Cellular Senescence is Complicated
Cellular senescence is a process that serves to reduce cancer risk by removing damaged cells from the cell cycle and irreversibly suppressing their ability to proliferate. Unfortunately it is also one of the root causes of degenerative aging, as when present in large numbers these cells cause significant damage to surrounding tissue structure and function. They don't go away either: by the time old age rolls around, a sizable fraction of skin cells are senescent, for example. Ideally these cells would be destroyed by the immune system, but that only happens for a fraction of them, and in any case the immune system itself progressively fails in all of its tasks due to the damage of aging.
As the tools of biotechnology rapidly become better and cheaper, researchers are discovering new complexities in every area of cellular metabolism, and senescence is no exception. Cells are exceedingly complicated machines. All of the consensus opinions on how senescence works might be thought of as high level generalities, but there are a lot of exceptions and new information. Senescence isn't as absolutely irreversible as thought; it plays a beneficial role in wound healing; it might steer embryonic development; there are a range of novel ways in which cells can enter a senescent state; and so forth.
Fortunately it is possible to short-cut all of this complexity and skip directly to destroying senescent cells. We know they are bad for us in volume regardless of how exactly they are coming into being, and thus the research community should aim at selective removal of these cells, producing a therapy for periodic application that is perhaps based on some of the work on targeting cell types taking place in the cancer research establishment. Say once a decade, since we know that humans can certainly live for at least three decades without significant impact from cellular senescence. Sadly the direct approach is poorly funded in comparison to ongoing investigations of senescence in detail, but this is par for the course in everything that might actually have some meaningful impact on aging. This must change. Meanwhile here is another research paper uncovering yet more of the complexity of cellular senescence:
Many cells within our bodies, including fibroblasts, hepatocytes, lymphocytes, stem cells and germ cells, are in the state of quiescence, defined as a reversible cell cycle arrest with temporary absence of proliferation. Quiescence is not a passive default state, but instead is actively maintained by specific molecular mechanisms. Some of these cells maintain a quiescent state for long periods of time, even years, and quiescent cells are defined to retain the ability to return into the cell cycle. In vivo, quiescence is considered to limit the uncontrolled proliferation of cells, especially stem cells, whose proliferation has to be controlled properly in order to maintain tissue function.In order to be reversible, quiescence must grant the return into the cell cycle. Consequently, quiescent cells repress transition into terminal differentiation in which cell cycle arrest is irreversible. However, when transition into irreversible cell cycle arrest is suppressed, reversible non-dividing quiescent cells are less protected against cancer development and are subject to tumor development. While short-term quiescent cells were described to be protected against transition into senescence, long-term quiescent cells may protect themselves against malignant transformation by implementing a senescence-associated cell cycle arrest over longer periods of time. Indeed, most of a human foetal skin fibroblast cell population while being long-term quiescent, were observed to transit into senescence. It remains to be shown to what extent these findings, observed for cultured cells, also hold for cells in tissue.
Telomere shortening as a basic concept for aging assumes that each successive cell division acts as a mitotic counting mechanism inducing replicative senescence. According to this concept, induction of quiescence for a defined amount of time would be predicted to prolong the lifespan of fibroblasts in comparison to constantly proliferating cells. In contrast to this prediction, after long-term quiescence primary human foreskin fibroblasts (HFF) were observed to transit into senescence despite of negligible telomere shortening, questioning that cell division and telomeric attrition is necessarily required for senescence. Here we detect that during long-term quiescence also other human fibroblasts enter senescence. Thus, other effects than telomere shortening, like oxidative stress induced DNA damage, may be responsible for this transition. This is supported by the fact that mouse fibroblasts senesce in culture although mice have very long telomeres.