**6. Gender and longevity**

were maintained at the physiological levels by several endogenous antioxidant systems, such as superoxide dismutatase (SOD), catalase, glutathione peroxidases and glutathione reductase (GR). Other antioxidant systems involving thiol-disulfide oxidoreductase systems include the cytosolic proteins thioredoxin (TRX) and glutaredoxin (GRX). ROS at physiological levels can interact with redox state and play a role in mediating cell signaling, while at pathological levels can result in oxidative damage to cellular components that activate several

The close interrelationship of redox balance to oxidative stress has in recent years become a more prominent aspect of the free radical theory of ageing that was extended to implicate the mitochondrial production of ROS [58]. In fact, studies in long-lived species showed the presence of reduced oxidative damage [59], reduced mitochondrial free radical production [60], increased antioxidant defences [60] and increased resistance to oxidative stress both in vivo and in vitro [61]. However, a lack of correlation of oxidation with lifespan [62], or even an increase in oxidative damage/stress associated with long lifespan, has also been reported [63]. In addition, in support of the importance of genetic factors in the ageing organism's ability to counteract the negative effects of oxidative stress, genetic modifications of the stress response with age have also been reported. These modifications may minimize health risks, and they

Several studies suggest that both genetic factors and modifiable lifestyle habits have major impact on the oxidative stress response, but the relative contribution of genes and lifestyle in promoting an efficient stress response in cells is difficult to estimate. Data collected in the literature shows that in experimental organisms and in exceptionally long-lived individuals, among the antioxidant enzymes, a major role in longevity seems to be attributed to genes

Knowing that oxidative stress accelerates telomere loss, the genes encoding the telomere maintenance pathway, mainly telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), are also important to happen [66, 67]. In addition, in support of gender difference in longevity, some genes involved in the stress response pathway, like heat shock

A study in Chinese centenarians and nonagenarians and younger controls identified significant genotype differences in the GNB3 and eNOS genes, whose variants have been implicated in hypertension and vascular function via nitric oxide (NO) generation, respectively [69]. Another study found that variants of two NO synthase genes, NOS1 and NOS2, decrease the probability of attaining longevity, suggesting that NO production and signaling may be

Mitochondrial genetic variability, both germ line and somatic, influences the stress response and is associated with human ageing/longevity. In both physiological and pathological conditions, a strict coordination between nuclear and mitochondrial genomes is necessary to ensure the biosynthesis and functional activity of mitochondria [71]. In normal conditions, signals from the nucleus to mitochondrion are essential for maintaining an adequate mitochondrial structure and function. The mitochondrial replication and transcription were modulated by

protein A1A (HSPA1A) or paraoxonase 1 (PON1), show sex-specific effects [68].

may increase the individual's possibilities of achieving a longer life [64].

cell death pathways.

12 Senescence - Physiology or Pathology

SOD2 and GPX [65].

involved in ageing [70].

The impact of gender difference in ageing has been extensively assessed, but the precise mechanisms of interaction between a series of fundamental aspects, such as hormonal, immunological and metabolic pathways as well as genetic background remain largely unknown. The high prevalence of women among centenarians suggests that men and women follow different trajectories to reach extreme longevity. In particular, females benefited from healthier lifestyles and favorable environmental conditions in the past century [81]. Moreover, the differences in longevity between genders are related to free radical production because mitochondrial oxidative stress is higher in males than females. Estrogens in women confer better protection against ageing, through an up-regulated expression of antioxidant longevityrelated genes [82]. In support of this, there are also some available epidemiologies of agerelated diseases confirming substantially different between genders and showing changes dramatically in women after menopause [83].

Much research has been carried out into the role of sex hormones in determining lifespan [84], and one hypothesis is that sex hormones appear to influence the immune system. It is well known that estrogens, androgens and progesterone affect cells of the innate and adaptive immune system differently during the reproductive phase of life [85]. It is widely recognized that estrogens inhibit natural killer cell cytotoxicity and reduce neutrophil chemotaxis and consequently inflammation [86, 87]. Moreover, macrophages treated in vitro with oestradiol display a reduced production of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α [88]. Estrogens and androgens are responsible for a reduced immature number of T-lymphocytes and thymus involution after puberty [89] and can also influence the adaptive immunity in an opposing way, contributing to an improved humoral response in women but also favoring the appearance of autoreactive clones and the susceptibility to autoimmune diseases [90].

The sudden loss of ovarian estrogen and progesterone production that characterizes menopause induces pathophysiological changes in different organs and systems [91], bone density, breast cellular composition, cardiovascular health, mood/cognitive function and sexual wellbeing. Menopause reflects the inevitable final hallmark of a woman's fertile lifespan and of the above-described beneficial effects of estrogens on immune responses. Rapid reduction of estrogen levels results in an increased susceptibility and mortality toward a series of infectious diseases caused in old women losing of their immunological privilege toward infection [85, 92].

It is noteworthy that women will soon spend half of their life in postmenopause, if the current trend of increasing human life expectancy should persist.
