A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Annibale A. Puca*, Mark J. Daly, Stephanie J. Brewster, Tara C. Matise, Jeffrey Barrett, Maureen Sammy Kang, Erin Joyce, Julie Nicoli*, Erica Benson, Louis M. Kunkel*, and Thomas Perls| *Howard Hughes Medical Institute, Genetics Division, Children's Hospital, and Harvard Medical School, Boston, MA 02215; Center for Genome Research at the Whitehead Institute for Biomedical Research, Cambridge, MA 02214; Department of Genetics, Nelson Biological Laboratories, Rutgers University, Piscataway, NJ 08854; Centagenetix, Boston, MA 02119; and Gerontology Division and Biometrics Center, Beth Israel Deaconess Medical Center and Division on Aging, Harvard Medical School, Boston, MA 02215.

Methods: Substantial evidence supports the familial aggregation of exceptional longevity. The existence of rare families demonstrating clustering for this phenotype suggests that a genetic etiology may be an important component. Previous attempts at localizing loci predisposing for exceptional longevity have been limited to association studies of candidate gene polymorphisms. In this study, a genome-wide scan for such predisposing loci was conducted by using 308 individuals belonging to 137 sibships demonstrating exceptional longevity. By using nonparametric analysis, significant evidence for linkage was noted for chromosome 4 at D4S1564 with a MLS of 3.65 (P = 0.044). The analysis was corroborated by a parametric analysis (P = 0.052). These linkage results indicate the likelihood that there exists a gene or genes that exert a substantial influence on the ability to achieve exceptional old age. Identification of the genes in humans that allow certain individuals to live to extreme old age should lead to insights on cellular pathways that are important to the aging process.

Subjects: Written informed consent was obtained from all participants and their legal proxies in accordance with the requirements of the Institutional Review Boards of Beth Israel Deaconess Medical Center and Children's Hospital of Boston. Proof of birth, in the form of a birth certificate, was obtained from 90% of subjects. Other acceptable proof was obtained from the remaining subjects; otherwise, a potential subject was not enrolled (7). The collection of centenarians or near-centenarians and their siblings began in 1997, well in advance of the specific planning for a genome scan analysis.

A minimum age of 98 years for at least one member of the sibship (the proband) was chosen because preliminary sibship recruitment efforts indicated that lowering the age from 100 to 98 was necessary to enroll enough sibships for a potential genetic study. All siblings aged 90 years and older were recruited. Before the conduct of the genome scan and subsequent analysis, it was decided that all sibships with a proband, at least one male sibling aged 91 years old or older, and/or a female sibling aged 95 years old or older would constitute the sample set to be analyzed. These sibling ages were chosen because they represented the 5% oldest individuals in the birth cohort based on U.S. and Canadian life tables. This selection resulted in 143 sibships and 322 individuals predominantly of European descent.

Centenarians have lived 20 years longer than the average life expectancy of those in their birth cohort who survived beyond the age of 65 years (1). For most centenarians, the majority of those additional years are spent in good health (2). We hypothesize that, relative to the general population, centenarians have a history of aging slowly, and they either markedly delay or escape age-associated diseases such as cardiovascular disease, stroke, diabetes, cancer, and Alzheimer's disease (3). While studying the phenotypic characteristics of centenarians in an attempt to discern characteristics that might explain this disease resistance and survival advantage, we frequently encountered subjects who reported similarly long-lived siblings. We therefore suspected that these siblings had genetic and environmental factors in common that conferred an unexpected survival advantage. Comparing the longevity of siblings of centenarians and siblings of a control group who were from a similar birth cohort, the siblings of the centenarians had a substantially greater chance of surviving to extreme old age compared with the siblings of the controls. This relative risk of survival steadily increased with age for siblings of the centenarians to the point that the siblings had a 4-fold greater probability of survival to age 91 (4). Moreover, in the course of recruiting subjects, we discovered four families with many exceptionally old individuals that also contributed to our suspicion that there is a significant genetic component to the ability to achieve exceptional old age (5). Finally, the dramatic degree of demographic selection that occurs in the nonagenarian years might indicate that few polymorphisms genes are significantly responsible for the survival of relatively few individuals achievingThe text appears to be a scientific report on a study of human longevity. Here is the processed text: