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The network and the remodeling theories of aging: historical background and new perspectives
Abstract
Two general theories, i.e. "the network theory of aging" (1989) and "the remodeling theory of aging" (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 fits 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 inflammation) and its recent development (the concepts of "immunological space" and "inflamm-aging"); (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.
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“As in children and adolescents, TIS is also believed to be a major driving force of frailty and other AEs in adults owing to its detrimental effect on tissue function via chronic inflammation, similar to 'inflammaging' , which is a chronic mild inflammatory process that develops with age 198,200,201 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [201]
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“In the latter example, the overall maintenance of T-cell number often masks the fact that the population is changing from one characterized by large numbers of relatively small T-cell clones, to one that contains fewer but larger clones (Franceschi et al., 2000).”
BackgroundSelf-citationGENETIC DETERMINANTS INFLUENCING THE RESPONSE TO INJURY, INFLAMMATION, AND SEPSIS
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“Biogerontological studies, however, have repeatedly shown that numerous ageinduced changes in the immune system, hormone levels and other proteins and enzymes are the sign of constant remodeling and adaptation for survival and health [68].”
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“The reasons for such a gradient are at present unknown, and differences related to differential mortality in women and men, as well as those related to social, genetic and anthropological factors, may play a role (Franceschi et al., 2000b).”
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Self-citationNF-κB Signaling in the Aging Process
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“This process is called inflamm-aging (see below) [3, 10].”
BackgroundHigh TNF-α levels in resting B cells negatively correlate with their response
Frasca, D., Diaz, A., Romero, M., Landin, A. M., & Blomberg, B. B. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.01.004 · Cited by 115
“Enhanced IL-6 (Bryl et al., 2001; Frasca et al., 2013) and TNF-α (Franceschi et al., 2000b) plasma levels have been associated with functional disability and mortality of the elderly.”
InfluentialSalminen, A., Kauppinen, A., & Kaarniranta, K. (2019) · Journal of Molecular Medicine · doi:10.1007/s00109-019-01795-9 · Cited by 122
The aging gut microbiota: New perspectives
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Self-citationControl of p53 and NF-κB signaling by WIP1 and MIF: Role in cellular senescence and organismal aging
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Aging, Functional Capacity and Eccentric Exercise Training
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“The age-related decline in the functions of immune cells involves both adaptive immunity, such as T and B cells, and innate immunity including macrophages as well as dendritic and natural killer (NK) cells [1, 2].”
Backgroundp53 and the Carcinogenicity of Chronic InflammationPreprint
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“Although acute inflammation serves to protect and promote regeneration of at-risk tissue, chronic inflammation is typically associated with tissue degeneration (Franceschi et al. 2000b; Franceschi and Campisi 2014).”
BackgroundFrom lifetime to evolution: timescales of human gut microbiota adaptation
Quercia, S., Candela, M., Giuliani, C., Turroni, S., Luiselli, D., Rampelli, S., Brigidi, P., Franceschi, C., Bacalini, M. G., Garagnani, P., et al. (2014) · Frontiers in Microbiology · doi:10.3389/fmicb.2014.00587 · Cited by 131
Self-citationB cells and immunosenescence: A focus on IgG+IgD−CD27− (DN) B cells in aged humans
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“These systems, they contended, work together to protect the cell from aging [13].”
BackgroundMethodA Molecular Mechanism for TNF-α–Mediated Downregulation of B Cell Responses
Frasca, D., Romero, M., Diaz, A., Alter-Wolf, S., Ratliff, M., Landin, A. M., Riley, R. L., & Blomberg, B. B. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003964 · Cited by 98
“Aging is characterized by a dysregulation of inflammatory and anti-inflammatory networks, which results in a low-grade chronic proinflammatory status called inflammaging (9).”
BackgroundThe role of myeloid-derived suppressor cells (MDSC) in the inflammaging process
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Inflammaging, hormesis and the rationale for anti-aging strategies
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Self-citationNaudé, P., Eisel, U. L. M., Comijs, H. C., Groenewold, N. A., Deyn, P. P. D., Bosker, F. J., Luiten, P. G. M., den Boer, J. A., & Voshaar, R. C. O. (2013) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2013.08.023 · Cited by 99
“The positive association between plasma NGAL levels and age is in accordance to the notion of “inflammaging” [33,34] whereby an increased low graded inflammatory response is associated with the normal aging process.”
BackgroundB cell immunosenescence: different features of naive and memory B cells in elderly
Buffa, S., Bulati, M., Pellicanò, M., Dunn‐Walters, D. K., Wu, Y.-C. B., Candore, G., Vitello, S., Caruso, C., & Colonna‐Romano, G. (2011) · Biogerontology · doi:10.1007/s10522-011-9353-4 · Cited by 104
Microbiomes other than the gut: inflammaging and age-related diseases
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Self-citationRecent advances in human gene–longevity association studies
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Self-citationGenetics of human longevity within an eco-evolutionary nature-nurture framework
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Inflammation and aging-related disease: A transdisciplinary inflammaging framework
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“Indeed, two older individuals of equal chronologic age will have had distinct acute and chronic exposures, live in different environments, and possess differential genetic susceptibilities that influence inflammation [2, 3, 15, 205].”
Context-Dependent Regulation of Autophagy by IKK-NF-κB Signaling: Impact on the Aging Process
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“During the last decade, mounting evidence has revealed that there is a clear imbalance between adaptive and innate immunity in mammals during the aging process [126, 127].”
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Self-citationImmunoproteasomes and immunosenescence
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Self-citationLifelong aerobic exercise protects against inflammaging and cancer
Nilsson, M. I., Bourgeois, J. M., Nederveen, J. P., Leite, M. R., Hettinga, B. P., Bujak, A. L., May, L. L., Lin, E., Crozier, M., Rusiecki, D. R., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0210863 · Cited by 98
Franceschi, C., Valensin, S., Lescai, F., Olivieri, F., Licastro, F., Grimaldi, L. M. E., Monti, D., BENEDICTIS, G. D., & Bonafè, M. (2001) · Aging Clinical and Experimental Research · doi:10.1007/bf03351475 · Cited by 87
Self-citationMyeloid-derived suppressor cells (MDSC): an important partner in cellular/tissue senescence
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“The levels of beta-amyloid, tau and phospho-tau were determined in the CSF using the following kits: Innotest® β-Amyloid(1-42); Innotest® phospho-tau (181P) e Innotest®htauAg from Innogenetics (Gent, Belgium).”
MethodApplying hormesis in aging research and therapy
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Glucose regulation and oxidative stress in healthy centenarians
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Self-citationBiogerontology: from here to where? The Lord Cohen Medal Lecture-2011
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“…space and the failure of maintenance and repair pathways (Rattan 2006). characteristics: (1) stress response (Singh et al. 2007); (2) the ability for damage prevention, repair and removal (Holliday 2006); and (3) the ability for continuous remodeling and adaptation (Franceschi et al. 2000).”
Is human immunosenescence clinically relevant? Looking for 'immunological risk phenotypes'.
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“Immunosenescence is associated with a low grade chronic pro-inflammatory status called inflammaging [27].”
BackgroundImpact of aging on immunity in the context of COVID-19, HIV, and tuberculosis
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Complexity of Anti‐immunosenescence Strategies in Humans
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Self-citationGenes, ageing and longevity in humans: Problems, advantages and perspectives
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“[234] Franceschi C, Valensin S, Bonafe M, Paolisso G, Yashin AI, Monti D, De Benedictis G.”
Self-citationChanges with ageing in several leukocyte functions of male and female rats
la Fuente, M. D., Baeza, I., Guayerbas, N., Puerto, M., Castillo, C., Salazar, V., Ariznavarreta, C., & F-Tresguerres, J. A. (2004) · Biogerontology (Dordrecht) · doi:10.1007/s10522-004-3201-8 · Cited by 76
“In fact, it is known that centenarians have a well-preserved immune function, and the reason for it is that they are well adapted to external and internal aggressor agents, in particular to those who act on the immune system (Franceschi et al. 2000).”
Abedin, S. M., Michel, J. J., Lemster, B. H., & Vallejo, A. N. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2005.04.012 · Cited by 70
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“A large body of research has demonstrated that the aging process is associated with the pro-inflammatory changes (e.g. Franceschi et al., 2000, 2007; Sarkar and Fisher, 2006; Salminen et al., 2008a; De Magalhaes et al., 2009).”
BackgroundBone structure and metabolism in a rodent model of male senile osteoporosis
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“Lessons come from the field of genetics of age-related diseases, where it has been theorized and demonstrated that the association of a genetic variant with a disease can vary during the life of an individual and according to the environmental conditions that he/she encountered, strictly depending from the birth cohor…”
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Proliferation and apoptosis of human CD8+CD28+ and CD8+CD28− lymphocytes during aging
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MicroRNAs miR-155 and miR-16 decrease AID and E47 in B cells from elderly individuals
Frasca, D., Diaz, A., Romero, M., Ferracci, F., & Blomberg, B. B. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500520 · Cited by 69
“A low-level chronic inflammatory state is common in the elderly (13, 26), and we have shown that the inflammatory status of the individual and of the B cells themselves negatively affects B cell function (27).”
BackgroundSalminen, A. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101280 · Cited by 77
Bonafè, M., Marchegiani, F., Cardelli, M., Olivieri, F., Cavallone, L., Giovagnetti, S., Pieri, C., Marra, M., Antonicelli, R., Troiano, L., et al. (2002) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5200806 · Cited by 69
Self-citationAdipose Tissue Inflammation Induces B Cell Inflammation and Decreases B Cell Function in Aging
Frasca, D., & Blomberg, B. B. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01003 · Cited by 66
Healthy ageing, but what is health?
Rattan, S. I. S. (2013) · Biogerontology · doi:10.1007/s10522-013-9442-7 · Cited by 66
Metadata
- Authors
- Franceschi, C., Valensin, S., Bonafè, M., Paolisso, G., Yashin, A. I., Monti, D., & De Benedictis, G.
- Affiliations
- Istituto Nazionale di Riposo e Cura per Anziani (IT)
- University of Bologna (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Max Planck Institute for Demographic Research (DE)
- University of Florence (IT)
- Corresponding author
- Franceschi, C
- Venue
- Experimental Gerontology
- Publisher
- Elsevier BV
- Published
- 2000-09
- Volume
- 35
- Issue
- 6-7
- Pages
- 879-896
- ISSN
- 0531-5565 (ISSN-L)
- OpenAlex
- W1984265860
- Cited by
- 335
- References
- 0
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 10 · 2023: 12 · 2022: 10 · 2021: 17 · 2020: 14 · 2019: 15 · 2018: 17 · 2017: 23 · 2016: 16 · 2015: 16 · 2014: 15 · 2013: 16 · 2012: 16
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Gerontology (publishedVersion)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Social Sciences › Psychology › Developmental and Educational Psychology › Aging and Gerontology Research
- Keywords
- aging, longevity, centenarians, inflammaging, stress response, inflammation, stress tolerance, unicellular organisms, yeast, Caenorhabditis elegans, mice, human
- MeSH terms
- Aging, Animals, Biological Evolution, Heat-Shock Proteins, Humans, Immune System, Inflammation, Saccharomyces cerevisiae, Mice
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