Life-long sustained mortality advantage of siblings of centenarians

Abstract

Although survival to old age is known to have strong environmental and behavioral components, mortality differences between social groups tend to diminish or even disappear at older ages. Hypothesizing that surviving to extreme old age entails a substantial familial predisposition for longevity, we analyzed the pedigrees of 444 centenarian families in the United States. These pedigrees included 2,092 siblings of centenarians, whose survival was compared with 1900 birth cohort survival data from the U.S. Social Security Administration. Siblings of centenarians experienced a mortality advantage throughout their lives relative to the U.S. 1900 cohort. Female siblings had death rates at all ages about one-half the national level; male siblings had a similar advantage at most ages, although diminished somewhat during adolescence and young adulthood. Relative survival probabilities for these siblings increase markedly at older ages, reflecting the cumulative effect of their mortality advantage throughout life. Compared with the U.S. 1900 cohort, male siblings of centenarians were at least 17 times as likely to attain age 100 themselves, while female siblings were at least 8 times as likely.genetics ͉ aging ͉ longevity ͉ sibling pair ͉ oldest old M any centenarians live the majority of their exceptionally long lives in good health, demonstrating a rapid decline only near the end of life (1). Deciphering why centenarians markedly delay or in some cases even escape age-associated diseases could help in better understanding the pathogenesis of diseases such as stroke, heart disease, cancer, and Alzheimer's dementia, and the relative contributions of environment, behavior, and genetics in determining rates of aging and susceptibility or resistance to diseases that cause premature mortality (2).Whereas survival to old age is known to have a strong environmental and behavioral component, mortality differences between social groups tend to diminish or even disappear at older ages (3-5). One explanation for this phenomenon is that genetic factors unrelated to social groupings play a predominant role in survival chances at older ages. If genetic factors are indeed an important component of longevity, there should be greater similarity of individual longevity within families or lineages than within the population as a whole. We have documented the familial component of longevity in a variety of ways, as part of a larger study of centenarians in the United States.In a previous study, four families, impressive for the number of individuals achieving extreme old age, were identified (6). The question was explored as to whether such intrafamilial clustering could be attributed to chance alone, or if shared characteristics might be responsible for a collective ability to achieve extreme old age. A mathematical analysis was performed to determine the probability of families such as these occurring by random variation alone. Such probabilities were found to be extremely small (less than 1 per all of the families that exist in the world...

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…Accordingly, longevity clusters within families as parents and siblings of centenarians present an increased probability of reaching advanced age (Perls et al ., 2000, 2002; Atzmon et al ., 2004; Willcox et al ., 2006). Alleles which are enriched in centenarians most likely represent genes that are significant for longevity and therefore a significant number of studies have been done in the quest for these alleles/genes.…”

“…The genetic contribution of lifespan increases with greater age, particularly after the age of 60, reaching estimates of 33% in women and 48% in men living to at least 100 (Sebastiani & Perls, 2012; Brooks‐Wilson, 2013). Accordingly, longevity clusters within families as parents and siblings of centenarians have an increased probability of reaching advanced age (Perls et al ., 2000, 2002; Atzmon et al ., 2004; Willcox et al ., 2006). …”

Power of non‐parametric linkage analysis in mapping genes contributing to human longevity in long‐lived sib‐pairs

“…The method makes use of the information on alleles shared identical by decent (IBD) between affected sib-pairs to infer the location of genes that are linked to the trait of interest . Higher probability for achieving longevity in the centenarians' siblings reported by recent studies [Perls et al, 1998[Perls et al, , 2002 suggests the feasibility of sampling long-lived sib-pair data for non-parametric linkage analysis. As the first application, Puca et al [2001] scanned the whole genome by applying non-parametric linkage analysis to long-lived sibpairs and reported a region on chromosome 4 that could possibly harbor a gene affecting human longevity.…”

“…2) indicating a growing importance of the allele in maintaining survival. However, one should not conclude that the genetic influence is increasing at extreme ages [Perls et al, 2002], as the phenomenon is only the result of a proportional hazard model.…”

The extreme longevity: The state of the art in Italy

“…These studies demonstrate that parents, siblings and offspring of long-lived subjects (but not the spouses of the long-lived subjects who shared with them most part of their adult life) have a significant survival advantage, a higher probability to have been or to became long-living persons and to have a lower risk to undergo the most important age-related diseases, such as cardio-and cerebro-vascular diseases, diabetes and cancer, when compared to the appropriate control (Perls et al, 2002;Terry et al, 2003Terry et al, , 2004Ikeda et al, 2006;Shoenmaker et al, 2006;.…”