ammation) and its recent
development (the concepts of ªimmunological spaceº and ªin¯amm-agingº); (iii) the profound
relationship between these two theories and the data which suggest that aging and longevity are
related, in a complex way, to the capability to cope with a variety of stressors. q 2000 Elsevier
Science Inc. All rights reserved.
Keywords: Aging; Immunosenescence; Longevity; Centenarians; Aging theories; Stress; In¯ammation

1. The network theory of aging (1989)
In 1989 one of us proposed a general theory suggesting that aging is indirectly
* Corresponding author. Address: Department of Experimental Pathology, University of Bologna, Bologna,
Italy. Tel.: 139-51-2094743; fax: 139-51-2094747.
E-mail address: clafra@kaiser.alma.unibo.it (C. Franceschi).
1
These authors contributed equally to the work.
0531-5565/00/$ - see front matter q 2000 Elsevier Science Inc. All rights reserved.
PII: S 0531-556 5(00)00172-8

880

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

controlled by a network of cellular and molecular defense mechanisms (the network theory
of aging) (Franceschi, 1989). The aim of this theory was to combine suggestions deriving
from evolutionary theories of aging (Kirkwood, 1977; Kirkwood and Holliday, 1979) with
data emerging from cellular and molecular biology of aging. We would like to report in
detail the conclusions of the 1989 paper:
ªOur integrated view of the mechanisms which most likely play a critical role in the
aging process at the cellular level may be summarized as follows:
² Cells are continuously exposed to a variety of internal and external stressors, which are
potentially dangerous for the maintenance of cell functional integrity.
² Such stressors are very diverse and include different physical (UV and gamma radiation, heat), chemical (components of the body and products of metabolism, such as
oxygen free radicals and reducing sugars), and biological agents (viruses).
² In the course of evolution a number of mechanisms have emerged which allow the cell
to cope with such a variety of potentially harmful agents.
² These mechanisms include DNA repair mechanisms, antioxidant defense systems
either enzymatic or non-enzymatic, production of heat shock proteins (HSPs), activation of poly(ADP-ribose)polymerase (PARP), among others.
² These mechanisms are in fact interconnected and integrated and constitute a network of
cellular defense systems; they have to be considered together and not one by one. These
considerations may explain the failure of all attempts to correlate aging and/or longevity with the ef®ciency of a single defense mechanism, e.g. DNA repair or antioxidants, and senescence or maximum life span.
² A failure of these mechanisms does not allow the cell to maintain its homeostasis and
this fact coincides with cell senescence (aging at the cellular level).
² The consequences of this failure are particularly important as far as two of the major
programs of the cell, namely cell proliferation and cell death, are concerned.
² [¼]
² Alterations of the network of cellular defense mechanisms may disturb cell physiology,
including its capacity to produce and/or to respond to growth factors, thus altering the
balance between cell proliferation and cell death at the level of tissues and organs.
² The neuroendocrine and the immune systems may be particularly affected by such a
situation since they are themselves networks of interconnected cells, which depend on
each other as far as growth factors and others mediators are concerned.º
According to this view, the ef®ciency of a core of highly integrated and evolutionary
conserved molecular and cellular mechanisms are responsible for the aging process.
Despite the anticipated complexity of such defense network, it appeared for the ®rst
time that the aging process could have a limited number of critical targets, i.e. the network
components and their interactions. Accordingly, together with Tom Kirkwood, we asked a
provocative question: is aging as complex as it would appear? (Kirkwood and Franceschi,
1992). Moreover, is it possible to identify strong commonalities despite the discouraging
diversity of the aging process at phenomenological level? It was argued that ªthe concept
of a network of interconnected cellular defense reactions bring coherence to the study of
the individual reactions and processes that contribute to the overall process of aging, but it

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

881

also underlines some of the dif®culties. Two main challenges arise in the study of
networks. The ®rst is to understand how each component process affect the function
and viability of the network as a whole. The second is to disentangle the interactions
between different processes and levels of functioning. [¼]. Recognition that the proximate
causes of aging involve the interplay between a network of damaging agents and a network
of cellular defenses generates a more complex picture of aging than simply suggesting that
aging is caused by a single agentº (Kirkwood and Franceschi, 1992). This perspective has
been subsequently pursued and modeled (Kowald and Kirkwood, 1994; Kowald and
Kirkwood, 1996). The fascinating problem was however that experimental evidence
and theory tell us that single genetic or environmental manipulation may profoundly affect
aging and longevity. Indeed, mutations at a single gene, such as Age1, Ras, p66shc,
(Migliaccio et al., 1999; Jazwinski, 1999; Kawano et al., 2000) as well as interventions
such as caloric restriction (CR), are by themselves able to prolong the life span of species
over the entire evolutionary scale, from yeast and Caenorhabditis elegans to mammals.
This apparent paradox can be explained assuming that in the ®rst case we are dealing with
master genes capable of inducing signi®cant modi®cations in the network of cellular
defense mechanisms because of their high hierarchical role in metabolic and biochemical
pathways of the network, while in the second case the manipulation is capable of modifying several basic targets among the components of the network. In other words, either the
above-mentioned genes or CR are likely to exert their action through the network, by
markedly modifying and modulating it (Lee et al., 1999). Throughout evolution and
accompanying the increasing complexity of the organisms, the basic network of evolutionary conserved defense mechanisms is enriched by new ingredients, which allow the
realizations of new hierarchically higher levels of organization. In particular, we are
referring to the emergence of the neuroendocrine system (NES) and the innate immunity
in invertebrates and the further appearance of adaptive clonotypical immunity in vertebrates, (Ottaviani et al., 1998). These new defense mechanisms are grafted on and interact
with the ancestral network within a framework of reciprocal interaction and modi®cation.
Their function is double, since they are not only generated to allow a further level of
structural and functional complexity, but also to act as a controlling modulatory system for
the coordination of elements belonging to the hierarchically and evolutionary lower
network layers. In other words, it can be speculated that the major role of this new
level of organization is to coordinate the responses brought about by the cells which
constitute multicellular organisms, by exerting an inhibitory tone and thus minimizing
the possible hypo- or hyper responsiveness of the single cells. Moreover, the role of the
higher levels of organization is likely to transform local information (local stress) into
general information to arrange a generalized response at the organismal level.
1.1. The anti-aging network at single cell level: the yeast (Saccharomyces cerevisiae)
Basically, single cell eucaryotes, contain ªin nuceº all the properties of the anti-aging
network. Therefore, the challenge of evolution was to ®nd out appropriate strategies to
manage them in a coordinated manner, i.e. to set the anti-aging network at optimal level. In
the unicellular yeast S. cerevisiae, life span and stress response are affected by RAS2 gene
over-expression. The protein is a homeostatic device, capable to coordinate information

882

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

regarding energy production/expenditure, mitochondrial status, energy substrate
availability, cell cycle status, and it participates to the response to a variety of stressors
(heat shock, UV) (Jazwinski, 1999). A mild, non-lethal stress extends life span if it is
administered early in life. Both RAS2 and RAS1 genes are required, since the phenomenon
does not occur late in life when RAS1 and RAS2 expression is low, or if RAS1 or RAS2
de®cient strains are examined. It is well recognized that the transient exposure to sublethal stress exerts long-term effects on the individual stress-response ability and longevity: this phenomenon has been called hormesis and has been interpreted as the consequence of an up-regulation of the anti-stress response network (Shama et al., 1998a). The
fact that this up-regulation is persistent implies that stress response is capable to elicit a
sort of molecular memory, i.e. that the exposure to a stressor modi®es the system in order
to set up subsequent responses. Memory has been thought as the major evolutionary
advance of the vertebrate clonotypical immune system and central nervous system, but
it is already present in the basic mechanisms of stress response. In contrast, the deleterious
effects of chronic stressors have been widely documented in all species. Yeast RAS2de®cient mutants have an impaired rescue from sub-lethal chronic stress, due to persistent
expression of HSPs even after the cessation of the stress stimulus. Their sustained presence
is responsible for detrimental effects on cell replication, and consequently on replicative
life span. Indeed, RAS2-de®cient strains have an advantage in survival when the yeast is
exposed to a lethal stress: in this situation the highest is the production of HSP, the most
probable is the consequent survival (Shama et al., 1998b). Thus, already in the yeast stress
response has to be optimized, and the inducibility of basic mechanisms, such as HSPs is far
beyond the necessity of the system (the cell in this case) and it has to be tightly controlled
in order to obtain an appropriate response. It is dif®cult to discriminate between mildstress and absence of stress (an unrealistic condition), and it is more appropriate to speculate that the crucial evolutionary constraint was the regulation of the threshold above
which a response has to occur (Shama et al., 1998b; Jazwinski, 1999). Under this perspective, those individuals within a species having the highest capability to respond to stress
will not be necessarily those subjects who will attain a successful survival and an extended
life span. According to the data on yeast, it would be paradoxically more useful for
survival to be incapable of responding or to set up a minimal response to some external
stimuli. Again this perspective, if applied to the immune system, will help in understanding the aging of the clonotypical system, as the result of chronic antigenic stress.
1.2. The anti-aging network in multicellular organisms: the worm (C. elegans)
An ancestral insulin pathway controls longevity and stress response capacity in C. elegans.
In fact, mutations of insulin/IGF1 peptide (Kawano et al., 2000), Daf-2 gene (the homologs of
human Insulin/IGF-1 receptor), unc-64 and unc-31 (homologs of human syntaxine and CAPS,
two proteins involved in the release of neuromediators by synaptic structures), Age-1 (the
homolog of human Insulin receptor downstream p110/85 lipid PI3-kinase), Daf-16 (the
homolog of human PTEN) confer resistance to environmental stress such as heat shock,
enhance resistance to starvation, and extend the life span (Babar et al., 1999). C. elegans,
at variance with the unicellular S. cerevisae, has a higher level of complexity, being a
multicellular organism. In such a complex animal the above-mentioned genes constitute a

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

883

primordial NES, where an insulin/IGF1 like peptide plays a major role, integrating information concerning the presence and intensity of environmental stressors and by monitoring nutritional availability, thus giving raise to a complex remodeling of metabolism in
order to attain survival and, ultimately, longevity (Ailion et al., 1999). Under such
perspective, this primitive NES has not only the capacity to harmonize the control of
what occurs in each tissue and cell but also to avoid the over-expression or the uncoordinated expression of stress response genes in each cell and tissue. This coordination
between hierarchical high and low components or layers of the anti-aging network is
even more evident from studies on vertebrates.
1.3. The anti-aging network in vertebrates: the mouse and humans (Mus musculus and
Homo sapiens)
Vertebrates have developed a complex hierarchy of multi-organ NES, integrated with
the immune system to form the immuno-neuro-endocrine system. It produces a variety of
local and systemic mediators, such as cathecolamines, in order to tolerate the myriad of
stress-induced insults that occur lifelong in tissues, organs and systems. It has been
demonstrated that in mammals the cellular HSP-mediated stress response has been
embedded into the cathecolamine-based systemic response machinery (Blake et al.,
1991). A variety of elemental (cold, heat) and complex (nutritional, but also psychological) stressors activate catecholaminergic pathways, which in turn induce HSPs in
adrenal cortex and vessel walls, thus indicating that the most ancestral mechanism of
stress response has been re-utilized to cope with complex and systemic stimuli (Blake
et al., 1995). HSPs participate not only to stress response but also to the normal regulation
of vasculature, indicating that, as it occurs in yeast, the optimization of HSP expression has
to be reached in order to attain the most useful strategy for survival (Blake et al., 1991). In
fact, hypertensive humans display an HSP hyper-responsiveness, indicating that in these
individuals the activation threshold for the production of HSP is lower than that observed
in normotensive subjects (Hamet et al., 1994). When HSP response in vasculature is
sustained by chronic stressors, hypertension (and their detrimental consequences) occurs,
thus suggesting that in certain circumstances adaptation and low responsiveness, rather
than prompt response could be the most appropriate strategy to attain survival (Blake et al.,
1995). In this perspective, NES is devoted to control HSP production in tissues and organs,
in order to decide about the appropriateness of the local response (Udelsman et al., 1994).
In fact, while the stress-response system is responsible for survival, its sustained activation, due to the unavoidable chronic overexposure to stressors, is highly pathogenic. Under
this perspective, many features of mammalian aging could be considered as the consequence of the long-term effects of chronic stress. Aged mammals have a lowered capability to cope with environmental changes (homeostenosis). In fact, a decreased number of
catecholamine receptors in peripheral tissues, together with a decline of HSP levels and
their inducibility by cathecolamines, characterize the age-related decline of sympathetic
response (Udelsman et al., 1993). As age increases, the exposure to potentially harmful
stimuli (such as increased blood pressure) is no longer able to induce HSPs from blood
vessels, allowing for deleterious damaging of the vessel surface, a phenomenon ultimately
predisposing to further damage. Elderly display also a progressively reduced capacity to

884

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

recover from stress-induced modi®cations. To this regard, data on humans reveal that aged
people can respond to psychological stress (such as catecholamine-mediated vascular
constriction) with intensity similar to that of young individuals, but the mechanisms of
recovery are inadequate (Castellani et al., 1998; Castellani et al., 1999). This feature
recalls the detrimental effects of the impaired recovery from stress observed in yeast.
Finally, aging exposes individuals to the deleterious side effects of stress response molecules. Indeed, the persistent elevation of HSPs is highly toxic for cellular metabolism, and
recent data demonstrate that the elevated expression of HSP70 is a key feature of a variety
of human malignancies (Jaattela, 1999). Even catecholamines are highly toxic
compounds, and are thought to be responsible for the selective loss of dopaminergic
neurons and for the increased vulnerability of hyppocampal neurons to amyloid betapeptide neurotoxicity (Yang and Lin, 1999). Hence, the strategy of long-term survival
is to maintain the stress response within a ®xed range. Outside this range the survival
ability of the individual progressively decays because of an insuf®cient response or
because of an excessive response. Inside the range of the ªusefulº stress response, chronic
stressors can render the system insensitive to changes either by up-regulating the activation threshold, or by down-regulating the sensitivity of peripheral effectors. However, as
predicted by studies on stress, peculiar pattern of stimulation can exert hormetic properties, favoring the natural capability of the individual to respond to stress. In a genetically
heterogeneous population such as humans this phenomenon is likely to depend on the
combination of variants (polymorphisms) of genes regulating stress response, together
with an appropriate environment: healthy centenarians could be the living example of this
unusual and uncommon situation.
2. The remodeling theory of aging (1995)
The remodeling theory of aging was proposed in 1995 in order to conceptualize the
results emerging from studies on human immunosenescence and the new model of healthy
centenarians (Franceschi et al., 1995; Franceschi and Cossarizza, 1995). The main question we were interested in was: which is the contributor of the immune system to longevity, i.e. to attain the extreme limits of the human life span? This question, which is
different from that, more usual, interested in assessing the deteriorative changes occurring
in the immune system with age, and thus in assessing the role of the immune system on the
human survival, was ®rstly addressed by the Gino Doria's group (Doria and Frasca, 1997).
They showed that mice genetically selected for high immune responsiveness display
longer life span and lower tumor incidence than do mice selected for low responsiveness.
The results of these studies on genetic selection suggest that age related immune dysfunction has a signi®cant impact on life span and disease. In order to answer to the question
about the possible relationship between immune system ef®ciency and longevity in
humans we had to ful®ll two requisites. The ®rst was to avoid as much as possible the
interference of pathological phenomena in order to study the physiology of the immunosenescence; the second was to ®nd a suitable human model for our purpose. We were
lucky that the ®rst requirement was addressed by other scientists who in 1984 proposed
strict admission criteria for immunogerontological studies in humans, in order to recruit

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

885

elderly in good health, according to clinical and laboratory parameters (Ligthart et al.,
1984). The second requirement was addressed by studying healthy centenarians as a model
of successful aging and successful physiological immunosenescence. Healthy centenarians are quite rare, and the assessment of their health status is methodologically dif®cult.
Despite the dif®culty in assessing the healthy status of very old people, using a new
simpli®ed set of criteria, capable of distinguishing at an operational level between healthy
and non-healthy subjects, we found in a large sample of 382 centenarians that 22% of them
were in good health status, de®ned as absence of major diseases and physical and cognitive
disabilities (Franceschi et al., 2000a). Subjects ful®lling those criteria were thoroughly
studied as far as a variety of immune responses are concerned, and compared with healthy
people of different ages, encompassing the entire human life span. Several unexpected
®ndings were obtained which constitute the basis of the remodeling theory of immunosenescence:
1. A variety of immune responses and parameters were unexpectedly well conserved in
centenarians (Paganelli et al., 1992; Mariotti et al., 1992; Sansoni et al., 1993, 1997;
Fagiolo et al., 1993; Cossarizza et al., 1996; Bagnara et al., 2000).
2. The different immune responses are differently affected by the aging process, and some
of them decline while others remain unchanged or increase (Fagnoni et al., 1996, 2000;
Wack et al., 1998).
In general, the hypothesis of remodeling suggests that immunosenescence is the net
result of the continuous adaptation of the body to the deteriorative changes occurring over
time. According to this hypothesis body resources are continuously optimized, and immunosenescence must be considered a very dynamic process, which includes both loss and
gain. The keyword is adaptation, and consequently the major prediction is that healthy
centenarians are those who have the better capacity to adapt to damaging agents and in
particular to immunological stressors. If this assumption is true a counterintuitive prediction can be formulated: contrary to the common sense it can be predicted that those
individuals who are the highest responders to immunological stressors and are capable
of mounting strong immune responses against bacteria, viruses, and other antigenic challenges, will have an advantage on the short run but will survive less than those who have a
lower but ef®cient capability to respond to antigenic stressors. In other words, at least from
an immunological point of view, but likely also in general, centenarians are probably not
ªthe bestº but ªthe best adaptedº. Finally, we would like to stress that the most intriguing
and fascinating hypothesis is that the remodeling capability is genetically controlled in
humans and other species. This hypothesis opens a new scenario, which will be addressed
in the ®nal section.
3. Remodeling at work
3.1. The evolutionary theory of immunosenescence (1999)
Another consequence of the remodeling theory of immunosenescence is that the aging
of the immune system is not a random process without rules or directions, but has

886

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

evolutionary constraints. The ®rst of them is that the immune system has been probably
selected to serve a soma living until reproduction. This was probably the evolutionary scenario when our ancestors lived until 30±50 years of age in an environment
which was relatively constant, usually devoid of new immunological challenges due
to immigration of people carrying unknown bacteria or viruses. Nowadays, the
immune system must serve the soma of individuals living 80±120 years, an enormous amount of time longer than predicted by evolutionary forces, in rapidly changing environments in which the probability to encounter new antigens is relatively
high. Other species, such as mice or rats, which also have a clonotypical immune
system, are subjected to the same constraints, but they have been evolutionary
selected to live much shorter than humans. The remodeling theory predicts that
the process of the immunosenescence is qualitatively the same in mice and men
but that the rate and the details of the process will be different according to their
evolutionary scaling in terms of life span and body size. The second constraint
concerns the evolution of the immune system that started as innate immunity in
invertebrates and then was added with the more sophisticated clonotypical adaptive
immunity in vertebrates (Ottaviani et al., 1998). Immunologists recently realized that
innate immunity, far from being an evolutionary remnant, is on the contrary essential for survival and is fully integrated within the clonotypical immune system, to
which it gives the ®rst signal fundamental for triggering immune responses. Probably, it is not by chance that innate immunity, which is so crucial for survival and
immune responses to occur, is less affected by the aging process, in comparison
with the most sophisticated but more delicate clonotypical and adaptive immune
response (Franceschi et al., 2000b). In particular, several experimental papers on
healthy centenarians indicate that the number and the activity of NK cells, dendritic
cells, macrophages and related cells, as well as the complement system, are well
preserved or less affected than the clonotypical immunity. (Sansoni et al., 1993;
Franceschi et al., 1999, 2000b,c; Bellavia et al., 2000; Lung et al., 2000). Thus, the
rules of the aging of the immune system in high vertebrates such as humans are
dictated by forces which molded the immune system during evolution. The early
involution of the thymus, a major phenomenon of immunosenescence, can be interpreted in evolutionary terms as a trade-off between its decreasing usefulness immediately after the set up of the T cell repertoire and the cost of maintenance of such
an organ in which an enormous wasting of cells occurs every day (more than 95%
of them die by apoptosis) in order to purge the T cell repertoire from potential autoreactive clones (George and Ritter, 1996).
3.2. The concept of immunological space (2000)
The development of immunological conceptualization is full of metaphors such as self
and non-self, cooperation, killer cells, helper cells, among others, which were very useful
not only to suggest and name new phenomena but also to inspire new experimental designs
and investigations. The study of immunosenescence led us to propose another metaphor,
i.e. the concept of immunological space in order to grasp the major characteristics of the
immune system as a system, i.e. the constraint represented by the availability of physical

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

887

space in which all possible interactions among immune cells and/or cell subsets must
occur (Franceschi et al., 2000b). This constraint strongly in¯uences the behavior of the
system as far as the synergistic or competitive properties of its elements are concerned.
The advantages of the concept of immunological space are the following:
1. It allows the comparison among different immune systems, such as those of mice and
men, the most usually investigated animals from an immunological point of view. Such
a comparison faces a lot of problems, as pointed out, for example, by Richard Aspinall
who asked himself if the immune system of mouse ages faster than the immune system
of humans (Aspinall, 1999). Indeed, the life span of mice is 40 times less than that of
humans and within the 2±3 years of mouse life a process of immunosenescence occurs
qualitatively quite similar to that of humans, in whom the same process takes more than
100 years. As a major characteristic of immunosenescence in both species is an accumulation of senescent T cells unable to proliferate, and since there are close similarities
between the replication rate and replicative life span of T cells from mice and human
sources, a paradox arises, because the onset of immunosenescence appears to be more
closely linked to the life span of the animals rather than the life span of the lymphocytes. In other words, how can we explain the much faster rate of immunosenescence in
mice, considering that at the lymphocyte level there are no major differences between
mouse and humans regarding intermitotic times, rate of activation, and replicative life
span? According to Aspinall this paradox has no possible explanations at present, all
being unsatisfactory for one reason or another (Aspinall, 1999). So, the question why
immunosenescence cells appear in mice and humans at the same stage of the life cycle
when the cells themselves have such similar properties in his opinion remains a paradox. We think that the concept of immunological space can help in solving this paradox, when considering that the immunological spaces of mice of humans are quite
different. Indeed, we have ®rstly to take into account that the process of immunosenescence involve a population of lymphocytes which is at least three orders of magnitude
bigger in humans than in mice, and thus, that, being equal the major biological characteristic of the single lymphocytes, the time needed to ®ll the available immunological
space with senescent T cells is consequently much shorter in mice than in humans.
Moreover, both systems have to be considered as complex systems where it is unlikely
to ®nd a linear correlation between the ratio of the simple physical size of the immune
system of mice and humans and the ratio of their immunosenescence rate. Indeed, even
if the elements composing both immune systems are the same, the different dimensions
of such systems and their cell compartments, have as a consequence a different
systemic behavior of the immune system as a whole.
2. It is interesting that similar metaphors or perspectives have been suggested by other
authors who proposed a geographical view of the immune response where antigen
alone regulates immune responses, dependent upon antigen localization, antigen
dose, and time (Zinkernagel et al., 1997). Combining this geographical perspective
with the concept of immunological space we end up with an immunological system
conceptualized as an organized space in which anatomical structures (such as follicles,
marginal zones, germinal centers, periarteriolar sheath, red pulp, and channeled pathways, directing lympho-hemopoietic interactions) allow cell±cell interactions ordered

888

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

anatomically in a timely sequence. Thus, the immunological space is not a simple box
full of a ®xed number of lymphocytes but it can be subdivided into geographical areas
and niches, in which the probability for the right cell±cell interactions and ligand±
receptor interactions to occur are favored and optimized.
3. The concepts of available space and limited space have been put forward by other
authors interested in the problem of maintenance of peripheral T cell pools in adult
animals and humans, especially after bone marrow transplantation, cancer chemotherapy, and reconstitution of the immune system after therapy in AIDS patients (Kieper
and Jameson, 1999; Tanchot and Rocha, 1998). The major outcome of these studies is
that the total number of memory and naive T cells is kept constant in adult mice, and
that these subsets do not compete for the same niches, their sizes being apparently
independently regulated. The two major forces which regulate and are responsible for
the total T cell number are the ªlimited spaceº, i.e. the space available in the periphery,
and the stimulatory effect of self class I and II MHC ligands. In the periphery naive T
cells can persist inde®nitely in a quiescent state without dividing, and this phenomenon
is independent from the age of the single cell. When space is available as a consequence
of chemotherapy or experimental manipulation, a phenomenon called homeostatic
expansion occurs, capable of inducing the proliferation of peripheral naive T cells,
despite the absence of foreign antigenic stimulation (Ernst et al., 1999). The mechanism
by which T cells perceive T cell space is unclear, but it has been suggested that T cells
can exert reciprocal inhibitory activity or that a reduced number of T cells in turn
reduces the competition for antigen presenting cells capable of stimulating T cell
proliferation. In any case, the concept of a competition between T cells for available
space is emerging.
4. Integrating recent data from the literature and our data on immunosenescence, the
immunological space can be envisaged as a container for survival, constituted by
and continuously presenting self peptides bound to class I and class II MHC molecules,
which represent an important survival signal for T cells in the periphery, similarly to
what occurs during T cell positive selection in the thymus (Tanchot and Rocha, 1998).
However, recent data suggest that memory CD41 and CD81 T cells can survive and
proliferate in the periphery in class I and class II de®cient hosts, and indicate that the
major stimulatory factors to undergo homeostatic T cells proliferation is represented by
an empty immune system, in a way which is MHC class I and class II independent
(Murali-Krishna et al., 1999; Swain et al., 1999).

3.3. Immunological space and immunosenescence (2000)
A major characteristic of immunosenescence is the accumulation of expanded clones,
mostly of memory and effector T cells (Fagnoni et al., 1996) . This phenomenon has been
described in mice (Ku et al., 1997) and in elderly humans (Schwab et al., 1997), most of
the literature concerning T cells. The age related expansion of T cell clones occurs in
CD41 and CD81 T cells, but being mostly prominent in CD81 T cells. Moreover, we
and others have shown that there is an age related shrinkage of T cell repertoire, as
assessed by PCR heteroduplex methodology applied to the study of Vbeta T cell repertoire

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

889

(Wack et al., 1998). Two other major characteristics of immunosenescence are the age
related decline of virgin T cells and the concomitant decrease in recent thymic emigrant T
cells as a consequence of the thymic involution. These three phenomena, i.e. the accumulation of expanded memory and effector T cell clones, the marked reduction of naive T
cells, and the reduced input of fresh thymic virgin T cells are probably correlated. The end
result is a ®lling of the immunological space with indolent cells with memory markers
which could exert a suppressor/negative effect on other bystander T cells, including the
few naive cells which are present in old people and centenarians. We recently showed that
an exhaustion of naive T cells, identi®ed by the absence of CD95 molecule, beside
presence of the other usual markers of virgin T cells, i.e. CD45RA and CD62L, occurs
in centenarians. This ®nding suggests that the number of virgin T cells, and specially
CD81 T cells, can be taken as a putative marker of mortality (Fagnoni et al., 2000), as
further supported by a mathematical model recently developed by our group (Luciani et
al., unpublished).
In conclusion, we propose the idea that the most important characteristic of immunosenescence is the ®lling of the immunological space with memory and effector cells likely
exerting an inhibitory role on the remaining immune cells as a consequence of the continuous and evolutionary unanticipated exposure to a variety of antigens. The predictions of
this hypothesis are the following:
1. Immunosenescence and probably morbidity and mortality will be accelerated in those
subjects who are exposed to an extra burden of antigenic load, for several reasons such
as the chronic infections due to parasites and viruses. Conversely, immunosenescence
will be delayed in those subjects who lived for most of their life in clean environments
in which exposure to persistent viral infections and parasitic infections are minimized.
Indeed, this is exactly what happened in the last century in the most economically
developed countries in which medicare, vaccination, and hygiene in food, water, and
house contributed to reduce the antigenic load and consequently the rate of immunosenescence. This delay in attaining the exhaustion of naive T cells and the ®lling of the
immunological space likely represented a strong contribution to the dramatic increase
in longevity that recently occurred in these countries.
2. It is conceivable that the immunological space changes with age either quantitatively (a
reduction of its size and of the mass of immune cells) or qualitatively. This last
possibility deserves particular attention as the number and the quality of self-peptides
available within the immunological space can change over time as a consequence of the
variety of damages that accumulate in the proteins of the body (oxidation, glycosilation,
and other reactions), as well as of the reduced activity of proteolitic enzymes and
proteasome with age. Thus, self peptides, which when bound to class I and II MHC
molecules are important survival factors for peripheral T cells, can undergo profound
changes which can explain not only autoimmune disorders but also other age associated
pathologies where immune responses play a role.
3. Rejuvenation strategies can be designed in order to make space, getting rid of accumulated T cell clones and reducing or delaying the ®lling of the immunological space.
Another strategy is to minimize the antigenic load in the elderly, paying particular
attention to chronic infections and to the antigenic load coming from the gut and

890

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

other possible sources. It is interesting to remember that during the human life span the
gut is confronted with about 700 tons of food mostly represented by foreign proteins
with high potential antigenic capacity. Even a minimal leakage of this material through
the gut wall or a minimal defect in oral tolerance could give a strong contribution to the
chronic antigenic stress which likely plays a major role in immunosenescence.

3.4. In¯amm-aging (2000)
Assuming that the major characteristic of human immunosenescence is the ®lling of the
immunological space by memory and effector T cell clones as a consequence of the
chronic antigenic stress, we recently argued that another major consequence of chronic
exposure to antigens is the progressive activation of macrophages and related cells in most
organs and tissues of the body (Franceschi et al., 2000c). In other words, the continuous
antigenic challenge could be responsible for a progressive pro-in¯ammatory status, which
appears to be a major characteristic of the aging process. We named this phenomenon
in¯amm-aging, which can be considered a theoretical extension of the network theory of
aging and of the remodeling theory of aging. As we have argued in the previous section,
immunosenescence is characterized by an evolutionary dichotomy in which innate immunity is largely preserved or even activated. Innate immunity is profoundly related from an
evolutionary point of view to the stress response and to in¯ammation, according to a series
of studies we performed in different animal species from invertebrates to humans. On the
basis of these evolutionary studies, we suggested that the immune response, the stress
response, and in¯ammation constitute an integrated, evolutionary conserved defense
network, and that antigens are nothing else than particular types of stressors (Ottaviani
and Franceschi, 1996, 1997; Ottaviani et al., 1997). The continuous attrition caused by
clinical and sub-clinical infections, as well as the continuous exposure to other types of
antigens (bacteria, viruses, food, allergens) in the gut, skin, dental caries, respiratory tract,
urinary tract, is likely responsible for the chronic activation of innate immunity as the ®rst
line of defense. Thus, an in¯ammatory status is compatible with extreme longevity in good
health (Baggio et al., 1998) and ªparadoxicallyº pro-in¯ammatory characteristics have
been documented in healthy centenarians, suggesting that the old concept of physiological
in¯ammation proposed by Metchnikoff is a real phenomenon. From this perspective,
in¯ammation and the pro-in¯ammatory status present in aged people and centenarians
is the result of a bene®cial responsiveness, which should help old people to cope with
chronic antigenic stressors. However, as for the stress response, excessive responsiveness,
i.e. a marked pro-in¯ammatory status, can be detrimental, as well as the opposite, i.e. a
hypo responsiveness to antigenic stress. The rate of reaching the threshold of pro-in¯ammatory status over which diseases/disabilities ensues, and the individual capacity to cope
with and adapt to stressors are assumed as complex traits having a genetic component.
Finally, we argue that the persistence of in¯ammatory stimuli over time represents the
biological background (®rst hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants)
is likely necessary to develop overt organ-speci®c age-related diseases, having an in¯ammatory pathogenesis, such as atherosclerosis, Alzheimer diseases, osteoporosis, diabetes.

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

891

In conclusion, the bene®cial effects of in¯ammation, devoted to the neutralization of
dangerous/harmful agents early in life and in adulthood, turn to be detrimental late in
life, in a period largely not foreseen by evolution, according to the antagonistic pleiotropy
theory of aging (Franceschi et al., 2000c).
3.5. Metabolic remodeling
The concept of remodeling to understand aging and longevity can be extended to
complex pathways other than those involved in immune response, such as the insulin
pathway. As we previously mentioned, an ancestral insulin pathway, belonging to a
primitive NES, controls longevity and stress response capacity in C. elegans (Ailion et
al., 1999). We also previously pointed out that vertebrate NES is characterized by an
extreme integration with primitive stress response mechanisms, as shown by the relationship between catecholamine synthesis and HSP expression. However, it seems that insulin
pathway and utilization per se could be evolutionary-conserved to promote individual
survival. Improvement of peripheral insulin sensitivity is a key feature of CR, the most
robust and reproducible way to extend life span of animals. The bene®cial effects of CR
are also evident in worms, in which, as it occurs in rats, they confer an improved ability to
survive heat-stress. Strikingly, CR diminishes the progressive age-related decrease of
stress response and promotes a series of neuro-endocrine changes in rats and primates,
leading to an ef®cient glucose regulation, and improved insulin sensitivity. Indeed, CR
reshapes the gene expression of muscle cells from aged rats causing a reduction of
oxidative stress response and a redirection of the energetic metabolism toward anabolic
pathways (Lee et al., 1999). This ®nding recalls the evidence that peripheral insulin
resistance in humans may be caused by an imbalance between caloric intake and metabolic
capacity, and that longevity could be attained by those individuals who achieve the most
optimized situation, by appropriate life-style and/or by appropriate genetic background. In
other words, a poor or a preserved insulin action in the elderly might be the result of an
unsuccessful or successful metabolic age remodeling, respectively (Paolisso et al., 2000).
A support to this hypothesis comes from the ªin vivoº measurements of insulin action in
healthy centenarians. Aging is frequently associated with impaired glucose handling,
mainly due to a decline in insulin action because of receptor and post-receptor defects
with a main reduction in oxidative glucose metabolism. Age-related increase of insulin
resistance is responsible for a variety of intermediate phenotypes (altered lipoprotein
pro®les), which predispose to common causes of morbidity and mortality, such as coronary heart disease in non-diabetic and diabetic aged subjects. Healthy centenarians did not
suffer of coronary heart diseases and are characterized by an insulin-mediated glucose
uptake greater than that observed in aged subjects and not different from the one found in
adults. Moreover, they have a preserved effect of insulin on glucose and adipose tissue
metabolism, whilst aged subjects display impaired insulin-mediated lowering effect on
plasma free fatty acid and triglyceride concentrations (Paolisso et al., 1999). Hyperglycemia and insulin resistance in aged people causes progressively increasing oxidative
damage. On the contrary, in healthy centenarians indices of oxidative stress (lipid peroxides, oxidized/reduced gluthatione ratio) are lower than those found in aged subjects,
while plasma vitamin E concentration (an antioxidant) was higher than that found in

892

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

aged subjects (Paolisso et al., 1998). The lack of insulin resistance and of elevated oxidative stress in healthy centenarians can be taken as an example of a successful metabolic
remodeling, likely contributing to attain longevity in good health. Moreover, healthy
centenarians show anthropometric characteristics, which are considered to be protective
towards cardiovascular diseases and cancer. In fact, they have a free fat mass not different
from aged subjects but lower than adults, and a waist/hip ratio lower than that of aged
subjects but not different from that found in adults (Paolisso et al., 1995). Healthy centenarians have also a waist girth lower than that of aged subjects, and they did not show any
correlation between insulin resistance and waist girth as it was found in aged subjects
(Paolisso et al., 1997a). Plasma IGF-1/IGFBP-3 is more elevated in healthy centenarians
than in aged subjects, and is negatively correlated with body mass index, body fat content,
fasting plasma triglyceride, free fatty acid and low density lipoprotein cholesterol concentrations. In contrast, the same group of subjects display a positive correlation between
plasma IGF-1/IGFBP3 and insulin-mediated glucose uptake that persisted after adjustment for body fat, fasting plasma insulin concentration, daily carbohydrate intake and
daily physical activity. Finally, healthy centenarians eat less than aged subjects and have a
more favorable body fat content and distribution: they are characterized by a lower leptin
production and/or a better hypothalamic sensitivity than aged subjects. Both phenomena
might contribute to keep under control energy intake and to avoid a rise in body fat content
(Paolisso et al., 1997b). In conclusion, a complex metabolic remodeling, particularly
evident as far as the insulin pathway is concerned, is present in people who reach the
extreme limit of human life in good health. This ®nding suggests that the remodeling
theory of aging has a wide range of applicability beside the immune system, and it can
represent a general theoretical framework to understand the phenotype of aging and
longevity.
4. Conclusions
A great effort has been done in the last 12 years to conceptualize emerging unexpected
experimental data coming from different areas and resulting from different experimental
models (yeast, worms, mice, centenarians). Most of the conceptualizations offered with
age in this review derive from three types of studies. The ®rst concerns the changes
occurring in the immune system of humans, and in particular of centenarians. The second
regards the study of evolutionary aspects of the immune and the stress response from
invertebrates to vertebrates encompassing a large variety of species, taxa, and phila. The
third regards the metabolic remodeling of the insulin pathway in centenarians. In this
review we tried to reconstruct the history of this theoretical development and to stress
the fecundity of this approach for understanding aging and longevity, predicting new data,
and suggesting new approaches. In particular, according to the theories proposed here it
could be concluded that longevity largely coincides with successful remodeling, which in
turn does not rely on the excessive capacity to cope with stressors. Indeed, high responders
to stressors can fail to attain longevity despite having survival advantages on the short
term. Healthy centenarians, taken as an example of successful aging, are not necessarily
the more robust individuals at the beginning but rather those individuals capable to afford

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

893

intermediate response to stress, i.e. neither too weak nor too strong, in relation to the
environment. Therefore, frailty and robustness cannot be decided on early life but they can
cross each other during the whole life of individuals (Yashin et al., 1999). A consequence
of this approach is that the phenotype of centenarians, which is quite heterogeneous, is the
result not only of the starting genetic makeup but also of the remodeling process occurring
lifelong. These considerations may help to interpret the available data on the genetics of
longevity in humans, as well as the complex age related trajectories of polymorphisms in
candidate longevity genes (De Benedictis et al., 1998a; Yashin et al., 1999). Indeed, it is
probably not by chance that mitochondrial DNA haplogroups (De Benedictis et al., 1999)
and polymorphisms of tyrosine hydroxilase (De Benedictis et al., 1998b), both deeply
involved in the anti-aging network, emerged as candidate longevity genetic traits. It can be
anticipated that several immune parameters which appear to be good candidates for
predicting morbidity and mortality in humans (number of CD81 and CD41 T cells
and their ratio, rate of declining of naive T cells, absence of organ speci®c autoantibodies,
preserved NK activity, capability to mount an in¯ammatory response within optimal
range, among others) are quantitative traits under genetic control. It can also be predicted
that the capacity to remodel is under genetic control although the possibility to govern this
fundamental process by environmental interventions is quite plausible and feasible.
Finally, concepts such as remodeling, immunological space, evolutionary-based immunosenescence, are amenable to strong theoretical approach and can be further developed
by mathematical models and in machina experiments on the immune system (Valensin and
Di Caro, 2000).
Acknowledgements
These studies have been supported by grants to C. Franceschi from E.U. ªGenageº;
MURST 1998 ªDeterminants of human longevity; the model of centenariansº; MURST
1999 ªA multidisciplinary approach to the regulation of the immune systemº; Ministry of
Health project ªThe prevention of chronic age-related diseases; the model of centenariansº.
References
Ailion, M., Inoue, T., Weaver, C.I., Holdcraft, R.W., Thomas, J.H., 1999. Neurosecretory control of aging in
Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 96, 7394±7397.
Aspinall, R., 1999. Does the immune system of a mouse age faster than the immune system of a human?
Bioessays 21, 519±524.
Babar, P., Adamson, C., Walker, G.A., Walker, D.W., Lithgow, G.J., 1999. P13-kinase inhibition induces dauer
formation, thermotolerance and longevity in C. elegans. Neurobiol. Aging 20, 513±519.
Baggio, G., Donazzan, S., Monti, D., Mari, D., Martini, S., Gabelli, C., Dalla Vestra, M., Previato, L., Guido, M.,
Pigozzo, S., Cortella, I., Crepaldi, G., Franceschi, C., 1998. Lipoprotein(a) and lipoprotein pro®les in healthy
centenarians: a reappraisal of vascular risk factors. FASEB J. 12, 433±437.
Bagnara, G.P., Bonsi, L., Strippoli, P., Bonifazi, F., Tonelli, R., D'addato, S., Paganelli, R., Scala, E., Fagiolo, U.,
Â
Monti, D., Cossarizza, A., Bonafe, M., Franceschi, C., 2000. Hemopoiesis in healthy old people and centenarians: well maintained responsiveness of CD341 cells to hemopoietic growth factors and remodeling of
cytokine network. J. Gerontol. A: Biol. Sci. Med. Sci. 55, B61±B66.

894

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

Bellavia, D., Frada, G., Di Franco, P., Feo, S., Franceschi, C., Sansoni, P., Brai, M., 1999. C4, BF, C3 allele
distribution and complement activity in healthy aged people and centenarians. J. Gerontol. A: Biol. Sci. Med.
Sci. 54, B150±B153.
Blake, M.J., Klevay, L.M., Halas, E.S., Bode, A.M., 1995. Blood pressure and heat shock protein expression in
response to acute and chronic stress. Hypertension 25, 539±544.
Blake, M.J., Udelsman, R., Feulner, G.J., Norton, D.D., Holbrook, N.J., 1991. Stress-induced heat shock protein
70 expression in adrenal cortex: an adrenocorticotropic hormone-sensitive, age-dependent response. Proc.
Natl. Acad. Sci. USA 88, 9873±9877.
Castellani, S., Ungar, A., Cantini, C., La Cava, G., Di Serio, C., Vallotti, B., Altobelli, A., Masotti, G., 1999.
Impaired renal adaptation to stress in the elderly with isolated systolic hypertension. Hypertension 34, 1106±
1111.
Castellani, S., Ungar, A., Cantini, C., La Cava, G., Di Serio, C., Altobelli, A., Vallotti, B., Pellegri, M., Brocchi,
A., Camaiti, A., Coppo, M., Meldolesi, U., Messeri, G., Masotti, G., 1998. Excessive vasoconstriction after
stress by the aging kidney: inadequate prostaglandin modulation of increased endothelin activity. J. Lab. Clin.
Med. 132, 186±194.
Cossarizza, A., Ortolani, C., Paganelli, R., Barbieri, D., Monti, D., Sansoni, P., Fagiolo, U., Castellani, G.,
Bersani, F., Londei, M., Franceschi, C., 1996. CD45 isoforms expression on CD41 and CD81 T cells
throughout life, from newborns to healthy centenarians: implications for T cell memory. Mech. Ageing
Dev. 86, 173±195.
Á
De Benedictis, G., Carotenuto, L., Carrieri, G., De Luca, M., Falcone, E., Rose, G., Yashin, A.I., Bonafe, M.,
Franceschi, C., 1998a. Age-related changes of the 3'APOB VNTR genotype pool in ageing cohorts. Ann.
Hum. Genet. 62, 115±122.
De Benedictis, G., Carotenuto, L., Carrieri, G., De Luca, M., Falcone, E., Rose, G., Cavalcanti, S., Corsonello, F.,
Á
Feraco, E., Baggio, G., Bertolini, S., Mari, D., Mattace, R., Yashin, A.I., Bonafe, M., Franceschi, C., 1998b.
Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). Eur. J. Hum. Genet. 6,
534±541.
De Benedictis, G., Rose, G., Carrieri, G., De Luca, M., Falcone, E., Passarino, G., Bonafe, M., Monti, D., Baggio,
G., Bertolini, S., Mari, D., Mattace, R., Franceschi, C., 1999. Mitochondrial DNA inherited variants are
associated with successful aging and longevity in humans. FASEB J. 13, 1532±1536.
Doria, G., Frasca, D., 1997. Genes, immunity, and senescence: looking for a link. Immunol. Rev. 160, 159±170.
Ernst, B., Lee, D.S., Chang, J.M., Sprent, J., Surh, C.D., 1999. The peptide ligands mediating positive selection in
the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173±181.
Fagiolo, U., Cossarizza, A., Scala, E., Fanales-Belasio, E., Ortolani, C., Cozzi, E., Monti, D., Franceschi, C.,
Paganelli, R., 1993. Increased cytokine production in mononuclear cells of healthy elderly people. Eur. J.
Immunol. 23, 2375±2378.
Fagnoni, F.F., Vescovini, R., Passeri, G., Bologna, G., Pedrazzoni, M., Lavagetto, G., Casti, A., Franceschi, C.,
Passeri, M., Sansoni, P., 2000. Shortage of circulating naive CD8(1) T cells provides new insights on
immunode®ciency in aging. Blood 95, 2860±2868.
Fagnoni, F.F., Vescovini, R., Mazzola, M., Bologna, G., Nigro, E., Lavagetto, G., Franceschi, C., Passeri, M.,
Sansoni, P., 1996. Expansion of cytotoxic CD81CD282 T cells in healthy aged people and centenarians.
Immunology 88, 501±507.
Franceschi, C., 1989. Cell proliferation and cell death in the aging process. Aging Clin. Exp. Res. 1, 3±13.
Franceschi, C., Monti, D., Sansoni, P., Cossarizza, A., 1995. The immunology of exceptional individuals: the
lesson of centenarians. Immunol. Today 16, 12±16.
Franceschi, C., Cossarizza, A., 1995. The reshaping of the immune system with age. Int. Rev. Immunol. 12, 1±4.
Franceschi, C., Motta, L., Valensin, S., et al., 2000a. Do men and women follow different trajectories to reach
extreme longevity? Aging Clin. Exp. Res. 12, 77±84.
Á
Franceschi, C., Bonafe, M., Valensin, S., 2000b. Human immunosenescence: the prevailing of innate immunity,
the failing of clonotypic immunity, and the ®lling of immunological space. Vaccine 18, 1717±1720.
Â
Franceschi, C., Bonafe, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E., De Benedictis, G., 2000c.
In¯amm-aging. An evolutionary perspective on immunosenescence. Ann. N.Y. Acad. Sci. 908, 244±254.
Á
Franceschi, C., Valensin, S., Fagnoni, F., Barbi, C., Bonafe, M., 1999. Biomarkers of immunosenescence: the
challenge of heterogeneity and the role of antigenic load. Exp. Gerontol. 34, 911±921.

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

895

George, A.J., Ritter, M.A., 1996. Thymic involution with ageing: obsolescence or good housekeeping? Immunol.
Today 17, 267±272.
Hamet, P., Sun, Y.L., Malo, D., Kong, D., Kren, V., Pravenec, M., Kunes, J., Dumas, P., Richard, L., Gagnon, F.,
1994. Genes of stress in experimental hypertension. Clin. Exp. Pharmacol. Physiol. 11, 907±911.
Jaattela, M., 1999. Escaping cell death: survival proteins in cancer. Exp. Cell. Res. 248, 30±43.
Jazwinski, S.M., 1999. The RAS genes: a homeostatic device in Saccharomyces cerevisiae longevity. Neurobiol.
Aging 20, 471±478.
Kawano, T., Ito, Y., Ishiguro, M., Takuwa, K., Nakajima, T., Kimura, Y., 2000. Molecular cloning and characterization of a new insulin/IGF-like peptide of the nematode Caenorhabditis elegans. Biochem. Biophys.
Res. Commun. 273, 431±436.
Kieper, W.C., Jameson, S.C., 1999. Homeostatic expansion and phenotypic conversion of naive T cells in
response to self peptide/MHC ligands. Proc. Natl. Acad. Sci. USA 96, 13 306±13 311.
Kirkwood, T.B.L., Franceschi, C., 1992. Is ageing as complex as it would appear? New perspectives in gerontological research. Ann. N.Y. Acad. Sci. 663, 412±417.
Kirkwood, T.B., Holliday, R., 1979. The evolution of ageing and longevity. Proc. R. Soc. Lond. B: Biol. Sci. 205,
531±546.
Kirkwood, T.B., 1977. Evolution of ageing. Nature 270, 301±304.
Kowald, A., Kirkwood, T.B, 1994. Towards a network theory of ageing: a model combining the free radical
theory and the protein error theory. J. Theor. Biol. 168, 75±94.
Kowald, A., Kirkwood, T.B, 1996. A network theory of ageing: the interactions of defective mitochondria,
aberrant proteins, free radicals and scavengers in the ageing process. Mutat. Res. 316, 209±236.
Ku, C.C., Kotzin, B., Kappler, J., Marrack, P., 1997. CD81 T-cell clones in old mice. Immunol. Rev. 160, 139±
144.
Lee, C.K., Klopp, R.G., Weindruch, R., Prolla, T.A., 1999. Gene expression pro®le of aging and its retardation by
caloric restriction. Science 285, 1390±1393.
Ligthart, G.J., Corberand, J.X., Fournier, C., Galanaud, P., Hijmans, W., Kennes, B., Muller-Hermelink, H.K.,
Steinmann, G.G., 1984. Admission criteria for immunogerontological studies in man: the SENIEUR protocol.
Mech. Ageing Dev. 28, 47±55.
Lung, T.L., Saurwein-Teissl, M., Parson, W., Schonitzer, D., Grubeck-Loebenstein, B., 2000. Unimpaired
dendritic cells can be derived from monocytes in old age and can mobilize residual function in senescent
T cells. Vaccine 18, 1606±1612.
Mariotti, S., Sansoni, P., Barbesino, G., Caturegli, P., Monti, D., Cossarizza, A., Giacomelli, T., Passeri, G.,
Fagiolo, U., Pinchera, A., Franceschi, C., 1992. Thyroid and other organ-speci®c autoantibodies in healthy
centenarians. Lancet 339, 1506±1508.
Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Reboldi, P., Pandol®, P.P., Lanfrancone, L., Pelicci, P.G., 1999.
The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309±
313.
Murali-Krishna, K., Lau, L.L., Sambhara, S., Lemonnier, F., Altman, J., Ahmed, R., 1999. Persistence of memory
CD8 T cells in MHC class I-de®cient mice. Science 286, 1377±1381.
Ottaviani, E., Franceschi, C., 1996. The neuroimmunology of stress from invertebrates to man. Progr. Neurobiol.
48, 421±440.
Ottaviani, E., Franceschi, C., 1997. The invertebrate phagocytic immunocyte: clues to a common evolution of
immune and neuroendocrine system. Immunol. Today 18, 169±174.
Ottaviani, E., Franchini, A., Franceschi, C., 1997. Pro-opiomelanocortin-derived peptides, cytokines, and nitric
oxide in immune responses and stress: an evolutionary perspective. Int. Rev. Cytol. 170, 79±141.
Ottaviani, E., Valensin, S., Franceschi, C., 1998. The neuro-immunological interface in an evolutionary perspective: the dynamic relationship between effector and recognition systems. Front. Biosci. 16, D431±D435.
Paganelli, R., Quinti, I., Fagiolo, U., Cossarizza, A., Ortolani, C., Guerra, E., Sansoni, P., Pucillo, L.P., Cozzi, E.,
Bertollo, L., Monti, D., Franceschi, C., 1992. Changes in circulating B cells and immunoglobulin classes and
subclasses in a healthy aged population. Clin. Exp. Immunol. 90, 351±354.
Paolisso, G., Tagliamonte, M.R., Rizzo, M.R., Giugliano, D., 1999. Advancing age and insulin resistance: new
facts about an ancient history. Eur. J. Clin. Invest. 29, 758±769.
Paolisso, G., Gambardella, A., Ammendola, S., Tagliamonte, M.R., Rizzo, M.R., Capurso, A., Varricchio, M.,

896

C. Franceschi et al. / Experimental Gerontology 35 (2000) 879±896

1997a. Preserved antilipolytic insulin action is associated with a less atherogenic plasma lipid pro®le in
healthy centenarians. J. Am. Geriatr. Soc. 45, 1504±1509.
Paolisso, G., Ammendola, S., Del Buono, A., Gambardella, A., Riondino, M., Tagliamonte, M.R., Rizzo, M.R.,
Carella, C., Varricchio, M., 1997b. Serum levels of insulin like growth factor-1 (IGF-1) and IGF-binding
protein 3 in healthy centenarians: relationship with plasma leptin and lipid concentration, insulin action and
cognitive function. J. Clin. Endocrinol. Metab. 82, 2204±2209.
Paolisso, G., Gambardella, A., Balbi, V., D'amore, A., Varricchio, M., 1995. Body composition, body fat
distribution and resting metabolic rate in healthy centenarians. Am. J. Clin. Nutr. 50, 746±750.
Paolisso, G., Tagliamonte, M.R., Rizzo, M.R., Manzella, D., Gambardella, A., Varricchio, M., 1998. Oxidative
stress and advancing age: results in healthy centenarians. J. Am. Geriat. Soc. 46, 833±838.
Á
Paolisso, G., Barbieri, M., Bonafe, M., Franceschi, C., 2000. Metabolic age remodeling: the lesson from centenarians. Eur. J. Clin. Inv. (in press).
Sansoni, P., Cossarizza, A., Brianti, V., Fagnoni, F., Snelli, G., Monti, D., Marcato, A., Passeri, G., Ortolani, C.,
Forti, E., Fagiolo, U., Passeri, M., Franceschi, C., 1993. Lymphocyte subsets and natural killer cell activity in
healthy old people and centenarians. Blood 80, 2767±2773.
Sansoni, P., Fagnoni, F., Vescovini, R., Mazzola, M., Brianti, V., Bologna, G., Nigro, E., Lavagetto, G., Cossarizza, A., Monti, D., Franceschi, C., Passeri, M., 1997. T lymphocyte proliferative capability to de®ned stimuli
and costimulatory CD28 pathway is not impaired in healthy centenarians. Mech. Aging Dev. 96, 127±136.
Schwab, R., Szabo, P., Manavalan, J.S., Weksler, M.E., Posnett, D.N., Pannetier, C., Kourilsky, P., Even, J., 1997.
Expanded CD41 and CD81 T cell clones in elderly humans. J. Immunol. 158, 4493±4499.
Shama, S., Lai, C.Y., Antoniazzi, J.M., Jiang, J.C., Jazwinski, S.M., 1998b. Heat stress-induced life span extension in yeast. Exp. Cell. Res. 245, 379±388.
Shama, S., Kirchman, P.A., Jiang, J.C., Jazwinski, S.M., 1998a. Role of RAS2 in recovery from chronic stress:
effect on yeast life span. Exp. Cell. Res. 245, 368±378.
Swain, S.L., Hu, H., Huston, G., 1999. Class II-independent generation of CD4 memory T cells from effectors.
Science 286, 1381±1383.
Tanchot, C., Rocha, B., 1998. The organization of mature T-cell pools. Immunol. Today 19, 575±579.
Udelsman, R., Blake, M.J., Stagg, C.A., Holbrook, N.J., 1994. Endocrine control of stress-induced heat shock
protein 70 expression in vivo. Surgery 115, 611±616.
Udelsman, R., Blake, M.J., Stagg, C.A., Li, D.G., Putney, D.J., Holbrook, N.J., 1993. Vascular heat shock protein
expression in response to stress. Endocrine and autonomic regulation of this age-dependent response. J. Clin.
Invest. 91, 465±473.
Valensin, S., Di Caro, G., 2000. A theoretical model for ªin machimnaº experiments on immunosenescence. Ann.
N.Y. Acad. Sci. 908, 344±348.
Wack, A., Cossarizza, A., Heltai, S., Barbieri, D., D'addato, S., Franceschi, C., Dellabona, P., Casorati, G., 1998.
Age-related modi®cations of the human alfa beta T cell repertoire as a consequence of clonal expansions. Int.
Immunol. 10, 1281±1288.
Yang, Y.L., Lin, M.T., 1999. Heat shock protein expression protects against cerebral ischemia and monoamine
overload in rat heatstroke. Am. J. Physiol. 276, H1961±H1967.
Á
Yashin, A.I., De Benedictis, G., Vaupel, J.W., Tan, Q., Andreev, K.F., Iachine, I.A., Carotenuto, L., Bonafe, M.,
Valensin, S., Franceschi, C., 1999. Genes, demography and life span: the contribution of demographic data in
genetic studies of aging and longevity. Am. J. Hum. Genet. 65, 1178±1193.
Zinkernagel, R.M., Ehl, S., Aichele, P., Oehen, S., Kundig, T., Hengartner, H., 1997. Antigen localisation
regulates immune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity. Immunol. Rev. 156, 199±209.