Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans

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Abstract

A large part of the aging phenotype, including immunosenescence, is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status we proposed to call inflammaging. Within this perspective, healthy aging and longevity are likely the result not only of a lower propensity to mount inflammatory responses but also of efficient anti-inflammatory networks, which in normal aging fail to fully neutralize the inflammatory processes consequent to the lifelong antigenic burden and exposure to damaging agents. Such a global imbalance can be a major driving force for frailty and common age-related pathologies, and should be addressed and studied within an evolutionary-based systems biology perspective. Evidence in favor of this conceptualization largely derives from studies in humans. We thus propose that inflammaging can be flanked by anti-inflammaging as major determinants not only of immunosenescence but eventually of global aging and longevity.

Section snippets

Aging is an adaptative process (remodelling) performed by an integrated panel of evolutionary selected mechanisms

Damaging agents are produced by the organism as a consequence of normal (inescapable) metabolic processes (e.g. reactive oxygen species, ROS, from oxidative metabolism) or derive from the exposure (also inescapable) to a variety of physical (e.g. UV rays from sun exposure) or biological (viruses, bacteria, parasites) agents. Collectively they represent the environment, and a clear distinction between internal and external environment is very difficult if not impossible. The body is equipped

Advantages and success of model systems: the crucial importance of the reductionist approach

Usually the above mentioned mechanisms thought to play a role in aging and longevity are considered separately, and a variety of approaches and model systems have been set up in order to assess the role played by each of them in the aging process. This is the case for example of DNA repair mechanisms, and indeed interesting results have emerged (Hasty et al., 2003). This approach has been followed in all fields of biology, and the molecular biology and genetics of aging is full of this kind of

Studies on human aging and longevity: the Cinderella of biogerontology

In this review, we will argue that the approach which exploit model systems and allows exciting, “mechanistic” experiments of molecular biology and molecular genetics, although still fundamental, must be enriched and accompanied by and extended to more systemic approaches. In particular, we will argue that much more space and credit should be given to studies on humans.

Research on aging and longevity has been dominated by studies performed in model systems, such as yeast, worms and flies, and

Human development and lifespan are quite long: events occurring in utero and developmental-related constraints can impact on aging and longevity

Human development and lifespan are much longer than that of most experimental animals used to study aging and longevity, and this characteristic has profound and pervasive effects on a variety of biological aspects critical for the aging process. Some of them can be summarized as follows:

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    the 9 months in utero developmental period is quite long and is several times longer that the entire lifespan of some model animals. Moreover, the placental type of reproduction typical of mammals implies a

Human mitochondrial DNA and its variants: a quite specific evolutionary history

An example of human studies which identified genetic markers impinging upon survival and extreme longevity and which do not have an animal model counterpart, is represented by mitochondrial DNA variants, either inherited or somatically acquired, and their interaction with nuclear gene variants. Although the first experiments considering the coevolution of mitochondrial and nuclear genomes were reported more than 30 years ago (Clayton et al., 1971), and recent evidence suggests that natural

Centenarians as a model to study the determinants of aging and longevity in humans

Studies performed on centenarians compared to old subjects (usually about 60 years, when mortality goes up dramatically, in order to avoid cohort effects) have evidenced that centenarians escaped the major age-related diseases, and a minority of them is still in quite good health (categorized as “group A” by Franceschi et al., 2000a, “escapers” by Evert et al., 2003, and “exceptionals” by Gondo et al., 2006). According to the perspective, we put forward, centenarians were not the most robust

The phenotypic heterogeneity of centenarians and the problems of the reproducibility of genetic studies in different populations

Studies on centenarians performed in different European Countries led also to discover another feature of centenarians, that is their extreme heterogeneity and geographic variability regarding, for example, physical performances, such as hand grip (Jeune et al., 2006). Also genetic studies on centenarians gave unexpected results that led us to speak about an “unusual genetics” of longevity (De Benedictis and Franceschi, 2006), whose features can be briefly summarized as follows:

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    a strong

The human environment is not “clean”: inflammaging is a systemic key event to understand aging and longevity

Apart from difference in their genomes, a major difference between humans and animals used in laboratory experiments to study aging and longevity is the quantity and quality of antigenic exposure. Typical lab organisms are usually housed in “artificially clean” environments and thus underexposed to pathogens, or even completely protected from them, except for limited period of time (acute infections) that can be required for experimental reasons. These animals are quite different from those

In centenarians inflammaging is always accompanied by anti-inflammaging and their balance is likely crucial to attain healthy aging and longevity

How can we reconcile the fact that low grade chronic inflammation is considered a reliable marker of high risk morbility and mortality and still it is present in long-living people (centenarians) who largely escaped from major age-related diseases having a strong inflammatory pathogenetic component? In fact in centenarians we found a complex and peculiar mix of pro- as well as anti-inflammatory characteristics, either phenotipically or genetically, which can be summarized as following

Inflammaging, change of microenvironment and stem cell function

A potentially important consequence of the age-related impairment of the balancing depicted in Fig. 2 between inflammatory and anti-inflammatory agents is a profound, systemic modification of cellular microenvironment(s), likely different in different organs and niches, which in turn can affect stem cells’ biology (migration, localization and activity). All the morpho-physiological changes that characterize the bodies of old people result from the remodelling of organs and tissues, aimed at

Conclusion: our understanding of the role inflammation and anti-inflammation in aging and longevity is inadequate, and we need a comprehensive, sistemic approach

The data we have reviewed, although impressive, are quite incomplete. Indeed, a series of molecules, such as annexin 1, galectins, ACTH and melanocortins, adenosine, prostanoids, lipoxin A4, heparin, nitric oxide, among others, are known to have potent anti-inflammatory effects, being capable to modulate and eventually turn off the inflammatory process (Perretti and Gavins, 2003, Damazo et al., 2006). As far as we know, their role in aging, and particularly in longevity, has not been addressed.

Acknowledgements

This work was supported by: European Union (EU) Grant “GEHA – Genetics of Healthy Aging” FP6-503270; the PRRIITT program of the Emilia-Romagna Region (and Fondi Strutturali Obiettivo 2); MIUR (Italian Ministry of University) Fondo per gli Investimenti della Ricerca di Base (FIRB) 2001, protocol #RBNE018AAP and #RBNE018R89 to CF; Italian Ministry of Health Grant (Ricerche Finalizzate 2002 and 2003) to CF and Project “Markers genetici di sindrome coronaria acuta e valutazione della l-arginina

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