Considering the Most Significant Cause of Aging
Aging is caused by a number of processes, each of which contributes its own form of cell and tissue damage to the bigger picture of breakage and decline. When shaping research strategy, it seems sensible to ask which of these processes is the most important cause of aging: there are limited funds for scientific and clinical development, and we'd like the research community to start at the top of the list. Is this a question that has a simple answer, however? The author of this open access paper would say no, pointing out that the processes and damage of aging interact with one another, and even in very simple models of interacting systems you cannot talk about significance of a single process in isolation, as interacting processes have synergies.
The background for this discussion is another question: can we obtain meaningful benefits to longevity by fixing just one of the forms of damage that cause aging? Insofar as there is a consensus at the moment, that consensus is "no." Even a perfect repair of one cause of aging will still leave medical conditions largely or completely caused by the others, conditions that will kill people on the same schedule as the smaller set of age-related diseases that are prevented or diminished by this narrow scope repair. Taking the other side, the author here proposes that the existence of interactions between forms of damage means that repair of one form of damage may indeed produce a large benefit - but whether this happens in reality is strongly dependent on details that we'll only learn in the near future by building and using rejuvenation therapies capable of this repair:
It becomes clearer and clearer that aging is a result of a significant number of causes and it would seem that counteracting one or several of them should not make a significant difference. Taken at face value, this suggests, for example, that free radicals and reactive oxygen species (ROS) do not play a significant role in aging and that the lifespan of organisms cannot be significantly extended. In this review, I point to the fact that the causes of aging synergize with each other and discuss the implications involved. One implication is that when two or more synergizing causes increase over time, the result of their action increases dramatically.Here is a summary of what we have learned so far as a result of the analysis of aging and its mechanisms in yeast: during the replicative lifespan of yeasts some damage, such as protein aggregates and some mutations, accumulates and this potentially may lead to further damage. The damage accumulated during the replicative lifespan, but not due to mutations, is sufficient to eliminate the ability of the cells to reproduce but does not kill them in the literal sense of the word. In the subsequent period, as a result of further damage, aging accelerates, likely because the causes of aging, whose levels increase, synergize with each other and this finally leads to death. The synergizing causes likely include genomic changes and aggregates formation, as well as other forms of damage such as oxidative stress.
Due to the existence of synergistic interactions between the causes of aging, our perception of which causes are most important is influenced by a relativistic effect. Thus, to the observers investigating the toxicity of free radicals and/or their role in aging, they appear as the main cause, while the other causes appear insignificant, but the opposite appears to be the case for those that study other causes. Both are correct but also incorrect, specifically since the "other causes" are not insignificant! In reality, the processes are interdependent and it cannot be said that a given cause is responsible for 3% of aging, while another one for 33.3%. This undermines the arguments of those who suggest that the free radical theory of aging is dead or about to die, while certainly the free radicals and ROS are not the only important causes of aging. The same could be said for other theories, so such theories are still alive, at least for now. Since the causes of aging are synergizing, it is also concluded that none of them is the major one but many including free radicals, etc, play significant roles. It follows that health/lifespan might be significantly extended if we eliminate or even attenuate the increase of a few or even just one of the causes of aging.