A Rate of Living Approach to the Concept of Programmed Aging

A vocal minority of gerontologists consider aging to be a genetic program. In their view, changes in regulation of cellular metabolism that drive aging are selected for in the course of evolution, and these changes cause the observed damage and dysfunction in older individuals. This is the reverse of the more widespread consensus view of aging, in which dysfunction and changes in regulation of cellular metabolism are the result of stochastic molecular damage that is either hard to repair, or gradually overwhelms repair capabilities. In this case, the damage precedes and causes harmful changes in cellular function.

Today, I'll point out a novel take on programmed aging, an open access paper in which the author proposes that the important aspect of aging is that every cell division causes a reduction in mitochondrial function - a very rate-of-living sort of a concept. I can't say that I agree with it, but it is an interesting idea to try to argue one way or another. Further, I do not agree with the author's proposition that failure to date to extend human life span is a failure of the stochastic damage models of aging. No-one has really much tried to repair the damage yet. Senolytic therapies to clear senescent cells are the first approach to aging based on damage repair to have reached the stage of earnest, widespread development efforts. They do very well in the lab, in animal models of age-related disease, but human trials have only just started. The numerous other approaches, aimed at different types of damage, have yet to reach fruition. If anything, the failures of past decades represent a failure on the part of the research and development community to engage seriously with the mechanisms of damage.

In the field of research into aging taken as a whole, there is a pretty good catalog of fundamental forms of molecular damage, and there is a pretty good catalog of age-related diseases and dysfunction. The understanding of how these two are linked is, unfortunately, very poor: knowing exactly how aging progresses would require a complete map of cellular metabolism, something that is decades away from realization at the very least. Thus it is quite easy for any given aspect of aging to be claimed and fit into either programmed aging therapies or stochastic damage theories. Cellular senescence, for example, is clearly important in aging, given that clearing these cells extends life and reverses age-related disease in animal models. Does the burden of senescent cells increase with age due to rising levels of cellular damage and consequent impairment of the immune system in its role of clearing senescent cells? Or does it rises with age because of programmed epigenetic changes that diminish resilience to the senescent state by, e.g. impairing autophagy and mitochondrial function. In areas in which complexity and lack of information makes it quite challenging to produce sound proofs, theorizing is rampant.

There is considerable variation in evolutionary models for how and why a program of detrimental change over time might be selected for. Some, like the hyperfunction theory, look a lot like the standard antagonistic pleiotropy view of why evolution doesn't tend to result in adult organisms that can last indefinitely. Biological systems evolve to do very well in early life, to optimize reproductive fitness right out of the gate, regardless of later consequences. So there are developmental programs that run wild in adult life, or systems that are incapable as constituted of running indefinitely, due to inadequate repair, limited space, or other issues. Other researchers suggest that aging is selected for directly, and invoke group selection arguments to suggest that it enhances fitness in times of environmental change, or acts to reduce the odds of ecosystem collapse due to population growth.

One of the more important advances in aging research made of late may turn out to be the discovery that repair of double strand breaks in nuclear DNA is the cause of shifts in epigenetic regulation characteristic of aging. If validated, it is a mechanism by which stochastic DNA damage, different in every cell, can produce the consistent result observed in old tissues, a detrimental change in metabolism that is much the same in all cells of a given type. That might explain the general decline in mitochondrial function, autophagy, and other processes in which changes in gene expression are the proximate cause. This should also place age-related epigenetic change firmly into the stochastic damage camp of aging, a downstream consequence of molecular damage, rather than being a program of some sort.

The Mechanism of Programed Aging: The Way to Create a Real Remedy for Senescence

Despite the breathtaking progress in all areas of science, especially in biology, and the emergence of powerful new technologies, gerontology has not made any progress in extending the maximum human lifespan. The primary reason for this stagnation is that the basal postulate of the dominant concept of aging states that the genes of longevity cannot exist, while age-related organism degradation is the result of the accumulation of stochastic errors. By now, it has been shown experimentally that genes of longevity exist and that their manipulation can influence the maximal lifespan. But, the obtained empirical data have no convincing substantiation.

It is time to conclude that further research in traditional direction is hopeless and we need to revive the initial ideas of Hippocrates and Weisman, which state that the aging process is programmed via the decline in bioenergetics. All conditions are maturated already for the realization of this way. Compared to the first half of the 20th century, genetics made enormous successes, the machinery of biological energy production has been studied substantially, and a huge amount of different fundamental knowledge has been accumulated.

Since the conception of stochastic errors has been dominant until now, gerontologists have not looked into the physicochemical essence of bioenergetics. Therefore, an age-related decline in bioenergetics is usually expressed by such inexplicit terms as "a decrease [decline] in energy production", "a defect of mitochondrial function", "mitochondrial dysfunction", "a defect in mitochondrial respiration", "a decline in mitochondrial function", or "dysregulated mitochondrial dynamics". A level of bioenergetics at the current time is usually measured by the amount of oxygen absorbed per unit of time. This is enough for resolving of some specific tasks but insufficient for understanding the mechanism of programed aging and resolving the longevity problem. To achieve the main goal, it is necessary to find out what parameter of bioenergetics is directly controlled by the genetic program, what molecular mechanism performs this program.

The ATP/ADP ratio generated by the mitochondrial bioenergetics machine predetermines the capacity of any biological system to work. It is this parameter of bioenergetics that is decreased by a genetic program to drive aging. The performance efficiency of bioenergetics depends on the ATP/ADP ratio rather than the absolute value of ATP or the number of mitochondria in cells. For example, the maximum weight that a weightlifter can lift, having a certain muscle mass, depends on the ATP/ADP ratio in his mitochondria, with the number of mitochondria in muscle cells determining how many times he can lift it. Over the years, the strength decreases, even if the muscle mass and the number of mitochondria in the muscles remain the same. The value of the ATP/ADP ratio is denoted below simply as the "bioenergetics level."

The conventional viewpoint on the mechanism of the Hayflick limit, based on the telomere shortening, is now discredited. Instead, another mechanism has been put forward. According to this proposition, there is a specific checkpoint at the boundary between the G1 and S phases in the cycle of cell division called the restriction point. All normal dividing somatic cells make a cycle suspension here; but, after a certain number of reduplication cycles, this checkpoint becomes impassable and cells enter the non-dividing state. The cyclin-dependent kinase inhibitor p27 prevents passage through this restriction point. There is a special molecular mechanism for its removal, and the efficiency of its work depends on the supply of energy. When bioenergetics levels decrease under a certain threshold, this mechanism stops inhibitor removal while cell division becomes impossible.

This leads to the conclusion that the level of cell bioenergetics, and therefore age, are strictly related to the number of duplications that have elapsed. This provides grounds for concluding that the genetic program reduces the level of cell energetics production intermittently in the process of every mitosis. Thus, the core of the mechanism of programmed aging appears to be very simple: every cell division is followed by a slight decrease in energetics generation which in turn causes some decline in viability. It has been shown that, as stem cells are divided, both in vitro and in vivo, their proliferative potential decreases and they reach the Hayflick limit, i.e., stem cells also grow old. It was concluded: "a living organism is as old as its stem cells." Thus, the bioenergetics aging clock regulates the aging process both in cell culture and in an organism.


Is not a reduction in mitochondrial function another way of saying that damage to mtDNA is a cause of aging, thus taking us back to aging as unrepaired damage?

Posted by: Abelard Lindsey at December 30th, 2019 3:28 PM

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