A Symposium regarding the Pathophysiology of Successful and Unsuccessful Ageing was held in Palermo, Italy between April 7-8th 2009. Comments and keynotes by E. Sikora, G. Scapagnini and M. Barbagallo are summarized here.

Ageing and age-related diseases

The ageing process, opposite to longevity, is not genetically programmed. There are no genes that have been selected to actually promote ageing. The theory of evolution assumes that there is a trade-off between body maintenance and investment in reproduction [1]. Lifespan is regulated by genes controlling the activity of metabolism, antioxidant systems, DNA repair, cellular senescence and cell death. Their functions gradually decline due to random errors in DNA replication and damage to macromolecules, what leads to the accumulation of senescent cells and damaged tissue with age. However, diverse tissues building various organs may show different patterns of senescence [2-4]. The lesions accumulating with age are mainly, but not exclusively, caused by the increasing level of reactive oxygen species (ROS), as originally proposed by Harman [5].

A key in the ageing of an organism is immunosenescence which may play a part in the age-related immunological changes [6]. Lifelong exposure to a plethora of antigens (bacterial, viral, exogenous, auto, which can be considered as stressors) leads to a gradual decline of naive T cells. In turn, there is an accumulation of memory T and effector CD8+CD28- T cells which secrete increased amounts of pro-inflammatory cytokines [7]. 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 creating an imbalance between inflammatory and anti-inflammatory networks. This results in the low grade chronic pro-inflammatory status (inflamm-ageing) [6]. Inflamm-ageing can be characterized by an increased level of a variety of pro-inflammatory cytokines in tissues, and other inflammatory markers, such as coagulation cascade components, and the presence of viral infections caused by the following viruses: CMV and Epstein Barr virus (EBV) [8]. Cellular participants in low-grade inflammatory status not only include cells of the immune sytem but also other ones which have undergone genotoxic stress-induced senescence and secrete many inflammatory cytokines, to the so-called senescence-associated secretory phenotype (SASP) [9].

Ageing, although not a disease by itself, makes the organism vulnerable to a plethora of them. Holliday claims that many age-related changes can not be distinguished from age-related diseases [10]. Indeed, it seems that many age-related pathologies share the signalling pathways with the process of ageing. It has been proposed that low-grade inflammation may not be the cause of ageing itself (inflamm-ageing and SASP), but also of many age-related diseases [11-13].

Several lines of evidence have led to the general acceptance of a link between inflammation and cancer. Generally, cancer and inflammation are connected by two pathways: the intrinsic and the extrinsic one. The intrinsic pathway means that oncogene activation induces in transformed cells the production of inflammatory mediators, mainly via the activation of the transcription factor NF-κB. Conversely, in the extrinsic pathway inflammatory or infectious conditions augment the risk of cancer development. Epidemiological studies have shown that chronic inflammation predisposes individuals to various types of cancer [14]. Recently inflammation has been proposed as the seventh feature of cancer [15] which should be added to the six canonical previously proposed ones [16].

Inflammation is also considered to be a critical initial step in the development of atherosclerosis [13]. The early phase of atherogenesis is characterized by the attraction/adherence of monocytes to the vascular endothelium and their migration into the vessel wall. The expression of cellular adhesion molecules promotes the adhesion of leukocytes to the vascular endothelium and is induced by inflammatory factors, including IL-1, TNF-a, and CRP. Furthermore, the progressive accumulation of macrophages and their uptake of oxidized LDL ultimately leads to the generation of the so called foam cells and initiation of fatty streaks [12]. It seems that NF-κB is the main mediator of inflammation and endothelial dysfunction in the elderly [17].

An inflammatory state has been documented in senile plaques and surrounding glia with an increased expression of the acute phase protein CRP as well as pro-inflammatory interleukins such as IL-6 and IL-1 in Alzheimer's disease (AD) patients and animal models [18]. The evidence of inflammatory mechanisms being involved in AD is also based on the fact that certain anti-inflammatory drugs could modify the course of the disease [19,20].

Obesity, insulin resistance and type 2 diabetes are also closely associated with chronic inflammation. Exposure to excess amounts of nutrients and energy can reactivate the ancient inflammatory potential of metabolically important tissues. The adipose tissue of obese individuals has in fact been shown to produce higher levels of the pro-inflammatory cytokines (TNF, IL-6) and other pro-inflammatory factors [21].

The assumption of a link between ageing and age-related diseases raises the pivotal question of whether concentrating the effort on just curing the age-associated diseases is the optimal approach to making our later lives more healthy and comfortable. Indeed, a new strategy hopefully leading to healthy ageing has been proposed. Recently, it has been postulated that interventions aimed at slowing down ageing could offer a much greater benefit than those targeted at individual diseases [22]. The evolutionary theory of disposable soma suggests that ageing is unavoidable but malleable and plastic [23] and perhaps this may be possible by dietary or pharmaceutical intervention or genetic alteration, to extend the lifespan [22].