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

p Value, CC vs CG/GG Trait CC, n = 113 CG/GG, n = 320 * † Female (%) 51 59 .15 .14 Age, y 70.2 ± 0.8 73.1 ± 0.5 .004 .004 Age range, y 44 – 92 49 – 93 Glucose, mg/dL 90 ± 4 95 ± 2 .25 .26 Insulin, mg/dL 19.2 ± 3.2 20.8 ± 2.3 .68 .33 CRP 0.39 ± 0.07 0.37 ± 0.04 .73 .53 Cholesterol, mg/dL 204 ± 4 203 ± 2 .78 .61 Apo-A1, mg/dL 154 ± 3 157 ± 2 .45 .42 Apo-B, mg/dL 105 ± 3 102 ± 2 .37 .40 VLDL particle size, nm 48.9 ± 1.7 47.6 ± 0.8 .45 .54 LDL, mg/dL 117 ± 4 116 ± 2 .85 .54 LDL 1 , mg/dL 67.2 ± 5.6 71.4 ± 2.9 .47 .72 LDL 3, mg/dL 32.8 ± 4.2 28.2 ± 2.3 .3 .46 LDL particle size, nm 20.9 ± 0.1 21.0 ± 0.1 .34 .77 HDL, mg/dL 59.5 ± 1.7 60.8 ± 1.1 .53 .4 Large HDL, mg/dL 28.8 ± 2.1 32.1 ± 1.2 .17 .72 Small HDL, mg/dL 18.2 ± 0.7 17.5 ± 0.5 .66 .92 HDL particle size, nm 9.06 ± 0.05 9.16 ± 0.03 .15 .48

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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 pre- sented as untransformed raw values. HDL = high-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoproteins.

† p Values between CC carriers and CG/GG carriers adjusted for age and sex (glucose [mg/dL], insulin [mg/dL], CRP, cholesterol [mg/dL], triglycerides [mg/dL], Apo-A1 [mg/dL], ApoB [mg/dL], VLDL particle size [nm], LDL [total levels, 1 and 3; mg/dL], LDL particle size [nm], HDL [total levels, large, and small; mg/dL], HDL particle size [nm]).

Figure 1. M TP g enotype f requencies in Ashkenazi centenarians, their offspring, and Ashkenazi controls. ( A ) The frequency of homozygosity ( CC ) for the MTP rs2866164 SNP of M TP in probands (n = 126), offspring ( n = 145), and Ashkenazi controls ( n = 288). The frequency of the CC genotype is 1.5 - and 1.6-fold increased in offspring ( p < .05) and probands ( p = .001), respectively, compared with controls. (B ) The frequency of the C allele for the M TP rs2866164 SNP in probands (n = 126), offspring ( n = 145), and controls ( n = 288). The frequency of the C allele is signifi cantly increased in offspring ( p = .001), but not in probands ( p = .26), as compared with controls .

gene is buffered by the favorable C ETP VV genotype [rs5882] (1 8) . Likewise, here, we demonstrate that the deleterious effect of the MTP CC genotype can be mitigated by any of the following favorable longevity genotypes, CETP ( VV ) [rs5882], APOC3 ( CC ) [rs2542052], and AdipoQ ( del/del APM1+2019) [rs56354395].

the MTP CC genotype, demonstrated a poorer survivorship than those with the M TP CG/GG genotype. These fi ndings lend support to the hypothesis that M TP CC is in fact a deleterious genotype, whose effects can be buffered by lon- gevity genes. However, the exact biologic al mechanism(s) whereby these favorable genotypes attenuate the harmful effect(s) of the MTP CC genotype are unclear.

Although our results were able to somewhat substantiate those of Geesaman and colleagues ( 6 ), albeit with a differ- ent interpretation, the fact that fi ve separate follow-up studies, utilizing unique populations of long-lived individuals and controls ( 8 – 12 ) , failed to detect any difference among groups deserves further clarifi cation. First, consistent with these follow-up studies, we also fail to see any signifi cant difference in allele frequency between younger controls and probands. However, our results demonstrate that a stark enrichment of the CC genotype exists in Ashkenazi cente- narians and offspring, as compared with controls. We attri- bute this fi nding in part to the unique risk posed by the C C genotype, as opposed to those harboring one or two copies of the G allele, to mortality in participants without longevity genotypes.

On the surface, our results seem to be in agreement with those of an initial fi ne- m apping experiment which fi rst linked an overrepresentation of the major allele (C ) of SNP rs2866164 in the MTP gene with longevity ( 6 ). However, our data clearly suggest that in spite of its enrichment in centenarians and their offspring, harboring two copies of this allele without buffering genes is not “ g ood” for aging, but rather is detrimental. Furthermore, our results provide a “ proof of concept ” regarding the necessity to obtain geno- type prevalence data over the life course coupled with func- tional analysis, in order to defi nitively distinguish benefi cial and deleterious genotypes. Indeed, we have previously shown that the hazards posed by a deleterious variant of the Lp(a)

A second important consideration that deserves further explanation is the issue of comparing two data points for the purpose of identifying either deleterious or longevity genotypes. Most human longevity studies are structured as

A 160 * 150 140 130 120 110 100 CC CG/GG B 100 * 90 80 70 60 CC CG/GG C 4 * 3 2 Figure 3. Prevalence of according to age and adjustment 1 Frequency of M TP CC genotype by the specifi ed age ranges with range: 55 – 64 y ea rs = 44, 65 – 74 y 0 )Ld/gm( sedirecylgirT)Ld/gm( LDLV)Ld/gm( snorcimolyhC

<P<.05° ° SS oO oe ¢ & °=(%) adAyouab 99 yo Aouanbal41008060Age (years) aS ° S o °°So oO oe + N=(%) edAjoueb 99 Jo Aouanbas480 90Age (years)7060