Sara Bozzini and Colomba Falcone

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http://dx.doi.org/10.5772/intechopen.69637

#### **Abstract**

Introduction: Life expectancy and the rate of survival into old age have risen dramatically throughout the past century. The positive ageing outcomes may be due to a variety of factors including healthy lifestyle behaviors, but it is clear that longevity has a genetic basis, with heritability estimate of 20–35%. In this contest, it was emerged that human longevity seems strongly influenced by gender defined as the combination between biological sexual characteristics and factors related to behavior, social role, lifestyle and life experiences. Body—research methods: Successful ageing seems to be related to gene involved in different pathways of regulation, such as immune-inflammatory responses and oxidative stress. The aims of the present review are to discuss recent findings and highlight the genetic basis of longevity. For these reasons we are aimed to describe the most important underpinning which is the gender differences in longevity between males and females. Conclusion—key results: It appears clear that longevity may represent a complex polygenic trait that is influenced by the interaction of multiple genetic variants, as was demonstrated by several genetic studies conducted in the last years. Furthermore, epigenetic and environmental factors actin on the longevity phenotype.

**Keywords:** longevity, genetic basis, healthy lifestyle, inflammation, oxidative stress, epigenetics

## **1. Introduction**

Human life expectancy has increased over the last two centuries worldwide [data shown by the World Health Organization, 2012], and this is mainly due to improvement of health care, lifestyle and nutrition. Considering the continuous increase of lifespan and the consequent growth of the elderly population, research on ageing has been continuously increasing in thelast decades. The age threshold used to define "longevity" varies by study but is typically ≥ 85 years old and "exceptional longevity" may be considered at age ≥ 95 years old [1].

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

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

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

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 kilobase to several megabases in size.

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.

During ageing, vital bodily function, such as regeneration and reproduction slowly declines and the loss of essential body function leads to age-related pathologies, which ultimately cause death [8]. A large part of ageing phenotype is explained by an imbalance between inflammatory and anti-inflammatory response, which result in "inflammaging", a low-grade chronic pro-inflammatory status of ageing. Successful ageing seems to be related to pointing out that polymorphisms for the immune system genes, which are involved in the regulation of immune-inflammatory responses, may play a key role in the genetics of ageing. Another important pathway implicated in longevity concerns the oxidative stress. The balance between pro-oxidants and enzymatic antioxidant systems may be of particular importance in the elderly. In this scenario, nutritional deficiencies and sedentary lifestyle concur with a depletion of dietary antioxidants and increased susceptibility to oxidative stress.

Women live longer than men, and this difference in life expectancy is a worldwide phenomenon indicating that human longevity seems strongly influenced by gender defined as the combination between biological sexual characteristics and factors related to behavior, social role, lifestyle and life experiences [9].

The aims of the present review are to discuss recent findings, highlight the genetic basis of longevity and describe the most important underpinning which is the gender differences in longevity between males and females.
