The quadratic hazard model for analyzing longitudinal data on aging, health, and the life span.

A better understanding of processes and mechanisms linking human aging with changes in health status and survival requires methods capable of analyzing new data that take into account knowledge about these processes accumulated in the field. In this paper, we describe an approach to analyses of longitudinal data based on the use of stochastic process models of human aging, health, and longevity which allows for incorporating state of the art advances in aging research into the model structure. In particular, the model incorporates the notions of resistance to stresses, adaptive capacity, and "optimal" (normal) physiological states. To capture the effects of exposure to persistent external disturbances, the notions of allostatic adaptation and allostatic load are introduced. These notions facilitate the description and explanation of deviations of individuals' physiological indices from their normal states, which increase the chances of disease development and death. The model provides a convenient conceptual framework for comprehensive systemic analyses of aging-related changes in humans using longitudinal data and linking these changes with genotyping profiles, morbidity, and mortality risks. The model is used for developing new statistical methods for analyzing longitudinal data on aging, health, and longevity.

Declining prevalence of dementia in the U.S. elderly population.

A decline in chronic disability prevalence occurred 1982 to 1999 in the U.S. elderly population parallel to declines in severe cognitive impairment. Comparative analysis of factors contributing to the incidence of dementia led us to suggest explanations for this decline. 42,000 disabled and non-disabled individuals aged 65+ participating in National Long Term Care Surveys (NLTCS) were drawn from Medicare enrollment lists to ensure the US population aged 65+ is represented. Severe cognitive impairment (SCI) was defined by the subject not being able to successfully answer any cognitive screen questions in survey interviews. This definition thus covered cases of dementia of different origin and clinical manifestation: Alzheimer's, non-Alzheimer's, stroke-related, vascular etc. Age-specific prevalence of SCI was calculated for 1982, 1984, 1989, 1994 and 1999, and Medicare record physician determined diagnoses of vascular, mixed and Alzheimer's dementia in 1994 and 1999 was determined by gender and age. We found 310,000 fewer severely cognitively impaired elderly in 1999 than in 1982. The average decline in prevalence was from 5.7% to 2.9% for this period. This was associated with a significant decline in mixed but not Alzheimer's dementias. On a gender basis, the male proportional decline was larger than that of female. Several possible explanations of such a surprising trend in elderly age dementias are discussed, including (i) increased proportion of better educated people among the oldest old; (ii) recent declines in stroke rates (these may contribute to decreasing risks of post-stroke dementias); (ii) expanding use of neuro-protective medications working prophylactically for selected dementias. A significant component of disability decline in the U.S. elderly population is the decline in vascular and mixed dementias, but not in Alzheimer's disease alone. Improved medical therapies and better education among the old appear to play important roles in this decline.

[Serotonin transporter gene polymorphism and factors influencing mental and physical health in aging]. / Sviaz' polimorfnykh variantov gena perenoschika serotonina s faktorami, vliiaiushchimi na fizicheskoe i psikhicheskoe zdorov'e v protsesse stareniia.

Genetic predisposition is thought to exert a certain influence on the indices related to longevity and quality of life. Many of the indices, namely cognitive functioning, stress resistance, metabolism control, may be related to serotonin activity. To study polymorphic serotonin transporter gene variants and their association with features relevant for survival and longevity prognosis, a sample of elderly Russians from Moscow community recruited in the project "Stress-related mechanisms in Russia", comprising 196 subjects, mean age 76.2+/-5.3 years, 155 men, 41 women, has been genotyped. Allele and genotype frequencies have been estimated in 3 groups, aged 60-69, 70-79 and 80-87 years, respectively. A trend (chi2=4.1; p=0.12) to the prevalence of individuals with SS genotype (21.8%), as compared to expected level (14.6%), was found in the group of octogenarians (n=55, mean age 82.8+/-1.9 years). An association analysis between genotype and physiological traits revealed a genotype contribution to past smoking on tendency level (p=0.069), waist to hip ratio (WHR) (p=0.012) and plasma insulin concentration (p=0.02), with a higher frequency of SS genotype among non-smokers and subjects with lower WHR and insulin concentration. Genotype effect on the traits was stronger, being considered in interaction with the age above 80 years. Genotype was not associated with cognitive functioning (MMSE), but proved to be a significant predictor of MMSE performance (p=0.03) in octogenarians. The results obtained are in line with current concepts of serotonin role in smoking, obesity and cognitive functioning.

The new trends in survival improvement require a revision of traditional gerontological concepts.

In 1960, Strehler and Mildvan (SM) theoretically predicted that the parameters of the Gompertz approximation to a mortality curve are negatively correlated. This means that the changes in the human mortality rate resulting from improvement in living standards, progress in health care or the influence of other factors must follow certain regularities prescribed by dependence between the Gompertz parameters. Such dependence, called SM correlation, was then confirmed in a number of empirical studies using period data on human mortality. Since the SM theory was based on the cohort model of mortality, it was tacitly assumed that period and cohort SM correlation patterns are similar. The remarkable stability of the SM correlation pattern revealed in these studies was often regarded as manifestation of a universal demographic law regulating changes in the age pattern of mortality rates. In this paper, we investigated trends in mortality decline in France, Japan, Sweden and the United States. In contrast with traditional expectations, we found that the SM correlation pattern was relatively stable only in certain periods of a population's survival history. Recently, several new correlation patterns emerged and, despite some differences in the timing of the changes, the new patterns are remarkably similar in all four countries. Contrary to traditional expectations, the patterns are not the same for cohort and period mortality data when SM correlations are calculated for France, Sweden and the United States. We show that some changes in the patterns of SM correlation admit interpretation in terms of a biological mechanism of individual adaptation (survival trade off). Some other patterns, however, contradict basic postulates of the SM theory. This indicates the need for revision of traditional concepts establishing the relationship between physiological and demographic patterns of aging.

Have the oldest old adults ever been frail in the past? A hypothesis that explains modern trends in survival.

Three important results concerning the shape and the trends of the human mortality rate were discussed recently in demographic and epidemiological literature. These are the deceleration of the mortality rate at old ages, the tendency to rectangularization of the survival curve, and the decline of the old age mortality observed in the second part of the 20th century. In this paper we show that all these results can be explained by using a model with a new type of heterogeneity associated with individual differences in adaptive capacity. We first illustrate the idea of such a model by considering survival in a mixture of two subpopulations of individuals (called "labile" and "stable"). These subpopulations are characterized by different Gompertz mortality patterns, such that their mortality rates cross over. The survival chances of individuals in these subpopulations have different sensitivities to changes in environmental conditions. Then we develop a more comprehensive model in which the mortality rate is related to the adaptive capacity of an organism. We show that the trends in survival patterns experienced by a mixture of such individuals resemble those obtained in an analysis of empirical data on survival in developed countries. Lastly, we present evidence of the existence of subpopulations of phenotypes in both humans and experimental organisms, which were used as prototypes in our models. The existence of such phenotypes provides the possibility that at least part of today's centenarians originated from an initially frail part of the cohort.

How individual age-associated changes may influence human morbidity and mortality patterns.

Patterns of human mortality share common traits in different populations. They include higher mortality in early childhood, lower mortality during the reproductive period, an accelerated increase of mortality near the end of the reproductive period, and deceleration in the mortality increase at oldest old ages. The deceleration of mortality rate is one of the most intriguing recent findings in longevity research. The role of differential selection in this phenomenon has been well studied. Possible contribution of individual aging in the shape of mortality curve is also recognized. However, this contribution has not been studied in details. In this paper, we specify most common patterns of age-associated changes in an individual organism and discuss their possible influence on morbidity and mortality in population. We subdivide individual age-associated changes into three components, having different influence on morbidity and mortality: (1) basal, (2) ontogenetic, and (3) time-dependent. Basal changes are connected with the universal decrease in the rate of living during an individual life. As a result, some phenotypic effects of aging may accumulate in an organism at a slower rate with age. Basal changes are likely to contribute to a plateau of morbidity often observed at old ages, and may partially be responsible for mortality deceleration at oldest old ages. Ontogenetic component is connected with change of the stages of ontogenesis (e.g., the growth, the reproductive period and the climacteric) during an individual life. The ontogenesis-related changes contribute to wave-like patterns of morbidity in population and may partially be responsible for mortality increase at middle ages and its deceleration at old ages. Time-dependent changes are connected with long-time exposure of an organism to different harmful factors. They are most likely to contribute to morbidity and mortality acceleration. We discuss how all three components of individual age-associated changes may interact in human organism and influence patterns of morbidity and mortality in population.

Recent advances in human gene-longevity association studies.

This paper reviews the recent literature on genes and longevity. The influence of genes on human life span has been confirmed in studies of life span correlation between related individuals based on family and twin data. Results from major twin studies indicate that approximately 25% of the variation in life span is genetically determined. Taking advantage of recent developments in molecular biology, researchers are now searching for candidate genes that might have an influence on life span. The data on unrelated individuals emerging from an ever-increasing number of centenarian studies makes this possible. This paper summarizes the rich literature dealing with the various aspects of the influence of genes on individual survival. Common phenomena affecting the development of disease and longevity are discussed. The major methodological difficulty one is confronted with when studying the epidemiology of longevity involves the complexity of the phenomenon, which arises from the polygenic nature of life span and historical mortality change. We discuss this issue and suggest new methodological approaches.

[Analysis of genetic heterogeneity of bronchial asthma in relation with the age at the onset of disease]. / Analiz geneticheskoi geterogennosti bronkhial'noi astmy v sviazi s vozrastom nachala zabolevaniia.

Earlier, the distribution of bronchial asthma (BA) morbidity with respect to the age of onset (AO) in the Moscow population was found to be bimodal. The distribution had two peaks (before and after 25 years of age) and a significant (P < 0.001) minimum between them. Based on these data, genetic heterogeneity of BA with respect to AO was hypothesized. The purpose of this study was to test this hypothesis via analysis of BA morbidity in families of probands with different AOs. The BA morbidity at different ages and the total recurrent risk of BA were estimated in 1518 relatives of 815 BA probands registered in several district outpatient clinics of Moscow. Based on the data obtained, phenotypic between relatives and correlation by genotype between early-onset and late-onset BA cases (with AOs under and over 25 years, respectively) were estimated. It was demonstrated for the first time that the age distribution of BA morbidity in families of probands was also bimodal. Moreover, when probands with early and late AOs were analyzed separately, proband relatives in each of the two groups exhibited these two peaks of morbidity. This suggests that BA that begins in adolescence and BA of adults are not genetically independent forms of the disease. This agrees with the data on the correlation by genotype between the "forms" with the early and late AOs, which does not significantly differ from 1. However, the prevalence of BA was higher in relatives of those probands who developed BA under the age of 25 compared to relatives of those who developed BA over the age of 25 (11.28 and 7.31%, respectively; P < 0.05). Therefore, patients with early-onset BA are more "burdened" genetically with respect to this disease. Since the BA genetic heterogeneity connected with AO has not been confirmed in this study, it is assumed that the observed bimodal distribution of BA morbidity with respect to age is accounted for by the effect of age itself. In other words, it is hypothesized that ontogenetic factors affect susceptibility to BA so that the susceptibility threshold varies with age.

[Computer programs SAN and EPID: family analysis and epidemiology of multifactorial diseases]. / Komp'iuternye programmy SAN i EPID: semenyi analiz i épidemiologiia mul'tifaktorial'nykh zabolevanii.

SAN software, a database management system, is elaborated. It is subject-oriented to family analysis in the genetics of multifactorial traits (diseases). The software allows creating and maintaining a family-oriented database and using the inputted information to calculate relative risk of disease, heritability, and correlations between several diseases or forms, with both actual frequency of the trait (prevalence) and probability of new cases (incidence). If appropriate data on sibships or nuclear families are available, one can calculate an empirical estimation of the risk of repeated cases of the disease in a family in relation to family anamnesis in different methods of sampling, sex-related morbidity, and varying age of onset. The database may also be used independently as a card index. The software allows one to represent pedigrees graphically, highlighting the desired set of traits. As application program, EPID, was developed, aimed at calculation and graphical presentation of age-related estimations of prevalence and incidence, as well as of the population risk of an individual to develop a disease within a time interval from birth to a certain age (accumulated morbidity).