Konstantin G. Arbeev

Cumulative Deficits Better Characterize Susceptibility to Death in Elderly People than Phenotypic Frailty: Lessons from the Cardiovascular Health Study

OBJECTIVES: To compare how well frailty measures based on a phenotypic frailty approach proposed in the Cardiovascular Health Study (CHS) and a cumulative deficits approach predict mortality.

Effect of the APOE Polymorphism and Age Trajectories of Physiological Variables on Mortality: Application of Genetic Stochastic Process Model of Aging

We evaluated effects of the APOE polymorphism (carriers versus noncarriers of the e4 allele) and age trajectories of total cholesterol (CH) and diastolic blood pressure (DBP) on mortality risk in the Framingham Heart Study (original cohort). We found that long-lived carriers and noncarriers have different average age trajectories and long-lived individuals have consistently higher levels and less steep declines at old ages compared to short-lived individuals. We applied the stochastic process model of aging aimed at joint analyses of genetic and nongenetic subsamples of longitudinal data and estimated different aging-related characteristics for carriers and noncarriers which otherwise cannot be evaluated from data. We found that such characteristics differ in carriers and noncarriers: (1) carriers have better adaptive capacity than noncarriers in case of CH, whereas for DBP the opposite situation is observed; (2) mean allostatic trajectories are higher in carriers and they differ from “optimal” trajectories minimizing mortality risk; (3) noncarriers have lower baseline mortality rates at younger ages but they increase faster than those for carriers resulting in intersection at the oldest ages. Such observations strongly indicate the presence of a genetic component in respective aging-related mechanisms. Such differences may contribute to patterns of allele- and sex-specific mortality rates.

Increasing Rates of Dementia at Time of Declining Mortality From Stroke

Background and Purpose— Stroke is associated with increased risk of dementia. There has been a decline in mortality from stroke among persons 65 and over in recent decades in the US. It is not clear, however, how this process has affected incidence of various dementias. Methods— We evaluated over time changes in stroke admission rates and survival, and in rates of newly diagnosed dementias (Alzheimer disease, senile, and cerebrovascular disease–related dementia) in persons with and without stroke aged 65 and over, using Medicare inpatient records, 1984 to 2001, linked to the National Long-Term Care Survey (about 380 000 person-years totally). Results— Age-adjusted stroke rate increased from 0.0066 to 0.008 (P=0.08) from 1984–1990 to 1991–2001. One-year survival after stroke improved from 53% in 1984 to 1990 to 65% in 1991 to 1996 (P<0.0001). Age-standardized rate of diagnosed dementias increased from 0.0062 in 1984 to 1990 to 0.0095 in 1991 to 2000 (P=0.001). Among stroke patients the rate rose from 0.043 to 0.080. The relative increase in risk was largest for cerebrovascular disease–related dementia (3.68). For senile dementia, the increase was small and not significant. Rates of dementia among persons without stroke rose mainly attributable to Alzheimer disease. Conclusions— Mortality from stroke declined mainly because of declining stroke case-fatality. In parallel, the rate of diagnosed dementia increased. The increase was larger for persons with stroke compared with stroke-free population. Improved survival from stroke may contribute to this trend. Other contributing factors may include better diagnostics, an increased propensity to make the diagnosis, and increasing dementia risk attributable to factors other than stroke.

Body Mass Index and Nine-Year Mortality in Disabled and Nondisabled Older U.S. Individuals

OBJECTIVES: To investigate the relationship between body mass index (BMI) and 9‐year mortality in older (≥65) Americans with and without disability.

Cumulative Index of Health Deficiencies as a Characteristic of Long Life

OBJECTIVES: To describe the accumulation of aging‐associated health disorders using a cumulative measure known as a frailty index (FI) and to evaluate its ability to differentiate long‐ and short‐life phenotypes as well as the FIs connection to aging‐associated processes in older people.

Age Patterns of Incidence of Geriatric Disease in the U.S. Elderly Population:: Medicare-Based Analysis

To use the Medicare Files of Service Use (MFSU) to evaluate patterns in the incidence of aging‐related diseases in the U.S. elderly population.

Heritability Estimates of Endophenotypes of Long and Health Life: The Long Life Family Study

BACKGROUND Identification of gene variants that contribute to exceptional survival may provide critical biologic information that informs optimal health across the life span. METHODS As part of phenotype development efforts for the Long Life Family Study, endophenotypes that represent exceptional survival were identified and heritability estimates were calculated. Principal components (PCs) analysis was carried out using 28 physiologic measurements from five trait domains (cardiovascular, cognition, physical function, pulmonary, and metabolic). RESULTS The five most dominant PCs accounted for 50% of underlying trait variance. The first PC (PC1), which consisted primarily of poor pulmonary and physical function, represented 14.3% of the total variance and had an estimated heritability of 39%. PC2 consisted of measures of good metabolic and cardiovascular function with an estimated heritability of 27%. PC3 was made up of cognitive measures (h(2) = 36%). PC4 and PC5 contained measures of blood pressure and cholesterol, respectively (h(2) = 25% and 16%). CONCLUSIONS These PCs analysis-derived endophenotypes may be used in genetic association studies to help identify underlying genetic mechanisms that drive exceptional survival in this and other populations.

Health decline, aging and mortality: how are they related?

The deterioration of human health with age is manifested in changes of thousands of physiological and biological variables. The contribution of some of such changes to the mortality risk may be small and cannot be reliably detected by existing statistical methods. A cumulative index of health/well-being disorders, which counts changes in observed variables on the way of losing health, may be an appropriate way to take the effects of such variables into account. In this paper we investigate regularities of the aging-related changes in human health/well-being/survival status described by such an index using the new version of the quadratic hazard model of human aging and mortality. We found that the shape and the location of the mortality risk, considered as a function of the introduced health-related index, changes with age reflecting the decline in stress resistance and the age-dependence of the “optimal” health/well-being status. Comparison of these results with findings from early studies using the Cox’s-like model of risk function indicates that the results are likely to describe regularities of deterioration in human health during the aging process.

Time trends of incidence of age-associated diseases in the US elderly population: medicare-based analysis

OBJECTIVES time trends of age-adjusted incidence rates of 19 ageing-related diseases were evaluated for 1992-2005 period with the National Long Term Care Survey and the Surveillance, Epidemiology and End RESULTS Registry data both linked to Medicare data (NLTCS-Medicare and SEER-Medicare, respectively). METHODS the rates were calculated using individual medical histories (34,077 individuals from NLTCS-Medicare and 199,418 from SEER-Medicare) reconstructed using information on diagnoses coded in Medicare data, dates of medical services/procedures and Medicare enrolment/disenrolment. RESULTS increases of incidence rates were dramatic for renal disease [the average annual percent change (APC) is 8.56%, 95% CI = 7.62, 9.50%], goiter (APC = 6.67%, 95% CI = 5, 90, 7, 44%), melanoma (APC = 6.15%, 95% CI = 4.31, 8.02%) and Alzheimers disease (APC = 3.96%, 95% CI = 2.67, 5.26%), and less prominent for diabetes and lung cancer. Decreases of incidence rates were remarkable for angina pectoris (APC = -6.17%, 95% CI = -6.96, -5.38%); chronic obstructive pulmonary disease (APC = -5.14%, 95% CI = -6.78,-3.47%), and ulcer (APC = -5.82%, 95% CI = -6.77,-4.86%) and less dramatic for carcinomas of colon and prostate, stroke, hip fracture and asthma. Incidence rates of female breast carcinoma, myocardial infarction, Parkinsons disease and rheumatoid arthritis were almost stable. For most diseases, an excellent agreement was observed for incidence rates between NLTCS-Medicare and SEER-Medicare. A sensitivity analysis proved the stability of the evaluated time trends. CONCLUSION time trends of the incidence of diseases common in the US elderly population were evaluated. The results show dramatic increase in incidence rates of melanoma, goiter, chronic renal and Alzheimers disease in 1992-2005. Besides specifying widely recognised time trends on age-associated diseases, new information was obtained for trends of asthma, ulcer and goiter among the older adults in the USA.

Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan

Progress in unraveling the genetic origins of healthy aging is tempered, in part, by a lack of replication of effects, which is often considered a signature of false‐positive findings. We convincingly demonstrate that the lack of genetic effects on an aging‐related trait can be because of trade‐offs in the gene action. We focus on the well‐studied apolipoprotein E (APOE) e2/3/4 polymorphism and on lifespan and ages at onset of cardiovascular diseases (CVD) and cancer, using data on 3924 participants of the Framingham Heart Study Offspring cohort. Kaplan–Meier estimates show that the e4 allele carriers live shorter lives than the non‐e4 allele carriers (log rank = 0.016). The adverse effect was attributed to the poor survival of the e4 homozygotes, whereas the effect of the common e3/4 genotype was insignificant. The e3/4 genotype, however, was antagonistically associated with onsets of those diseases predisposing to an earlier onset of CVD and a later onset of cancer compared to the non‐e4 allele genotypes. This trade‐off explains the lack of a significant effect of the e3/4 genotype on survival; adjustment for it in the Cox regression model makes the detrimental effect of the e4 allele highly significant (P = 0.002). This trade‐off is likely caused by the lipid‐metabolism‐related (for CVD) and nonrelated (for cancer) mechanisms. An evolutionary rationale suggests that genetic trade‐offs should not be an exception in studies of aging‐related traits. Deeper insights into biological mechanisms mediating gene action are critical for understanding the genetic regulation of a healthy lifespan and for personalizing medical care.