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