Thomas T. Perls

A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4.

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 exerts 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.

Life-long sustained mortality advantage of siblings of centenarians

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.

Genetic Signatures of Exceptional Longevity in Humans

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.

Achieving and maintaining cognitive vitality with aging.

Cognitive vitality is essential to quality of life and survival in old age. With normal aging, cognitive changes such as slowed speed of processing are common, but there is substantial interindividual variability, and cognitive decline is clearly not inevitable. In this review, we focus on recent research investigating the association of various lifestyle factors and medical comorbidities with cognitive aging. Most of these factors are potentially modifiable or manageable, and some are protective. For example, animal and human studies suggest that lifelong learning, mental and physical exercise, continuing social engagement, stress reduction, and proper nutrition may be important factors in promoting cognitive vitality in aging. Manageable medical comorbidities, such as diabetes, hypertension, and hyperlipidemia, also contribute to cognitive decline in older persons. Other comorbidities such as smoking and excess alcohol intake may contribute to cognitive decline, and avoiding these activities may promote cognitive vitality in aging. Various therapeutics, including cognitive enhancers and protective agents such as antioxidants and anti-inflammatories, may eventually prove useful as adjuncts for the prevention and treatment of cognitive decline with aging. The data presented in this review should interest physicians who provide preventive care management to middle-aged and older individuals who seek to maintain cognitive vitality with aging.

Middle-aged mothers live longer

Comparing two groups of women born in 1896, we found that women who lived to at least age 100 were four times more likely to have had children while in their forties than women who survived only to age 73. The ability to have children in the fifth decade may be a marker for slow ageing and subsequent ability to achieve extreme longevity. We propose that the evolutionary pressure to extend lifespan is closely linked to prolonging the period of time during which women can bear children.

Centenarians: the older you get, the healthier you have been

A retrospective analysis of the health and functional status of centenarians shows they are healthy and independent for most of their lives and experience a relatively rapid terminal decline.

Siblings of centenarians live longer

demographic characteristics between the two groups of probands. In fact, it may be true that centenarians come from larger sibships. We (TTP) recently reported the finding that 19% of female centenarians had children after the age of 40 compared with 6% of women who died at the age of 73 years. 1

Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span.

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.

Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan

We previously reported a genomewide linkage study for human longevity using 308 long-lived individuals (LLI) (centenarians or near-centenarians) in 137 sibships and identified statistically significant linkage within chromosome 4 near microsatellite D4S1564. This interval spans 12 million bp and contains ≈50 putative genes. To identify the specific gene and gene variants impacting lifespan, we performed a haplotype-based fine-mapping study of the interval. The resulting genetic association study identified a haplotype marker within microsomal transfer protein as a modifier of human lifespan. This same variant was tested in a second cohort of LLI from France, and although the association was not replicated, there was evidence for statistical distortion in the form of Hardy–Weinberg disequilibrium. Microsomal transfer protein has been identified as the rate-limiting step in lipoprotein synthesis and may affect longevity by subtly modulating this pathway. This study provides proof of concept for the feasibility of using the genomes of LLI to identify genes impacting longevity.

Disentangling the Roles of Disability and Morbidity in Survival to Exceptional Old Age

BACKGROUND Although it is commonly held that survival to age 100 years entails markedly delaying or escaping age-related morbidities, nearly one-third of centenarians have age-related morbidities for 15 or more years. Yet, we have previously observed that many centenarians compress disability toward the end of their lives. Therefore, we hypothesize that for some centenarians, compression of disability rather than morbidity is a key feature for survival to old age. METHODS This cross-sectional, nationwide study included 523 women and 216 men 97 years or older. The participants were stratified by sex and age at onset (age <85 years [termed survivors] and age >or=85 years [termed delayers]) of chronic obstructive pulmonary disease, dementia, diabetes, heart disease, hypertension, osteoporosis, Parkinson disease, and stroke. Dependent variables were the Barthel Activities of Daily Living Index (Barthel Index) and the Information-Memory-Concentration test of the Blessed Dementia Scale. RESULTS Thirty-two percent of the participants were survivors. For men with hypertension and/or heart disease for 15 or more years, the median Barthel Index score was 90 (independence range, 80-100). For female survivors with hypertension, heart disease, and/or osteoporosis, the median Barthel Index score was 65 (minimal assistance range, 60-79). Generally, men had better function than women: 60% of male survivors had Barthel Index scores of 90 or higher compared with 18% of female survivors (P < .001) and 50% of male delayers had Barthel Index scores of 90 or higher compared with 27% of females delayers (P < .001). CONCLUSIONS Whereas the compression of both morbidity and disability are essential features of survival to old age for some centenarians, for others, the compression of disability alone may be the key prerequisite. Though far fewer in number, male centenarians tend to have significantly better cognition and physical function than their female counterparts.