APOEAlleles and Extreme Human Longevity

Abstract

We assembled a collection of 28,297 participants from 7 studies of longevity and healthy aging comprising New England Centenarian, Long Life Family, Longevity Gene Population, Southern Italian Centenarian, Japanese Centenarian, the Danish Longevity and the Health and Retirement Studies to investigate the association between the APOE alleles ɛ2, ɛ3 and ɛ4 and extreme human longevity and age at death. By using 3 different genetic models and two definitions of extreme longevity based on either a threshold model or age at death, we show that ɛ4 is associated with a substantially decreased odds for extreme longevity, and increased risk for death that persists even beyond ages reached by less than 1% of the population. We also show that carrying the ɛ2ɛ3 or ɛ2ɛ3 genotype is associated with significantly increased odds to reach extreme longevity, with decreased risk for death compared to carrying the genotype ɛ2ɛ3 but with only a modest reduction in risk for death beyond an age reached by less than 1% of the population.

A serum protein signature of APOE genotypes in centenarians

“…Table displays characteristics of the NECS patients included in the analysis. We enriched the sample selection of carriers of the e 2 e 2 genotype of APOE that is more prevalent in healthy agers and centenarians (Sebastiani et al, ). The ages of study participants varied between 45 years and 114 years, but mean age per genotype groups was comparable.…”

“…The e 3 allele is the “neutral allele” in many ethnicities, while e 2 is the least common allele that emerged as a longevity variant when Schachter et al noted an increased frequency of e 2 in French centenarians (Schachter et al, ). Since then, several studies have provided evidence that e 2 has a beneficial neuroprotective effect (Kim et al, ), decreases neuroinflammation (Dorey, Chang, Liu, Yang, & Zhang, ), and promotes longevity (Sebastiani, Bae, et al, ; Sebastiani, Gurinovich, et al, ; Sebastiani et al, ) and healthy aging (Kulminski et al, ; Wu & Zhao, ). Therefore, we hypothesize that targets of this allele may lead to the discovery of treatments that help maintain good cognitive function and escape cognitive impairment with aging.…”

The Aging Metabolome—Biomarkers to Hub Metabolites

“…[ 22,23 ] Subjects with APOE4 genotype have substantially decreased extreme longevity unlike subjects with E2E3 genotype. [ 24 ] Though increased risk of AD pathology conferred by the APOE4 genotype has been studied, the basal metabolomic differences on “normal” aging remain to be elucidated and represent a significant opportunity.…”

Preditores do envelhecimento saudável: fatores epigenéticos e o gene APOE

“…Até o momento, estudos longitudinais De forma robusta, estudos demonstram efeito protetor do alelo ε2 para sobrevivência e longevidade, além de associação com redução de níveis de colesterol e doenças cardiovasculares, neuroproteção contra doença de Alzheimer e morte neuronal, redução de risco de acidente vascular cerebral em homens, redução de câncer gástrico e algumas doenças infecciosas, proteção celular do estresse oxidativo e morte celular, além de melhora de reparo ao DNA celular. Por outro lado, exemplificando o efeito pleitrópico do gene APOE, dados menos consistentes sugerem associação da presença do alelo ε2 com aumento de incidência de pneumonia, redução de densidade óssea e aumento de osteoporose, e risco aumentado de câncer de cólon(Rosvall et al, 2009; Kulminski et al, 2016; Souza et al, 2017;Sebastiani et al, 2018;Bos et al, 2018 Bos et al, ). 2016Bos et al, 2018).…”

“…O alelo APOE ε4, por sua vez, está fortemente relacionado a fenótipos de doenças relacionadas ao envelhecimento, especialmente doença de Alzheimer e doenças cardiovasculares. Estudos demonstram associação positiva com aumento de mortalidade e redução de expectativa de vida, aumento de colesterol total e LDL-colesterol, risco aumentado de doença ateromatosa (de grandes vasos, doença coronariana e cerebrovascular), de hipertensão arterial sistêmica, de diabetes não insulino-dependente, de progressão de nefropatia diabética e glomerulopatias, de arritmias cardíacas e de demências, em especial doença de Alzheimer(Rea et al, 2001;Bahia et al, 2008; Kulminski et al, 2016;Tindale et al, 2017;Bos et al, 2018; Shi et al, 2018;Sebastiani et al, 2018;Liehn et al, 2018). No metabolismo celular, APOE ε4 está associado com aumento de estresse oxidativo, disfunção de macrófagos e inflamação, menor retirada de colesterol dos neurônios, aumento de neuroinflamação e de morte celular(Dose et al, …”