What the Exponential Rise in Mortality with Age Tells Us About the Nature of Aging

When charting rising mortality against increasing chronological age, the result is a smooth exponential curve - the Gompertz-Makeham law of mortality. We might well ask how the exceptionally complicated process of degenerative aging, consisting of many distinct mechanisms butting heads and breaking things in a stochastic manner, can produce this outcome. This is one of the questions posed by epidemiologists in today's open access paper. It is a good example of the way in which a scientist can hypothesize about the operation of mechanisms given only data on the outcomes of those mechanisms.

For context, the authors of the paper here are the same researchers who applied reliability theory to aging some years ago. Reliability theory has historically been used to model the deterioration of complex machinery (such as electronics, and now biological organisms) by assuming the machinery to be a collection of various types of redundant parts. Loss of redundancy is the primary form of damage that takes place, and failure occurs when insufficient redundancy remains. Conceptually, this maps well to an organism consisting of cells, or an organ (a liver) consisting of repeated units (such as bile ducts), and so forth.

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

Discussing the age-related dynamics of mortality, we should consider the following relevant question in the study of aging: how is it possible for different diseases and causes of death to "negotiate" with each other in order to produce a simple exponential function for mortality from all causes of death combined (given that contribution of the different causes of death to total mortality varies greatly with age)? Linked to this question is the traditional approach to life extension, based on combating individual causes of death.

Indeed, it is well known which causes of death were reduced in order produce the mortality decrease that took place in the first half of the 20th century. These are primarily pneumonia, influenza, tuberculosis, enteritis and other infectious diseases. It is also known that mortality from each of these causes changes with age. Therefore, their elimination should inevitably change the age dynamics of total mortality and the size of its age-related component. However, mortality increases with age according to the fairly simple Gompertz formula (the Makeham term is close to zero in recent decades and has little effect on mortality dynamics). The only way to resolve this contradiction is to admit that the causes of death are not independent of each other, but are coordinated so that the age-related component of mortality increases exponentially with age, despite a dramatic change in the structure of causes of death. However, then the following question arises: how do the causes of death "agree" with each other so that the age-related component of mortality grows with age in accordance with a fairly simple Gompertz law?

The above facts can be explained by using the hypothesis of limited organism's reliability. According to this hypothesis, an organism is a multi-redundant system with high, but not infinitely high reliability. Therefore, there is always some probability that the interference in the work of individual elements of the organism will coincide randomly in time and the organism will move into a state of non-specific vulnerability. Such failure causes a whole cascade of dependent failures of other systems in the organism, so there are many observed causes of death.

In the simplest illustration of the idea of this hypothesis, an organism in a normal state can die only in extreme situations, certainly lethal for any organism (corresponding to the background component of mortality, which in the developed countries is already close to zero). In addition, as a result of the failure of one of the bodily systems, it may also pass into a state of non-specific vulnerability, which is called "non-survivor". It should be noted that this state has a quite clear biological meaning. For example, failures of immune system, the frequency of which sharply increases with age, create a nonspecific vulnerability to the widest range of diseases, both endogenous and exogenous.

Having fallen into a state of nonspecific vulnerability, an organism quickly dies from any of the first causes it has caught. This concept to a certain extent echoes the new concept of phenoptosis, when an organism is eliminated from the population as a result of multiple systems failure. The age-related component of mortality is determined by the rate of the first limiting stage of the organism's transition from a normal state to a state of non-specific vulnerability ("non-survivor"). This means that the age-related component of mortality is not summed-up of individual causes of death but, on the contrary, is being distributed between them.

In other words, the rate of the first limiting stage determines the value of "death quota", which is then distributed among its various particular manifestations, called "causes" of death. This explains why elimination of the separate age-dependent causes of death is not always capable of changing the size of the age component of mortality. In fact, any reduction of the death rate of organisms, being in a state of non-specific vulnerability, inevitably leads to the increase of share of the organisms being in this state, and to restoration of the former mortality rate due to increase of mortality from other causes.

The hypothesis of limited organism's reliability explains the phenomenon of historical stability of the age-related component of mortality before the early 1950s, as well as the facts of "independent" behavior of the total mortality in relation to its components. Moreover, this hypothesis makes it possible to justify the Gompertz-Makehan formula using such simple notions of the nature of aging as reduction of reserves of organism systems with age. Therefore, the idea of limited reliability of the organism is sufficiently well-founded and natural to be used as a working hypothesis in determining the ways and prospects for extension of human life.

This hypothesis argues that the problem of human lifespan extension is not reduced to fighting individual causes of death. Moreover, the hypothesis of limited reliability predicts that reduction of mortality from individual causes of death will only lead to a significant reduction of total mortality when the initial stage of organism's destruction (transition to a state of non-specific vulnerability) ceases to be a limiting stage of the whole process.

Apparently, the future belongs to another strategy based on explaining the mechanisms of organism's reliability providing nonspecific resistance to a wide range of damaging factors. If successful in this direction, we can expect simultaneous reduction in mortality from a wide variety of diseases. These ideas are conceptually close to the currently developing direction in gerontology, which is called geroscience. This direction is based on the well-known idea that in order to increase lifespan and healthy longevity in particular, it is necessary to move from combating specific diseases of old age to slowing down the pathological processes leading to aging (e.g., reduction of systemic sterile inflammation). Apparently, further success in gerontology should be expected in the development of this particular direction of research.

Comments

Obvious. Parasites against the host in trench warfare. Too simple and too unexploitable at this time.

Posted by: morris39 at March 22nd, 2021 8:03 PM

I wonder why they talk only about "slowing down the pathological processes leading to aging" but not about reversing them, particularly so because they have been funded by SRF in the past and thus should know about SENS.

Posted by: Antonio at March 23rd, 2021 6:04 AM

@Antonio
It is (intended as) a mainstream publication. For all it is worth it is pushing the agenda that you cannot really (effectivity)treat the down stream consequences without addressing the root causes.

Posted by: Cuberat at March 23rd, 2021 9:14 PM

I totally agree that the exponential rise of mortality with age is a critical fact that needs to be accounted for by any theory of aging. Recently, we have compared the mortality data of Canadian men and women with the predictions of a model of Short Telomere Length Induced Senescence (STLIS). Using only 4 parameters obtained directly from telomere length measurements we achieved remarkable agreement with the mortality data. Ref:
Mathematical Connection between Short Telomere Induced Senescence Calculation and Mortality Rate Data
by Jerry B. Torrance 1,*,† and Steve Goldband 2,‡Int. J. Mol. Sci. 2020, 21(21), 7959; https://doi.org/10.3390/ijms21217959 (A more rigorous comparison is in progress.)

We would also point out that the exponential behavior in the mortality data is only for a limited age range, typically between 40 and 80 years old. Younger deaths are dominated not by aging, but by accidents and childhood diseases, while at much higher ages, the data saturate at a value of 1, where the number of people who die approach the total number of people left living.

Jerry

Posted by: Jerry B. Torrance at April 8th, 2021 1:25 PM

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