The Many Roles of Senescent Cells

Long-lived senescent cells accumulate with age, initially quite slowly as they are efficiently removed by the immune system when their own programmed cell death processes fail, but once the immune system starts to decline with age, the burden of cellular senescence ramps up dramatically. Senescent cells secrete a potent mix of signals known as a senescence-associated secretory phenotype (SASP). It spurs chronic inflammation, destructively remodels nearby tissue, encourages nearby cells to also become senescent, and causes all sorts of other issues as well. It is very harmful, and the more senescent cells there are, the worse the consequences.

Fortunately, the research and development communities have finally woken up to the fact that senescent cells are an important contributing cause of aging. Numerous animal studies have demonstrated rejuvenation, reversal of specific age-related conditions and measures of aging, via the targeted destruction of senescent cells, using senolytic therapies of one form or another. Human trials of first generation senolytics are underway and the first results were published this year. Some of those compounds are cheap and readily available, and we might hope that they will be pushed into the clinic quite soon as people realize just how beneficial they might be. Meanwhile, startup biotech companies are developing what will hopefully be better second generation treatments, to arrive in the clinic in the years ahead.

Senescent cells do actually have a number of beneficial purposes. They are involved in regeneration from injury, in suppression of cancer, and embryonic development. Fortunately all of these are short-term roles, and thus do not conflict with a strategy of periodic clearance of lingering senescent cells. A senescent cell in its proper time and place emerges, does its job, and then is destroyed quite soon thereafter. It is the few that stick around for the long term that are the problem, and destruction is the most straightforward approach to take; it aligns with the outcome that our biochemistry attempts for all senescent cells,but fails for the lingering few.

Cellular senescence in development, regeneration and disease

Cellular senescence is a form of permanent cell cycle arrest that can be induced in primary cells in response to a variety of stimuli. Senescence was first discovered in primary cells that were grown for extended periods in culture, reaching what became known as a state of replicative senescence, the cellular equivalent of old age. Subsequently, it was shown that cells exhibiting markers of senescence accumulate in aging tissues, further linking the senescence process with aging. Later, a landmark study identified that the expression of active oncogenes (such as those encoding mutant Ras) in primary cells could induce senescence prematurely, in a process now known as oncogene-induced senescence (OIS). This introduced the concept that senescence might function as a tumor-suppressive mechanism to block the aberrant proliferative effects of oncogenic mutations in cells.

Following on from this, many diverse stress-inducing stimuli including irradiation, chemotherapy, cytokine treatment and even induced pluripotent stem cell(iPSC) reprogramming have been shown to induce a senescent response in a variety of cell types. In summary, senescence functions as a cellular process that prevents the proliferation of old, damaged and potentially tumorigenic cells, but the consequence of which is increased aging at the organismal level. Although the regulated induction of senescence is beneficial in preventing tumor formation, prolonged aberrant persistence of senescent cells can have detrimental effects in promoting cancer. For example, if the timely clearance of OIS cells by the immune system is perturbed, this leads directly to tumor formation. Similarly, although chemotherapy can, in part, exert beneficial effects by inducing tumor-cell senescence, the persistence of therapy-induced senescent cells can, via the SASP, promote tumor recurrence and metastasis.

The senescence process has long been linked to aging, including in the original study demonstrating that aging human skin has increased numbers of cells that are positive for the senescence marker senescence-associated beta-galactosidase (SA-ß-gal). In recent years, perhaps the most conclusive data linking senescence with organismal aging has come from the use of senescence 'deletor' mouse models, in which cells expressing p16INK4A are selectively targeted for elimination. In such models, the removal of senescent cells results in significant improvements in health and vigor, and also in lifespan. These studies unequivocally demonstrate how the accumulation of senescent cells during aging can have a negative impact on health and lifespan.

Much of what we understand about senescence has been extrapolated from studies of disease or aging. However, more recent discoveries of beneficial roles for senescence in non-disease conditions has helped to create a clearer understanding of the physiological function of senescence. Beneficial roles for senescent cells have been described in various conditions of wound repair. After wounding, the deposition of extracellular matrix (ECM) aids the repair process but, if excessive, can result in fibrosis, which subsequently impairs proper repair. Senescence has been demonstrated to have a role in wound repair and the fibrotic response in a number of tissues.

The discovery of cells exhibiting markers and features of senescence in developing embryos was an exciting finding. This was primarily based on studies describing senescent cells in mouse embryos. However, cells bearing some or many features of senescence have also been described in human embryos. Interestingly, in many cases, senescent cells were found in signaling centres, with the secretory function of these structures contributing to cell fate specification and tissue patterning. The emerging details suggest that senescent cells may have multiple functions in the embryo. Senescent cells that appear in the embryo arise in very precise patterns in time and space, appearing during specific time windows, before subsequently disappearing, demonstrating that the induction, presence and removal of these cells is a tightly controlled programmed cellular process.

Senescence is also intricately linked with cellular reprogramming, with studies of iPSCs providing key clues. Indeed, expression of the four reprogramming factors Oct4, Sox2, Klf4, and Myc (OSKM) causes widespread induction of senescence markers in cells that ultimately do not undergo reprogramming, whereas those that successfully reprogram manage to silence key senescence mediators. Interestingly, induction of reprogramming in tissues also activates a senescence response, but in cells adjacent to those that undergo reprogramming. It appears that the SASP, and in particular IL6 from the senescent cells, enhances OSKM activity and reprogramming in nearby cells.