What Can We Learn about Aging and COVID-19 by Studying Mortality?

Promising ideas and directions for further research into biology of aging are discussed using analysis of the age-related kinetics of organisms' mortality. It is shown that the traditional evolutionary theory explaining aging by decreasing force of natural selection with age is not consistent with the data on age-related mortality kinetics. The hypothesis of multistage destruction of organisms with age, including the rate-limiting stage of transition to a state of non-specific vulnerability ("non-survivor"), is discussed. It is found that the effect of the COVID-19 coronavirus infection on mortality is not additive (as it was the case with the Spanish flu epidemic in 1918), but multiplicative (proportional) for ages over 65 years.

Testing predictions of the programmed and stochastic theories of aging: comparison of variation in age at death, menopause, and sexual maturation.

One of the arguments against aging being programmed is the assumption that variation in the timing of aging-related outcomes is much higher compared to variation in timing of the events programmed by ontogenesis. The main objective of this study was to test the validity of this argument. To this aim, we compared absolute variability (standard deviation) and relative variability (coefficient of variation) for parameters that are known to be determined by the developmental program (age at sexual maturity) with variability of characteristics related to aging (ages at menopause and death). We used information on the ages at sexual maturation (menarche) and menopause from the nationally representative survey of the adult population of the United States (MIDUS) as well as published data for 14 countries. We found that coefficients of variation are in the range of 8-13% for age at menarche, 7-11% for age at menopause, and 16-21% for age at death. Thus, the relative variability for the age at death is only twice higher than for the age at menarche, while the relative variability for the age at menopause is almost the same as for the age at menarche.

The reliability theory of aging and longevity.

Reliability theory is a general theory about systems failure. It allows researchers to predict the age-related failure kinetics for a system of given architecture (reliability structure) and given reliability of its components. Reliability theory predicts that even those systems that are entirely composed of non-aging elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Aging, therefore, is a direct consequence of systems redundancy. Reliability theory also predicts the late-life mortality deceleration with subsequent leveling-off, as well as the late-life mortality plateaus, as an inevitable consequence of redundancy exhaustion at extreme old ages. The theory explains why mortality rates increase exponentially with age (the Gompertz law) in many species, by taking into account the initial flaws (defects) in newly formed systems. It also explains why organisms "prefer" to die according to the Gompertz law, while technical devices usually fail according to the Weibull (power) law. Theoretical conditions are specified when organisms die according to the Weibull law: organisms should be relatively free of initial flaws and defects. The theory makes it possible to find a general failure law applicable to all adult and extreme old ages, where the Gompertz and the Weibull laws are just special cases of this more general failure law. The theory explains why relative differences in mortality rates of compared populations (within a given species) vanish with age, and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels. Overall, reliability theory has an amazing predictive and explanatory power with a few, very general and realistic assumptions. Therefore, reliability theory seems to be a promising approach for developing a comprehensive theory of aging and longevity integrating mathematical methods with specific biological knowledge.

Evolution, mutations, and human longevity: European royal and noble families.

The evolutionary theory of aging predicts that the equilibrium gene frequency for deleterious mutations should increase with age at onset of mutation action because of weaker (postponed) selection against later-acting mutations. According to this mutation accumulation hypothesis, one would expect the genetic variability for survival (additive genetic variance) to increase with age. The ratio of additive genetic variance to the observed phenotypic variance (the heritability of longevity) can be estimated most reliably as the doubled slope of the regression line for offspring life span on paternal age at death. Thus, if longevity is indeed determined by late-acting deleterious mutations, one would expect this slope to become steeper at higher paternal ages. To test this prediction of evolutionary theory of aging, we computerized and analyzed the most reliable and accurate genealogical data on longevity in European royal and noble families. Offspring longevity for each sex (8409 records for males and 3741 records for females) was considered as a dependent variable in the multiple regression model and as a function of three independent predictors: paternal age at death (for estimation of heritability of life span), paternal age at reproduction (control for parental age effects), and cohort life expectancy (control for cohort and secular trends and fluctuations). We found that the regression slope for offspring longevity as a function of paternal longevity increases with paternal longevity, as predicted by the evolutionary theory of aging and by the mutation accumulation hypothesis in particular.

Mutation load and human longevity.

Since paternal age at reproduction is considered to be the main factor determining human spontaneous mutation rate (Crow, J. (1993) Environ. Mol. Mutagenesis, 21, 122-129), the effect of paternal age on human longevity was studied on 8,518 adult persons (at age 30 and above) from European aristocratic families with well-known genealogy. The daughters born to old fathers (50-59 years) lose about 4.4 years of their life compared to daughters of young fathers (20-29 years) and these losses are highly statistically significant, while sons are not significantly affected. Since only daughters inherit the paternal X chromosome, this sex-specific decrease in daughters' longevity might indicate that human longevity genes (crucial, house-keeping genes) sensitive to mutational load might be located in this chromosome.

A typical interdisciplinary topic: questions of the mortality dynamics.

Dynamic characteristics of mortality experience are intensely studied in demography and in experimental gerontology. The classic Gompertz-Makeham function is also a significant starting point of numerous investigations in this topic. By comparative analysis of human vital statistics, one can observe characteristic secular and topological variations of the Gompertz parameters. Some of these findings are reviewed briefly in the article. Some other related questions are also touched upon. For example, the concept of the maximum life span is criticised. A thorough overview of literature data makes it clear that the general male mortality excess is by far not so unambiguous as is widely supposed. Surprisingly simple stochastic models, published by one of us in the recent past, can serve as theoretical background for the Gompertz law. Further studies would be necessary to check the biological relevance of these models.

[Biological-demographic aspects of investigating the duration of life]. / Biologo-demograficheskie aspekty issledovaniya prodolzhitel'nosti zhizni.

PIP: The author discusses the importance of investigating the biological factors that influence mortality, with a focus on the positive impact such investigations have on research concerning population reproduction.^ieng

Epidemiologic approach to the biology of human life span.

The present work suggests a new, epidemiologic approach to the study of the biological mechanisms determining human life span. The proposed approach is based on revealing the biological component of human mortality with a subsequent analysis of its regional and sex variability. The biological component of mortality is defined as a component which is age-dependent, but historically stable with respect to socio-economic transformations. It has been shown that the Gompertz function elaborated in the Gompertz-Makeham Law known since 1860 can serve as the biological component. The Gompertz function values, being historically stable. For the first time ever, biological mortality maps have been drawn for the male and female population of Europe. Possible mechanisms of these regional and sex-related biological distinctions are likewise considered.

[Does a limit of the life span really exist?]. / Sushchestvuet li predel prodolzhitel'nosti zhizni organizmov?

Mathematical models of aging are in conflict with real data on centenarian's survival, when these models are based on the concept of maximal life span potential. It seems that there is no absolute superior limit for the duration of life.

Human life span stopped increasing: why?

To account for the cessation of human life span increase in developed countries, we have studied the Swedish vital statistics over the period of 1901-1978. Approximating age-related mortality dynamics as the sum of the constant (age-independent mortality) and exponential (age-dependent mortality), we have discovered a striking phenomenon consisting in historical stability of age-dependent mortality. It appeared that decrease in total mortality was exclusively due to age-independent mortality which is close now to the limiting (zero) level. The results obtained prove the existence of the biological limit for the average life span and show that the conventional reserves for decrease in mortality have been exhausted. Thus, the problem of life prolongation requires a new way of thinking.