Apolipoprotein E is a Longevity-Associated Gene
It remains unclear as to why apolipoprotein E (APOE) variants are associated with longevity in humans. The gene has a well-studied role in Alzheimer's disease, but the reasons why APOE variants are associated with aging remain to be determined. The most likely mechanisms involve (a) interactions with age-related disruptions of lipid metabolism, both in the brain and elsewhere, and (b) indirect effects on the inflammatory behavior of innate immune cells such as microglia. There are plenty of other interactions to further study, however, such as in bone tissue, or effects on the gut microbiome. As is often the case, a great deal of data exists, but making sense of that data lags far behind the ability to generate more of it.
The APOE variants, respectively ε2 ε3, ε4, and ε3r, are determined by four haplotypes at the APOE locus (19q13.32). These four APOE alleles are probably the most investigated variants in the human genome. Remarkably, the APOE exon 4 region, encompassing the ε2/ε3/ε4 allele variants, is a well-defined CpG islands-rich area. Moreover, the two common SNPs rs429358 and rs7412 are CpG-altering and modify the CpG content of this area. This APOE CpG island-rich area is a transcriptional enhancer with a specificity linked to the ε4 allele and cell-type.
A genetic association of APOE with both human longevity and Alzheimer's disease (AD) was found, but the mechanistic contribution of APOE in aging and long life is largely under investigation. APOE pleiotropic roles may be explained by its exceptional epigenetic properties. In the AD brain, these epigenetic changes could contribute to neural cell dysfunction. Additionally, DNA methylation modifications have been found on specific genes associated with AD pathology such as APOE. In the AD brain, it was shown that APOE CpG islands were differentially methylated in an APOE-genotype and tissue-specific way.
In the lipid metabolism pathophysiology, ApoE may be related with normal/pathological aging, while its function in CNS pathophysiology needs further clarification. In fact, in the CNS, there was about a quarter of total body cholesterol that may exert a significant impact on synaptic plasticity. With advancing age, cholesterol metabolism may modify, and its related brain changes may be associated with the pathophysiology of AD. So, in longevity and healthy aging, lipid and cholesterol maintenance are a critical factor also from an interventional point of view.
Studies on longevity and healthy aging are related because subjects who live longer tend to be healthier for a greater part of their lives. Healthy aging can be described as achieving older age maintaining intact cognition and/or mobility and without disabilities or multimorbidity. This last can be defined as the coexistence of two or more chronic diseases in the same subjects. The detrimental effects of the APOE ε4 allele on longevity could influence the probability of a long human lifespan. The APOE ε2 allele has a greater frequency in long-lived individuals than the ε4 allele. Thus, the main longevity factor is the APOE ε3/ε3 genotype. The greater frequency of the ε3 allele in older individuals and their offspring than in controls derives from the higher amount of the homozygous APOE ε3/ε3 genotype in comparison with the ε2/ε3 or ε3/ε4 genotypes