**9. Discussion**

Chromatin and epigenetic factors influenced gene expression dynamically by regulating access of transcriptional machinery to DNA. It is clear that, with age, there is a general loss of histones coupled with local and global chromatin remodeling, an imbalance of activating and

Additionally, particularly in mammalian systems, there is a global and local change in DNA methylation, site-specific loss and gain in heterochromatin and significant nuclear reorganization Methylation patterns of genes involved in, for example, development and morphogenesis, DNA binding and regulation of transcription [108, 109], seem to change with age; a progressive linear increase in methylation with age at the ELOVL2 gene was found in a cohort of 501

The epigenomic field recently became more accessible for the screening of large study populations; however, larger studies, new methodologies and the consistent use of different study designs to follow up results might help to unravel the genomic component of healthy ageing

It was proposed that a mathematical model, on the basis of the methylation levels of 353 CpG units, formulated a mathematical model, the so-called epigenetic clock, which was able to predict the chronological age of a subject starting from the methylation level of several cells and tissues of his body [111]. This model also indicates that methylation represents one of the most accurate biomarkers of age and it was able to predict all-cause mortality also after adjusting for traditional risk factors [112]. Finally, when it was used to estimate the biological age of several tissues from supercentenarians, it has been demonstrated that the brain and

However, even if the relationship between methylation process and ageing is still not clear, this discovery has some wide potential applications, ranging from detailed monitoring of changes occurring with age to forensic purposes. It therefore appears clear that future advances in this field could help the understanding of the complex physiology of ageing,

Starting from the observations, epigenetic modifications affect not only the ageing process but also its quality [114]. Epigenome-wide association studies identified hundreds of sites spread along the entire genome in which methylation levels change between the oldest old

Although serum microRNAs play roles in the diagnosis of various diseases, little is known about circulating miRNAs in the ageing process. Human serum from healthy individuals contains abundant quantities and species of circulating miRNAs, and they can be readily detected with almost all routine RNA analysis techniques, including qRT-PCR. Zhang et al. evaluated miRNA expression profiles in the sera of healthy individuals at different steps of the ageing process, and they found a different miRNA regulation in the ageing process. In particular, they found that miRNAs changed significantly in the ageing process: miR-29b, miR-106b, miR-130b, miR-142-5p and miR-340 decreased, and miR-92a, miR-222 and miR-375

muscle represent the youngest tissues of these exceptional individuals [113].

repressive histone modifications and transcriptional change in all ageing models.

long-lived individuals [110].

16 Senescence - Physiology or Pathology

lifespan and age-associated diseases.

and younger subjects.

increased [115].

and longevity.

Human longevity is an extremely complex trait on which genetic, epigenetic and environmental factors act. It is becoming evident that the genetic differences concur lowly to life expectancy before 60 years, but their impact on survival becomes more prominent at old ages. Unfortunately, the currently available knowledge is not sufficient to explain the secret of longevity, even because available data, reviewed in this work, are sometimes conflicting. The precise reason for these data discrepancy is unknown; however, several factors may be involved, such as ethnic, lifestyle and cultural differences among the population analyzed in the diverse studies.

During the past decade, several longevity gene candidates have been identified; the majority of them concern components of the inflammatory system, stress response or lipid and glucose metabolism.

As discussed above, longevity is characterized by a balance between pro-inflammatory and anti-inflammatory agents, which act as key players. A pro-inflammatory propensity can confer high resistance against infectious diseases, but it also may increase susceptibility to inflammation-based diseases. On the other hand, an anti-inflammatory tendency, instead, may cause an increased susceptibility to infections and might not allow to reach a more advanced age. According to a perspective suggested in recent years, the best candidates to become centenarians are not the strongest, and most robust subjects among their age cohort, but subjects that better adapt to the environment, show more biological plasticity.

Since genetic variants may exert small to moderate effects on human longevity, additional prospective investigation with large sample size is needed to elucidate the role of genetic variation. It may also be worthwhile for future studies to evaluate the genetic basis of ageing separately in male and female, which is especially importantly given the longer lifespan of females.

Therefore, the balance between lifestyle and physiological changes during ageing on the one hand and risk factors for age-associated diseases on the other should be taken into consideration. Several studies suggest that on the oxidative stress response both genetic factors and modifiable lifestyle have major impact. Studies in experimental organisms and in exceptionally long-lived individuals have tried to identify genetic factors modulating 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 deriving from different studies indicate that stress response pathway is an integrated network of molecular activities, ranging from immunity to inflammatory regulation and activation, to glucose homeostasis and mitochondrial metabolism. Therefore, ageing seems to be associated with a loss of complexity in the dynamics of multiple control systems that may reduce the ability to adapt to stress, leading to a state of impaired homeostasis and vulnerability to internal and external stressors. On the contrary, the healthy oldest old seems be able to maintain a higher level of integration among the different physiological pathways operating within the cell, thus interacting more successfully with stressors.
