Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic ...contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different "genetic signatures" of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.
The New England Centenarian Study (NECS) was founded in 1994 as a longitudinal study of centenarians to determine if centenarians could be a model of healthy human aging. Over time, the NECS along ...with other centenarian studies have demonstrated that the majority of centenarians markedly delay high mortality risk-associated diseases toward the ends of their lives, but many centenarians have a history of enduring more chronic age-related diseases for many years, women more so than men. However, the majority of centenarians seem to deal with these chronic diseases more effectively, not experiencing disability until well into their nineties. Unlike most centenarians who are less than 101 years old, people who live to the most extreme ages, e.g., 107+ years, are generally living proof of the compression of morbidity hypothesis. That is, they compress morbidity and disability to the very ends of their lives. Various studies have also demonstrated a strong familial component to extreme longevity and now evidence particularly from the NECS is revealing an increasingly important genetic component to survival to older and older ages beyond 100 years. It appears to us that this genetic component consists of many genetic modifiers each with modest effects, but as a group they can have a strong influence.
Summary
Because people age differently, age is not a sufficient marker of susceptibility to disabilities, morbidities, and mortality. We measured nineteen blood biomarkers that include constituents ...of standard hematological measures, lipid biomarkers, and markers of inflammation and frailty in 4704 participants of the Long Life Family Study (LLFS), age range 30–110 years, and used an agglomerative algorithm to group LLFS participants into clusters thus yielding 26 different biomarker signatures. To test whether these signatures were associated with differences in biological aging, we correlated them with longitudinal changes in physiological functions and incident risk of cancer, cardiovascular disease, type 2 diabetes, and mortality using longitudinal data collected in the LLFS. Signature 2 was associated with significantly lower mortality, morbidity, and better physical function relative to the most common biomarker signature in LLFS, while nine other signatures were associated with less successful aging, characterized by higher risks for frailty, morbidity, and mortality. The predictive values of seven signatures were replicated in an independent data set from the Framingham Heart Study with comparable significant effects, and an additional three signatures showed consistent effects. This analysis shows that various biomarker signatures exist, and their significant associations with physical function, morbidity, and mortality suggest that these patterns represent differences in biological aging. The signatures show that dysregulation of a single biomarker can change with patterns of other biomarkers, and age‐related changes of individual biomarkers alone do not necessarily indicate disease or functional decline.
APOE Alleles and Extreme Human Longevity Sebastiani, Paola; Gurinovich, Anastasia; Nygaard, Marianne ...
The journals of gerontology. Series A, Biological sciences and medical sciences,
01/2019, Letnik:
74, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract
We assembled a collection of 28,297 participants from seven studies of longevity and healthy aging comprising New England Centenarian, Long Life Family, Longevity Gene Population, Southern ...Italian Centenarian, Japanese Centenarian, the Danish Longevity, and the Health and Retirement Studies to investigate the association between the APOE alleles
ε2ε3
and
ε4
and extreme human longevity and age at death. By using three different genetic models and two definitions of extreme longevity based on either a threshold model or age at death, we show that
ε4
is associated with a substantially decreased odds for extreme longevity, and increased risk for death that persists even beyond ages reached by less than 1% of the population. We also show that carrying the
ε2ε2
or
ε2ε3
genotype is associated with significantly increased odds to reach extreme longevity, with decreased risk for death compared with carrying the genotype
ε3ε3
but with only a modest reduction in risk for death beyond an age reached by less than 1% of the population.
We analyze the relationship between age of survival, morbidity, and disability among centenarians (age 100-104 years), semisupercentenarians (age 105-109 years), and supercentenarians (age 110-119 ...years). One hundred and four supercentenarians, 430 semisupercentenarians, 884 centenarians, 343 nonagenarians, and 436 controls were prospectively followed for an average of 3 years (range 0-13 years). The older the age group, generally, the later the onset of diseases, such as cancer, cardiovascular disease, dementia, and stroke, as well as of cognitive and functional decline. The hazard ratios for these individual diseases became progressively less with older and older age, and the relative period of time spent with disease was lower with increasing age group. We observed a progressive delay in the age of onset of physical and cognitive function impairment, age-related diseases, and overall morbidity with increasing age. As the limit of human life span was effectively approached with supercentenarians, compression of morbidity was generally observed.
The search for the genetic determinants of extreme human longevity has been challenged by the phenotype's rarity and its nonspecific definition by investigators. To address these issues, we ...established a consortium of four studies of extreme longevity that contributed 2,070 individuals who survived to the oldest one percentile of survival for the 1900 U.S. birth year cohort. We conducted various analyses to discover longevity-associated variants (LAV) and characterized those LAVs that differentiate survival to extreme age at death (eSAVs) from those LAVs that become more frequent in centenarians because of mortality selection (eg, survival to younger years). The analyses identified new rare variants in chromosomes 4 and 7 associated with extreme survival and with reduced risk for cardiovascular disease and Alzheimer's disease. The results confirm the importance of studying truly rare survival to discover those combinations of common and rare variants associated with extreme longevity and longer health span.
Hierarchical clustering is a simple and reproducible technique to rearrange data of multiple variables and sample units and visualize possible groups in the data. Despite the name, hierarchical ...clustering does not provide clusters automatically, and "tree-cutting" procedures are often used to identify subgroups in the data by cutting the dendrogram that represents the similarities among groups used in the agglomerative procedure. We introduce a resampling-based technique that can be used to identify cut-points of a dendrogram with a significance level based on a reference distribution for the heights of the branch points. The evaluation on synthetic data shows that the technique is robust in a variety of situations. An example with real biomarker data from the Long Life Family Study shows the usefulness of the method.
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