What Else can be Achieved with Better Control of Senescent Cells?

At the present time, the main focus of therapeutic development involving senescent cells is the safe, selective destruction of as many such cells as possible. The accumulation of senescent cells is an important cause of aging and age-related pathology, and removing even just a quarter or a half of them - and in only some organs and tissues - has been shown to significantly extend life and improve health in mice. The first human trials are underway and the results will be published over the next year or so.

While senescent cells do a good job of accelerating our demise, it is undeniably the case that these cells also serve quite useful purposes for a short time after their creation. They exist for a reason, and the problem is not their existence per se, but that they are not removed efficiently enough after the job of the moment is accomplished. Senescence cells secrete a potent mix of signals that is well adapted for those tasks, but if allowed to continue for the long term, this signaling is highly disruptive of tissue structure and organ function.

Cellular senescence as a process serves to help define the shape of tissues during embryonic development, but in adult life its primary positive roles involve suppression of cancer and guidance of wound healing. Since cells become senescent in response to damage, such as the mutational damage to DNA that can lead to cancer, countless potential cancers are avoided because the cells involved enter a senescent state in which they can no longer replicate. They then rouse the interest of the immune system via inflammatory signaling, to ensure destruction. In the case of wound healing, the signal molecules secreted by senescent cell encourage the activities needed for regrowth and restructuring.

In a near future in which senescent cells can be very efficiently destroyed, then it becomes possible to think about delivering senescent cells to patients, or selectively forcing patient cells into a senescent state. This could have applications in the treatment of cancer, in which provoking cancerous cells into senescence has long been a desirable goal for chemotherapy, or in acceleration of wound healing, for example. After the job is done, efficient senolytic therapies could be delivered to remove the senescent cells, preventing them from causing long-term harm to the patient.

Senescent cells: A new Achilles' heel to exploit for cancer medicine?

In response to various intrinsic and/or extrinsic stimuli, cells enter an essentially irreversible senescent state. Senescent cells are frequently implicated in multiple disorders, mainly through secretion of numerous bioactive molecules, a distinctive phenomenon found a decade ago and termed as the senescence-associated secretory phenotype (SASP). The full SASP spectrum comprises a myriad of soluble factors including pro-inflammatory cytokines, chemokines, growth factors, and proteases, whose functional involvement can be classified into several aspects including but not limited to extracellular matrix formation, metabolic processes, ox-redox events, and gene expression regulation. The SASP promotes embryonic development, tissue repair, and wound healing, serving as an evolutionarily adapted mechanism in maintaining tissue and/or organ homeostasis.

Although the SASP is beneficial to several health-associated events, more evidence has showed that it actively contributes to the formation of a pro-carcinogenic tumor microenvironment. Long-term secretion of the SASP factors by senescent cells can impair the functional integrity of adjacent normal cells in the local tissue, serving as a major cause of chronic inflammation which drives aging-related degeneration of multiple organs. Thus, senescent cells and their unique phenotype, the SASP, can be defined as a form of antagonistic pleiotropy, a property that is beneficial in early life and during tissue turnover, but deleterious over time with advanced age.

A new function of the SASP was recently discovered, which is linked with increased expression of stem cell markers and keratinocyte plasticity upon short term exposure of cells to the SASP in vitro and liver regeneration in vivo, thus raising the possibility that transient therapeutic delivery of senescent cells could be harnessed to promote tissue regeneration.

Interestingly, a study of spontaneous escape from cellular senescence found that cells released from senescence can re-enter the cell cycle with pronouncedly enhanced stemness and Wnt-dependent growth potential. Thus, senescence-associated reprogramming promotes cancer stemness (senescence-associated stemness, or SAS), a distinct property that has profound implications for cancer therapy and presents new mechanistic insights into cancer cell plasticity. Partially resembling cancer cells which pose substantial threat to human lifespan, senescent cells are functionally involved in tumor progression and can be viable targets for some reasons. Fortunately, senescent cells share common biochemical features, allowing use of a single therapeutic agent to eliminate them from the tissue microenvironment. Given that many chemotherapeutics induce collateral senescence, pharmaceutical agents targeting senescent cells can be a key component of advanced anticancer arsenal.

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