In the open access paper I'll point out today, a group of researchers who focus on the phenomenon of cellular senescence present their argument for cellular senescence to be the central process in aging. It has to be said that I'm bullish on the clearance of senescent cells as a strong first step towards a toolkit of therapies for human rejuvenation, especially now that startup companies are working on it, but it is important to recognize that the accumulation of senescent cells is just one of a number of fairly independent mechanisms that contribute to aging. Yes, the damage caused by these mechanisms interacts, but the sources of that damage are very different. Removing one only helps to the degree that you have removed one. The others will still get you, because all of them are associated with at least one fatal age-related disease. You can take a look at the introduction to the SENS vision for rejuvenation therapies for a list of the forms of cell and tissue damage that contribute to degenerative aging.
I think we've all heard the fable of the blind men and the elephant deployed in connection with aging research. The life sciences are overwhelmingly populated by specialists, as biochemistry and medicine are both so very complex that productive work requires a narrow focus. Investigating one tiny area of cellular biochemistry can be the focus of an entire career. Even when you can see what you are doing, when poised two centimeters from an elephant's face, the creature is essentially a trunk - and maybe some other stuff back there that obviously can't be as important as the giant trunk occupying your field of vision. The elephant of aging is surrounded by hundreds of researchers, each of whom is focused intently upon a small piece of the whole. There are far too few generalists working to link parts of the field and make otherwise disconnected researchers aware that they are looking at the same biochemistry through different lenses.
In any case, this is a very long-winded way of saying that one should be cautious about any analysis that places one particular mechanism at the center of aging. It isn't at all clear to me that aging has a center, and the research community is still unable to say with confidence that any one of the the forms of cell and tissue damage listed in the SENS view of aging is more or less important than the others. The way we will find out which of the forms of age-related damage is the most important is by firstly developing the means to repair that damage and then secondly watching the results of repair therapies in animal models - which is exactly what is happening at the moment for senescent cell clearance. The try it and see approach will get to answers a lot faster than any of the much more analytical alternatives.
In 1881 the evolutionary biologist August Weismann proposed that "Death takes place because a worn-out tissue cannot forever renew itself, and because a capacity for increase by means of cell division is not everlasting but finite." How did he arrive at such a bold conclusion? Weismann observed that during evolution, simple multicellular organisms such as Pandorina Morum, which were immortal, gradually evolved into mortal organisms such as Volvox Minor. The absolutely crucial difference between these two organisms is that while Pandorina's cells were undifferentiated and divided without limit, Volvox's cells had differentiated into two very different types: the Somatic (body) cells, and the Germ (reproductive) cells. Thus, while the germ line has retained the capacity for infinite renewal, the body cells have not; they age and expire. While Weismann's hypotheses were remarkably prescient, at that time neither DNA nor cultured cells were sufficiently understood to allow his theory to be adequately tested. In fact, it was not until nearly one hundred years later, following the development of sophisticated animal cell culture protocols, that he was proven correct: it was shown that somatic cells grown in culture have limited growth potential. After approximately forty passages, human cells stop proliferating and undergo cellular senescence.
Besides Weismann's evolutionary theory, many additional theories have been proposed to explain the complexity of aging. These include the antagonistic pleiotropy theory, the free radical theory, age-associated shortening of telomeres, development of insulin resistance, decreased immune function, the mitochondrial theory, as well as deregulation of the circadian clock. While these theories indicate functional diversity in the etiology of aging, it must be stressed that each one relies on the concept of internal alterations in individual cells, and does not explain how the microscopic cellular damage manifests as macroscopic aging and tissue breakdown in the organism (with a few exceptions, such as changes in hormone function and declines in immune function). Theories of mutation accumulation and antagonistic pleiotropy address the genetic causes of aging, and environmental stress or lack of it contributes to modulation of the epigenome as well as physiological alterations in different tissues of the whole organism, but each theory revolves around the functional competence of different components of cells and again does not explain how this manifests as macroscopic organismal aging. Experimental evidence unifying the interactions of some components has started to emerge, but we propose that all of the changes described by diverse theories ultimately converge on the cellular senescence theory.
Since aging is a progressive condition that steadily advances from invisible to visible and localized to ubiquitous, the central question as to the direct cause of the entire process is key. The answer has been elusive due to its complex nature. Our model proposes that the process of aging results from a sequential passage through three distinct phases and can be described by the following blueprint: (1) molecular damage which results in (2) cessation of proliferation leading to cellular senescence followed by (3) body-wide aging of the organism. The first step occurs when localized, microscopic damage accumulates to a point where the burden to repair overwhelms the system. Despite the tissue source or broad input of molecular damage, crossing of this threshold results in the second phase, the crux of the entire process - arrest of cellular proliferation, acquisition of the senescence-associated secretory phenotype (SASP), and imminent cellular senescence. Once this occurs, the third phase of aging begins. This final phase is marked by tissue dysfunction and breakdown that results in the visible signs of comprehensive organismal aging.
The incremental advance proposed by our model is that while there are many undisputed factors that trigger the onset of cellular senescence and result in cessation of proliferation and SASP, the first phase in the model (cumulative molecular damage) is a precursor, rather than a final cause of aging. The complexity normally imposed by countless variables (i.e., age of onset, site of damage, affected cell type, mechanism of damage, and even species) that need to be overcome is rendered manageable by eliminating the first phase in the aging schematic. And since organismal aging can be artificially and reversibly induced by blocking and restarting cellular proliferation, this indicates that the second phase in the model - cessation of proliferation followed by cellular senescence - clearly represents the essential cause of aging. Placing cellular senescence in the pivotal junction between cause and effect, the causal nexus, to yield an integrated model of aging will serve to advance identification of crucial targets for future therapeutic investigation. By identifying cellular senescence as the causal nexus of aging, the process of treating, reversing and possibly even eventually eliminating this once inevitable outcome draws closer to reality.