**3. Lipid metabolism**

Lipid metabolism is downregulated with time, leading to age-dependent diseases, such as metabolic syndrome and atherosclerosis. As previously demonstrated, dyslipidemia is associated with altered activity in a number of genes.

Three major genes of lipid metabolism are involved longevity, the genes encoding for apolipoprotein E (APOE), cholesteryl ester transfer protein (CETP) and peroxisome proliferator-activated receptor (PPAR).

In prior candidate gene association, variants of APOE have been consistently associated with longevity. The APOE gene encoded for the apolipoprotein E, a protein that combines with lipids in the body to form lipoproteins, and are responsible for packaging cholesterol and other fats and carrying them through the bloodstream. Maintaining normal levels of cholesterol is essential for the prevention of disorders that affect the heart and blood vessels (CVD), including heart attack and stroke, and consequently it contributed to good ageing.

The APOE gene has three common polymorphic alleles, leading to six possible genotypes [20], called ε2, ε3 and ε4. The most common allele is ε3, which is found in more than half of the general population. Both ε4 and ε2 alleles have been associated with cardiovascular disease (CVD) risk [21]. The associations with CVD may be related to the involvement of these isoforms in inflammation, elevated lipid levels and oxidative stress [22]. Some studies have observed that APOE2 occurs at a higher frequency in the elderly and centenarians, suggesting an association with longevity [23]; on the contrary, APOE4 may be less common in these groups and associated with early mortality [24]. However, a study conducted in Italian subjects showed that the ε2 allele is associated with an increased likelihood of longevity. Interestingly, all of the Italian centenarians of the study were free of cognitive impairment and major age-related diseases, suggesting an association of ε2 allele with successful ageing [25].

A particular chromosomal region, 19q13.11–q13.32 showed linkage with longevity, as shown in a large genome-wide linkage scan among nonagenarian sibling pairs of the European ancestry [19]; subsequent association analyses using GWAS data found that APOE4 and APOE2 alleles explain linkage at this region. Further studies are needed to elucidate the role of rare APOE variants on longevity and healthy ageing.

Variants in the CETP gene, which is involved in the regulation of high-density lipoprotein levels, were previously suggested as markers of exceptional longevity and healthy ageing in Ashkenazi Jews and Japanese-American men, respectively [26, 27]. However, in a recent case-control study among Han Chinese long-lived individuals, none of the four SNPs in the promoter region of the CETP gene was associated with longevity [28]. Additionally, a metaanalysis of eight studies did not observe an association between CETP polymorphisms and longevity [29].

Peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily. PPAR ligands comprise fatty acids and their derivatives. PPARα is activated by fatty acids, eicosanoids, 15-d prostaglandin and oxidized fatty acids. PPARα function antagonizes the metabolic syndrome and ageing in general [30], through regulation of genes promoting lipid oxidation and metabolism of lipoproteins, such as main apolipoprotein of high density, Apo A-1.
