Dellara F. Terry

Cardiovascular Risk Factors Predictive for Survival and Morbidity-Free Survival in the Oldest-Old Framingham Heart Study Participants

Objectives: To examine whether midlife cardiovascular risk factors predict survival and survival free of major comorbidities to the age of 85.

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.

Genetics of exceptional longevity

Centenarians exist at the extreme of life expectancy and are rare. A number of pedigree and molecular genetic studies indicate that a significant component of exceptional longevity is genetically influenced. Furthermore, the recent discovery of a genetic locus on chromosome 4 indicates the powerful potential of studying centenarians for genetic factors that significantly modulate aging and susceptibility to age-related diseases. These studies include siblings and children of centenarians. Siblings have a significantly increased propensity to achieve exceptional old age and have half the mortality risk of their birth cohort from young adulthood through extreme old age. The children of centenarians are emerging as a promising model for the genetic and phenotypic study of aging relatively slowly and the delay and perhaps escape of important age-related diseases.

RNA Editing Genes Associated with Extreme Old Age in Humans and with Lifespan in C. elegans

Background The strong familiality of living to extreme ages suggests that human longevity is genetically regulated. The majority of genes found thus far to be associated with longevity primarily function in lipoprotein metabolism and insulin/IGF-1 signaling. There are likely many more genetic modifiers of human longevity that remain to be discovered. Methodology/Principal Findings Here, we first show that 18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study of centenarians, the New England Centenarian Study. We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently in the four populations and suggest a strong effect that is independent of the different genetic backgrounds and environments. To evaluate the functional association of these genes with lifespan, we demonstrate that inactivation of their orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. We further demonstrate that inactivation of the argonaute gene, rde-1, a critical regulator of RNA interference, completely restores lifespan to normal levels in the context of adr-1 and adr-2 loss of function. Conclusions/Significance Our results suggest that RNA editors may be an important regulator of aging in humans and that, when evaluated in C. elegans, this pathway may interact with the RNA interference machinery to regulate lifespan.

Serum Heat Shock Protein 70 Level as a Biomarker of Exceptional Longevity

Heat shock proteins are highly conserved proteins that, when produced intracellularly, protect stress exposed cells. In contrast, extracellular heat shock protein 70 (Hsp70) has been shown to have both protective and deleterious effects. In this study, we assessed heat shock protein 70 for its potential role in human longevity. Because of the importance of HSP to disease processes, cellular protection, and inflammation, we hypothesized that: (1) Hsp70 levels in centenarians and centenarian offspring are different from controls and (2) alleles in genes associated with Hsp70 explain these differences. In this cross-sectional study, we assessed serum Hsp70 levels from participants enrolled in either the New England Centenarian Study (NECS) or the Longevity Genes Project (LGP): 87 centenarians (from LGP), 93 centenarian offspring (from NECS), and 126 controls (43 from NECS, 83 from LGP). We also examined genotypic and allelic frequencies of polymorphisms in HSP70-A1A and HSP70-A1B in 347 centenarians (266 from the NECS, 81 from the LGP), 260 NECS centenarian offspring, and 238 controls (NECS: 53 spousal controls and 106 septuagenarian offspring controls; LGP: 79 spousal controls). The adjusted mean serum Hsp70 levels (ng/mL) for the NECS centenarian offspring, LGP centenarians, LGP spousal controls, and NECS controls were 1.05, 1.13, 3.07, 6.93, respectively, suggesting that a low serum Hsp70 level is associated with longevity; however, no genetic associations were found with two SNPs within two hsp70 genes.

Cardiovascular Disease Delay in Centenarian Offspring: Role of Heat Shock Proteins

Abstract: Cardiovascular disease is a major cause of morbidity and mortality of older Americans. We have demonstrated recently that centenarian offspring, when compared with age‐matched controls, avoid and/or delay cardiovascular disease and cardiovascular risk factors. Given recent evidence suggesting that higher circulating levels of HSP70 predict the future development of cardiovascular disease in established hypertensives and a recent study demonstrating a decrease in HSP60 and HSP70 with advancing age, we hypothesized that HSP70 levels would be lower in centenarian offspring compared with controls. The circulating serum concentration of HSP70 in 20 centenarian offspring and 9 spousal controls was analyzed using a modified HSP70 ELISA method. Centenarian offspring showed approximately 10‐fold lower levels of circulating serum HSP70 compared with spousal controls (P < .001). The exact biological significance of the extremely low levels of circulating serum HSP70 observed in centenarian offspring thus far is not clear. However, circulating HSP has been shown to correlate in diseases or disorders in which there is destruction or damage to target tissues or organs, including cardiovascular diseases and numerous autoimmune disorders. We hypothesize that low levels of circulating serum HSP70 may be an indicator of a healthy state and point to longevity of the host; therefore, our results suggest that levels of circulating serum HSP70 may be a marker for longevity.

Centenarian offspring: start healthier and stay healthier.

OBJECTIVES: To assess the relative incidence of age‐related diseases in a group of centenarian offspring who have thus far been considered to be predisposed to “healthy” aging.

Cancer in the oldest old

Our previous work revealed that 88% of centenarians delay or escape the age-related lethal diseases cardiac disease, stroke and diabetes. In the cases of those having a history of cancer we have observed anecdotes of centenarians presenting with large primary tumors that would have otherwise been expected to have metastasized and to have been lethal. However, these tumors were removed without consequence. To better understand the relationship between cancer and exceptional longevity, we quantified age of cancer diagnoses, life-time clinically evident cancer prevalence, tobacco use and family histories through medical record review and interviews. One thousand one hundred and forty-three subjects were studied revealing 20% (N=152) of female and 22% (N=80) of male centenarians with a history of non-skin cancer. The most common cancers were prostate (11.7% of males), breast (8.2% of females), and colon (5.7%). The average age of diagnosis was 80.5 years compared to 63.2 years in the general population according to National Cancer Institute SEER data. Similar delays were noted when age of onset was examined according to specific type of cancer. In conclusion, the age of diagnosis of cancer is relatively delayed in those who live to 100 years. Some cancers are very rare among these individuals suggesting that there are certain cancers that may be incompatible with survival to extreme old age.

The Brachial Artery Remodels to Maintain Local Shear Stress Despite the Presence of Cardiovascular Risk Factors

Objective—Under physiological conditions, arteries remodel in response to changes in blood flow to maintain local shear stress. Risk factors and developing atherosclerosis may be associated with maladaptive remodeling that produces relatively large arteries with low levels of shear stress. Recent studies have shown that the brachial artery and other peripheral arteries are enlarged in patients with risk factors and cardiovascular disease, and we tested the hypothesis that this finding represents maladaptive remodeling. Methods and Results—We measured brachial artery diameter and flow by ultrasound and calculated shear stress in a diverse cohort of 1583 subjects (age 53±17 years, 62% male, and 51% with coronary artery disease and/or peripheral arterial disease). In a stepwise linear regression model, age (P<0.001), gender (P<0.001), body mass index (P<0.001), hypertension (P=0.005), and hypercholesterolemia (P=0.02) were associated with larger brachial diameter. Older age was associated with lower shear stress (P<0.01), consistent with maladaptive remodeling. However, body mass index, hypertension, hypercholesterolemia, and prevalent atherosclerosis were associated with proportionate changes in blood flow and no difference in shear stress compared to reference groups, suggesting adaptive remodeling. Conclusions—These findings suggest that enlargement of the brachial artery in the setting of obesity, hypertension, hypercholesterolemia, and atherosclerosis reflects adaptive remodeling. The results provide further support for the concept that arterial remodeling is an important homeostatic response that is maintained despite the presence of risk factors and developing atherosclerosis.

A hierarchical and modular approach to the discovery of robust associations in genome-wide association studies from pooled DNA samples

BackgroundOne of the challenges of the analysis of pooling-based genome wide association studies is to identify authentic associations among potentially thousands of false positive associations.ResultsWe present a hierarchical and modular approach to the analysis of genome wide genotype data that incorporates quality control, linkage disequilibrium, physical distance and gene ontology to identify authentic associations among those found by statistical association tests. The method is developed for the allelic association analysis of pooled DNA samples, but it can be easily generalized to the analysis of individually genotyped samples. We evaluate the approach using data sets from diverse genome wide association studies including fetal hemoglobin levels in sickle cell anemia and a sample of centenarians and show that the approach is highly reproducible and allows for discovery at different levels of synthesis.ConclusionResults from the integration of Bayesian tests and other machine learning techniques with linkage disequilibrium data suggest that we do not need to use too stringent thresholds to reduce the number of false positive associations. This method yields increased power even with relatively small samples. In fact, our evaluation shows that the method can reach almost 70% sensitivity with samples of only 100 subjects.