How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity

Abstract

Increasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field.

Keywords: Genetic heterogeneity; Health of the elderly; Longitudinal data; Pleiotropy; Population aging; Quadratic hazard.

Figure 1

The age patterns of survival improvement in Italy (A) and in Sweden (B) obtained from the Human Mortality Database (HMDB).

Figure 2

An illustration of a decline in resistance to stresses with increasing age using Gompertz’s model of human mortality evaluated for SSA life table data on the 1900-birth cohort, females. Each additional year of life lived after age 90 is associated with higher mortality risk than each additional year lived after age 70. Equivalently, for each y, the annual increases in mortality risk are larger among 90-year old than among 70-year old individuals.

Figure 3

Scheme illustrating the mechanism that regulates age trajectories of individual physiological variables in the stochastic process model of human mortality and aging. The white noise W_t,, enhanced by the coefficient B(t, G) and the difference between the value of the physiological variable Y_t and the effect of allostatic adaptation f₁(t, G) multiplied by the negative feedback coefficient a(t, G) are added and integrated to produce the value of the physiological variable Y_t at age t. The variable Y_t is used in the feedback regulation mechanism. Taken together with age, t, and genetic background, G, the variable Y_t is used for evaluating the mortality risk μ(t, Y_t, G) at age t.

Figure 4

Illustration of hypothetical two-dimensional U-shaped mortality risks (quadratic hazards) considered as a function of two risk factors Y_1x and Y_2x (e.g., physiological variables) for 30- and 80-year old individuals. The width of each paraboloid characterizes resistance to stresses for the young and old individuals. The coordinates of the minimal values of each paraboloid correspond to physiological norms. The model allows the normal values to be different at different ages. Individual physiological states are allowed to change with increasing age.

Figure 5

The changes in the U-shapes of mortality risks with increasing age for carriers (A) and non-carriers (B) of the APOE e4 allele evaluated from data on serum cholesterol and survival for individuals from the original FHS cohort.