This paper is, more or less, a complaint that the research community still knows far too little of the relative importance of different mechanisms of aging. That is fair enough, certainly true. The authors put that complaint in the context of the current prevalent attitude of using the hallmarks of aging as a checklist for development of therapies to intervene in aging, which in some cases (such as the dysregulation of nutrient sensing) is also fair enough. Not all of the hallmarks are evidently good places to intervene, as they are most likely far downstream of the causes of degenerative aging. That said, I do feel that the authors are deliberately ignoring the copious in vivo evidence for the efficacy of clearing senescent cells in the service of making their point, however. Given the many studies showing rapid reversal of diverse forms of age-related pathology in mice following treatment with senolytic drugs, it is a little ridiculous to suggest that we really don't know much about whether nor not removing of senescent cells is meaningfully beneficial.
The critical outstanding question is: Can aging processes be slowed down? Evidence in nature suggests a positive answer to this fundamental question. For instance, similar pathobiological changes associated with aging develop over very different time scales in different mammalian species. While it may take 70 years for a senile cataract to develop in a human, similar age-related changes develop in horses within 20 years, in dogs within 10 years, and in mice in even only 2 years. Analogous considerations also apply to many other age-related alterations (hair greying, muscle loss, etc.). Although the biology underlying these differences in aging rate are not well understood, these examples demonstrate that similar aging phenomena in comparable tissues can develop over very different absolute time scales. Therefore, there seems to be some plasticity that could be harnessed, in theory, for slowing down the aging process.
Much of what is currently thought to be known about the biological underpinnings of the aging process has been presented in concepts like the "hallmarks of aging" which summarize processes claimed to be involved in driving organismal aging phenomena. Here, we carefully examine the evidence presented in favor of such links between these processes and aging. As we will explain in detail below, we identify limitations that are often grounded in the choice of models and/or the way aging is measured. We conclude by outlining experimental designs that are suited to overcome these current limitations and that can be used to address if and to what extent putative aging regulators are in fact involved in regulating organismal aging rate.
Aging research essentially deals with a many-to-many mapping problem. There are changes in many age-sensitive phenotypes (collectively representing the aging process, i.e., the transition of a young adult organism to an aged one) that could, in theory, each be influenced by a large set of regulators. Advances in aging research will critically depend on a better definition of this problem. In conclusion, aging research will benefit from a better definition of how specific regulators map onto age-dependent change, considered on a phenotype-by-phenotype basis. Resolving some of these key questions will shed more light on how tractable (or intractable) the biology of aging is.