**2. Insulin-like signaling pathway**

Many epidemiological data conducted in different populations indicate the presence of a strong familial component of longevity. These studies demonstrate that parents, siblings and offspring of long-lived subjects have significant survival advantage. In particular, it seems that these subjects had higher probability to become long-lived persons and to have a lower risk to undergo the most important age-related diseases, such as cardiovascular diseases (CVD), diabetes and cancer. For these reasons, most of the human ageing studies concentrate

The presence of strong familial component of longevity led to hypothesize the presence of a genetic basis, most likely expected to be polygenic, and was demonstrated a heritability estimates of 20–35% [2]. In fact, human lifespan is a complex trait which is assumed to be

The gerontogenes, genes controlling ageing and longevity, are highly interconnected and related to stress response [4]. Prolonged or severe stress exposure exhausts the defence mechanism accelerating the process of ageing by accumulation of mistakes and physiological abnormalities. Nevertheless, on the other hand, it is known that moderate stress could have beneficial effects stimulating innate defence resources of the body thereby by expression of gene responsible for stress resistance. This stimulation increases the body ability to cope with higher levels of stress and slows down ageing in the so-called lifespan hormesis effect [5].

Genomic studies into ageing thus far focus on the determinants of human lifespan variation by using age at death, prospective survival, disease-free survival or exceptional longevity as outcome. From a genomic perspective, individuals from long-lived families are assumed to be characterized by a decreased prevalence of disease-promoting variants and an increased prevalence of variants conferring maintenance of health and protection from disease, when compared to population controls [6]. However, in 2010 a study conducted by Beekman et al. [7] tested whether a set of alleles increase the risk of coronary artery disease, cancer and type 2 diabetes for compatibility with human longevity, but they found that longevity is not com-

Studies in the field of genetics aim to decipher the impact of variation in the DNA structure that either can be inherited and are therefore found in the germ line DNA or that arises during an individual's lifespan. Core end points in the field of genetics are (1) single nucleotide polymorphisms (SNPs), which are single base variations in the DNA structure which are found in 1% of the population or more and (2) copy number variations, which are segments of DNA that vary in copy number between genomes of different individuals ranging from one

Genome-wide association study (GWAS) of human longevity has accumulated lots of data. In order to provide insight into the process of ageing, the applications of integrative genomic may to evaluate heritability of transcripts and identify sequence polymorphism can be useful. Very few copy number variations (CNVs) have been found to be linked with successful ageing and remain the area of active investigation in immune-related genes involved in ageing. A comprehensive consciousness of the interactions between genetic factors involved in the regulation of immune system will help know their roles in longevity and age-related diseases. They also will provide guidance for personalized efforts to intervene in the ageing process.

promised by the cumulative effect of this set of risk alleles for common disease.

kilobase to several megabases in size.

around long-lived families, including highly and middle-aged members.

determined by many genes with small individual effects [3].

6 Senescence - Physiology or Pathology

The most studied pathway that regulates the ageing process is the insulin-like pathways. Briefly, upon insulin-like growth factor-1 (IGF-1) binding to IGF-1 receptor (IGF-1R), the intracellular phosphoinositol-3-kinase (PI3K) is activated, leading to formation of the downstream intermediate phosphoinositide-3,4,5-trisphosphate. The latter binds to 3-phosphoinositide-dependent kinase 1 (PDK-1), which, in turn, phosphorylates and activates the kinases Akt/PKB and *s*erum- and *g*lucocorticoid-inducible *k*inase (*SGK-1*) that control regular growth processes in the cell. Together, the stress resistance factors, among which forkhead box gene, group O (FOXO) transcriptional factor, are activated [10]. This signaling activity is reduced in long-lived subjects of different species, such as nematode, mice and humans.

Gene encoding for protein involved in this pathway contains mutation correlated to longevity. In particular, mutation in IGF-1R gene in humans was associated to longer survival compared to usual [11]. Furthermore, in animal models, mutation in genes encoding for substrates of insulin receptors 1 and 2 results in the extended lifespan [12], and mutations in genes encoding kinases PI3K, AKT/PKB and PDK are associated with a prolonged life [13].

Insulin-like signaling inhibits the mechanisms of stress response regulated by FOXO transcription factor [14]. In mammals, there are four FOXOs (FOXO1, FOXO3, FOXO4, FOXO6) that regulate different genes in different cell types [15]: FOXO3 may undergo a greater decline with ageing. The mechanism by which longevity-associated alleles of FOXO3 reduce age-related mortality is currently of great clinical interest. FOXO3 has been associated with longevity in multiple candidate gene association studies in diverse groups including German, Italian and Chinese centenarians [16–18]. The precise mechanism by which FOXO3A influences longevity may be due to its effects on oxidative stress, insulin sensitivity and cell cycle progression [2]. A recent GWAS meta-analysis observed only a modest association of FOXO3 with survival to ≥90 years of age [6]. Further, in a genome-wide linkage analysis among nonagenarians, linkage to FOXO3 and another forkhead box gene, FOXO1, was not detected [19]. The lack of an association observed in these studies may be due to small sample sizes of exceptionally long-lived individuals, as the association of FOXO3 with longevity is stronger in persons aged ≥ 95 years and especially in centenarians [17, 18].
