Subjects

All subjects provided proof of age. There was a predominance of female subjects in our cohort, likely reflecting the original ascertainment criterion of having a proband of at least 98 years of age regardless of gender [24]. Only self-identified white or Caucasian subjects (the vast majority of our cohort) were analyzed since population stratification can confound non-parametric linkage analysis when parental genotypes are unobserved [increase in longevity, assuming a heritability of 0.3 and a genomewide significance threshold of LOD=3.6. Our study identified two chromosomal regions, on 3p24-22 and 9q31-34, respectively, with overall maximum LOD scores of 4.02 and 3.89 in specific age categories. The stability of these linkage peaks was confirmed using different SNP subsets. The hLOD scores suggested a dominant mode of inheritance for both peaks, with reduced locus heterogeneity in the oldest sibships for the chromosome 9 peak. The use of SNP arrays provided substantial improvements in power over previous microsatellite panels. Our findings provide new insights into the genetic basis of exceptional longevity and may lead to the identification of novel longevity-associated genes.analysis), respectively. The text discusses the results of a study on human aging and genetics. The study identified three novel loci of interest on chromosomes 3p24-22, 9q31-34, and 12q24 using nonparametric linkage analysis. The results were supported by parametric analysis and warrant replication studies. The study did not provide substantial evidence for linkage to FOXO3 or APOE genes. The text also mentions the characteristics of the linkage peaks and candidate genes in the identified loci.The text seems to be a combination of tables, figures, and results from a scientific paper. As an AI language model, I cannot determine the exact formatting of the original source document, so I will focus on correcting any spelling, grammar, and coherence issues in the text to improve its readability. Here is the processed text:

The study reports nonparametric linkage data for four subgroups, namely Previous, New, MC, and FO. The boundaries for the Total group for chromosomes 3 and 9, the New subgroup for chromosome 12, and the Previous subgroup for chromosome 4 are identified. The boundaries of the chromosome 9 peak are a composite of Categories 8 and 9 which had overlapping but slightly offset peaks of similar magnitude. NA indicates that scores were not noted or P values were not determined. Category 5 indicates that this category has been identified. Category 9 indicates that this category has been identified as well. Category 2 indicates that this category has also been identified.

The study also identifies genes like WRN (MIM 604611) [69] and BLM (MIM 604610) [70] that encode RecQ helicases which cause progeroid disorders such as Werner syndrome [71] and Bloom syndrome [72], respectively. DBC1 (MIM 602865) in the chromosome 9 linkage peak directly interacts with SIRT1 (MIM 604479) and inhibits its activity [73]. SIRT1 is activated by resveratrol [74] and has been implicated in several age-related phenotypes in mammals [75]. The sirtuin family members are key regulators of lifespan in yeast [76], worms [77], and flies [78] and mediate the effects of caloric restriction [79,80]. Caloric restriction is known to increase lifespan in a wide variety of organisms, including mammals [81]. FOXO3 [82], in which variants have been reproducibly associated with human longevity [1318], stimulates SIRT1 in response to nutrient withdrawal. 

The study also identifies different SNPs in or near TLR4 (MIM 603030) in the chromosome 9 linkage peak that have been associated with exceptional longevity in men [83,84], bone-related proxy for biological age [85], and various age-related diseases [86]. Mutations in ANK2 (MIM 106410), which is within the previously reported chromosome 4 linkage peak, cause long-QT syndrome [87]. Common variation in ANK2 has been reported to regulate the QT interval [88]. QT interval prolongation is a risk factor for sudden cardiac death in healthy individuals [89] as well as those with ischemic heart disease [90] and chronic congestive heart failure [91], which are more common causes of death among centenarians than younger individuals [92]. Heterozygous Ank2+/2 knockout mice displayed multiple signs of premature senescence, and their lifespan was significantly reduced compared to wild-type littermates [93]. The study also reports a nominally significant association between a SNP in ALPK1 (MIM 607347) and both age at death and morbidity-free status at age 65 [85].

The study suggests that case-control studies can benefit from direction or corroboration by linkage scans since cross-sectional study designs for longevity are subject to unique methodological complications [11], and longitudinal cohort designs can be prohibitively expensive. The study also suggests that the results could help inform deep resequencing efforts to identify rare variants that influence lifespan. Discovery and confirmation of human longevity genes will provide insight into the biology of aging and the genetic basis for resistance to age-related disease.

The study provides subject characteristics by age category for four subgroups, plus parametric analysis settings. Age, gender, and sibship composition statistics for the Previous, New, MC, and FO subgroups, plus parametric linkage parameters for all groups, are given across ten categories defined by gender-specific minimum requirements for expected age at death. The designations 2-ship, 3-ship, 4-ship, and 5-ship refer to sibships with two, three, four, or five siblings, respectively.