Table 1. Demographic and Metabolic Characteristics of Ashkenazi Probands, Offspring , and Controls

p Value, Offspring vs Control Trait Probands, n = 205 Offspring, n = 145 Controls, n = 288 * † Female (%) 69 55 58 0.58 Age, y 98 ± 0.2 68.2 ± 0.6 74.0 ± 0.5 <.0001 <.0001 Age range, y 95 – 109 53 – 92 44 – 93 Glucose, mg/dL 101 ± 2 94 ± 3 93 ± 2 .76 .57 Insulin, mg/dL 27.9 ± 3.3 22.6 ± 3.2 17.8 ± 1.8 .19 .14 CRP 0.76 ± 0.18 0.44 ± 0.08 0.34 ± 0.03 .16 .11 Cholesterol, mg/dL 189 ± 3 209 ± 3 200 ± 3 .03 .09 Triglycerides, mg/dL 139 ± 5 149 ± 8 126 ± 4 .002 2e-3 Apo-A1, mg/dL 141 ± 3 156 ± 3 156 ± 3 .94 .59 Apo-B, mg/dL 100 ± 2 104 ± 2 101 ± 2 .38 .52 VLDL-TG, mg/dL 85 ± 5 82 ± 7 74 ± 3 .17 .06 VLDL particle size, nm 49.4 ± 0.9 48.8 ± 1.3 47.1 ± 0.3 .38 .52 LDL, mg/dL 109 ± 5 116 ± 3 117 ± 2 .8 .76 LDL 1, mg/dL 78.6 ± 4.3 69.6 ± 4.6 70.6 ± 3.1 .85 .79 LDL 3, mg/dL 13.3 ± 2.6 29.3 ± 3.5 29.7 ± 2.4 .93 .94 LDL particle size, nm 21.4 ± 0.1 21.0 ± 0.1 21.1 ± 0.1 .55 .91 HDL, mg/dL 55.5 ± 1.2 63.8 ± 1.6 58.4 ± 1.1 .005 .13 Large HDL, mg/dL 32.2 ± 1.8 29.4 ± 1.8 32.1 ± 1.2 .21 .47 Small HDL, mg/dL 15.3 ± 0.6 20.3 ± 0.7 16.0 ± 0.5 <.0001 .18 HDL particle size, nm 9.47 ± 0.05 9.10 ± 0.05 9.30 ± 0.05 .005 .01 Chylomicrons, mg/dL 2.65 ± 0.56 2.27 ± 0.84 0.73 ± 0.16 .01 .06

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Notes : Data are expressed as means ± SE . Crude means are shown. TG, which were not normally distributed, were log-transformed for analysis but presented as untransformed raw values. LDL = low-density lipoprotein; HDL = high-density lipoprotein ; VLDL = very low-density lipoproteins . * p V alues between o ffspring v ersu s c ontrol unadjusted. † p V alues between o ffspring v ersu s c ontrol adjusted for age and sex ( g lucose [mg/dL], i nsulin [mg/dL], CRP, c holesterol [mg/dL], t riglycerides [mg/dL], VLDL-TG [mg/dL], LDL [ t otal levels, 1 and 3; mg/dL], HDL [ t otal levels, large and small; mg/dL], VLDL particle size [nm], LDL particle size [nm], HDL particle size [nm], Chylomicron [mg/dL]).

However, after adjustment for the presence of favorable longevity genotypes, this difference in mortality no longer remained ( p = .53, Figure 4B ).

Treating age as a continuous variable to describe the distri- bution pattern of CC over the life course, we found that the prevalence of the C C genotype demonstrated a monotonic decline of ~ 16%, from 38% to 22% between 60 and 80 y ea rs of age, respectively. However, between 80 and 100 ye ar s of age, the prevalence markedly increased by nearly 10% to near 30% prevalence, resulting in a U- s hape frequency pat- tern with aging ( p < . 05). Using interaction analysis, when the frequency of the MTP CC genotype was assessed in the absence of favorable genotypes ( AdipoQ [rs56354395], CETP [rs5882], and ApoC3 [rs2542052]) in offspring and controls, we observed a monotonic decline with aging from ~ 33% at 60 y ea rs to near 0% survivorship by age 90 y ea rs ( Figure 3B , p < .05). However, in individuals possessing one or more favorable longevity genotypes, the prevalence of the MTP CC genotype was relatively unchanged from the six th to eigh th decade of life but was followed by a marked enrichment to near 60% by 90 y ea rs of age ( Figure 3B ), as predicted by the buffering hypothesis ( 18 ).

D iscussion

Here , we show that the prevalence of the M TP CC geno- type is enriched in centenarians and their offspring, as compared w ith Ashkenazi Jew controls. Paradoxically, this genotype was associated with an unfavorable lipid profi le, including greater concentrations of TG, VLDL , and chylo- microns, all known risk factors for cardiovascular and metabolic diseases. This paradox between phenotype and genotype is explained by the fact that the MTP CC genotype demonstrated a monotonic decline with aging until ~ 80 ye ar s of age, followed by a marked increase in centenarians, forming a U- s hape pattern with aging.

Offspring and individuals belonging to the control group with the M TP CC genotype across ages were then catego- rized by presence or absence of one or more known lon- gevity genotypes { CETP ( VV ) [rs5882] ( 13 ), APOC3 ( CC ) [rs2542052] ( 14 ), and A dipoQ (d el/del APM1 +2019) [rs56354395] ( 15 )}. Absence of these genotypes resulted in a monotonic decline in C C prevalence to near 0% by 90 ye ar s, w hereas a sharp rise in prevalence was observed in those harboring longevity genotypes beyond 80 y ea rs old. Finally, we show that control and offspring without any of the three favorable longevity genotype variants, but possessing

MTP CC Genotype and Survivorship in Ashkenazi Offspring and Controls

Kaplan – Meier curves comparing survivorship between MTP genotypes are presented in Figure 4A and B . As com- pared w ith Ashkenazi offspring and controls with either CG /G G genotypes, those with the CC genotype demon- strated signifi cantly worse survival ( p < .05, Figure 4A ).

Table 2. Demographic and Metabolic Characteristics of Ashkenazi Offspring and Controls Categorized by MTP Genotype

Percentage in group (%) >woPercentage in group (%)60[= Controlc OffspringCi Proband            5040302010cc CG GG70605040302010[= ControlOffspringC= Proband