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Honoris Causa Lecture, Claudio Franceschi (University of Bologna, Italy), Aging beyond chronological age
12 March 2018 | 15 h 30 min - 19 h 30 min
University of Bologna and Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy
Honoris Causa Conference
Université de Bordeaux
Domaine du Haut-Carré – Talence
Salle BadianeAGING BEYOND CHRONOLOGICAL AGE:
from Immunosenescence and Inflammaging to Immunobiography
Aging is the major risk factor for chronic age-related diseases (CARDs) and geriatric syndromes (GSs) such as frailty, and a large panoply of experimental data show that both share a common set of few basic mechanistic pillars which largely converge on inflammation, i.e. a basic phenomenon crucial for survival that can turn detrimental later, in the post-reproductive period of life. A variety of stimuli fuels inflammation, and they are sensed by a limited set of evolutionary-selected receptors whose degeneracy allows them to recognize a large variety of signals and to activate the innate immune system. These stimuli include bacterial and viral pathogens and their products (non-self), cell debris generated by dead cells and misplaced/altered molecules (self), and nutrients and gut microbiota products (quasi-self). As such stimuli occur lifelong and increase with age, eventually a chronic, sterile, low-grade inflammation dubbed “inflammaging” develops. Aging and inflammaging are accompanied by a variety of changes that occur in the immune system and a decline in many immune parameters, collectively termed “immunosenescence”. Together, immunosenescence and inflammaging are suggested to stand at the origin of most of CARDs and GSs. If the same molecular and cellular mechanisms, including immunosenescence and inflammaging, underpin both aging and CARDs/GSs, a major question emerges: which is the difference, if any, between aging and CARDs/GSs? I will propose the hypothesis that CARDs and GSs can be conceptualized as accelerated aging. According to this integrated view, aging and CARDs/GSs become part of a continuum where precise boundaries do not exist, and the two extremes are represented by centenarians, who largely avoided or postponed most CARDs/GSs and are characterized by decelerated aging, and patients who suffered one or more severe CARDs in their sixties, seventies and eighties and show signs of accelerated aging, respectively. In between these two extremes there is a continuum of intermediate trajectories representing a sort of grey area. Why there is such large phenotypic heterogeneity regarding the health status of the elderly and of the oldest old ? Whether an individual will follow a trajectory of accelerated or decelerated aging will depend on his/her genetic background interacting lifelong with environmental and lifestyle factors. To this regard I will propose that a key to understand such heterogeneity and these different health trajectories is the individual “immunobiography”, i.e. the unique combination of type, dose, intensity, and temporal sequence of antigenic/inflammatory stimuli that each subject has been exposed to lifelong, starting in utero. Owing to their memory and plasticity the innate and adaptive immune systems of each individual are capable of recording and adapting to all the immunological experiences encountered lifelong. Accordingly, I will illustrate the concept of “liquid immune self” and I will challenge the tenet that immunosenescence and inflammaging are basically only negative phenomena. From an evolutionary perspective I will argue that they can be viewed preferably as adaptive or example of remodeling rather than solely detrimental, and may be needed for extended survival/longevity.
In conclusion: i) if CARDs and GSs are manifestations of accelerated aging, it is urgent to identify markers capable of distinguishing between biological/inflammatory and chronological age in order to identify subjects at higher risk of developing CARDs and GSs. To this aim I will propose the use of DNA methylation, N-glycans profiling and gut microbiota composition to complement the available disease-specific markers; ii) the primary target of Medicine is to combat aging instead of any single CARD/GSs one by one, as favored by the present fragmentation into hundreds of specialties and sub-specialties; iii) I caution biogerontologists about all attempts to intervene on the aging immune system by targeting its rejuvenation.
- Contact: Jean-François Moreau