Cellular Senescence and Aging

So far, we have looked at aging by two processes. One process (involving the insulin signaling pathway) concerns a general pathway that limits life span. The other (involving random epigenetic drift) concerns random disruptions that may be repaired or not, depending on the cell type and species. Both are at the gene level. At another level, however, one has to ask how ectopic gene silencing or activation would cause an aging phenotype. What processes might be being activated or suppressed? In recent years, several lines of evidence have pointed to chronic sterile inflammation (an inflammatory response not initiated by bacteria) as a major common factor of the age-related diseases. Chronic sterile inflammation can occur in just about any type of tissue. The hallmarks of inflammation include elevated cytokine levels that attract lymphocytes and macrophages and digestive enzymes. These have been found in tissues where diabetes, dementias, atherosclerosis, and cancer originate (see Tchkonia et al. 2013; Muñoz-Espin and Serrano 2014). The lymphocytes and macrophages are thought to kill or cripple the cells and prevent the organ from functioning optimally. Inflammation is a major factor producing the age-related frailty syndrome, wherein the body becomes susceptible to dying from stresses it could otherwise tolerate.

So, then, what stimulates chronic sterile inflammation? The evidence is pointing to the persistence of senescent cells in a tissue as the cause of the inflammatory reaction. Senescent cells are cells that no longer divide. They are usually the mesenchymal stromal cells that underlie the epithelial cells (that perform the functions of the organ). Senescent cells are not necessarily bad cells to have around. In fact, like apoptosis, senescence seems to be a normal and important part of organogenesis. For instance, after the axes of the fetal limbs have been established, the apical ectodermal ridges that formed those axes become senescent and are removed. Likewise, the developing kidney and inner ear each use cellular senescence to change the shape of the organ and allow new cells entry into new places (Muñoz-Espin et al. 2013; Storer et al. 2013). Cell senescence also prevents the proliferation of disabled cells, and it thereby may stop cells from initiating tumors (Campisi 2001; Krtolika et al. 2001; Prieur and Peeper 2008). During development, cell senescence appears to organize a local immune response (i.e., an inflammation), attracting macrophages that ingest the senescent cells and enabling tissue modeling. Chronic sterile inflammation may be the result of having the senescent cells, helpful during development, accumulate in adult tissue, where they are no longer helpful.

Inflammation is good and normative in small amounts and small durations at specific places in the embryo, and it may also be beneficial when produced locally and for small durations in the adult to get rid of senescent cells and replace them (through stem cell division) with functional cells. But chronic (long-term) inflammation may be deleterious and unhealthy in adults. In this case, what is normal in the embryo becomes abnormal in the adult. This pattern will be seen again in our discussions of cancer.

The senescent cells appear to be inducing the inflammation by producing a cocktail of secreted factors called the senescence-associated secretory phenotype (SASP). SASP includes paracrine factors (proteins that can change the behaviors of nearby cells), cytokines (proteins that attract and activate lymphocytes and macrophages), and proteases (enzymes that digest proteins). Senescent cells and SASP increase as we grow older, primarily because senescence is a defense against cells with DNA damage. In small doses and short durations, SASP can remove the cells with DNA damage and replace them with healthy cells. This is thought to protect against cancers. However, if the senescent cells persist and are not removed, then the tissue is compromised by having such nonfunctional cells, which are also producing a chronic inflammatory response that might alter tissue structure and function (Tchkonia et al. 2013).

So, then, if the phenotypes of aging are caused by chronic inflammations, and chronic inflammations are caused by the accumulation of senescent cells, then what causes cellular senescence? In the mammalian embryo, senescence is mediated by paracrine factors produced by the mesenchymal stromal cells. In the embryonic ear these factors include TGF-β family proteins, while in the limb they are probably members of the Fgf family. These paracrine factors activate transcription factors that elevate levels of the p21 protein that inhibits the cell cycle and initiates the senescent phenotype (Figure 1; Banito and Lowe 2013; Campisi 2014; Muñoz-Espin and Serrano 2014). In adult cells, “oncogenic stress”—mainly damage to DNA from mutations, telomere shortening, and reactive oxygen species—can activate the p53 protein, which is often seen as the “guardian of the genome.” Among p53’s many powers is the ability to activate p21. In this way, both the normal developmental mechanisms of senescence and the normal anticancer mechanism of senescence feed into the same pathway. However, if the adult senescent cells accumulate, chronic inflammation and functional decline may be the result.

We therefore have a model wherein cellular senescence normally coordinates developmental tissue modeling by inducing a stable arrest in proliferation followed by a secretory phenotype (SASP) that recruits macrophages and other immune cells to eliminate the senescent tissue. This prevents the further functioning of this tissue. In some cases, the removal of senescent cells may allow nearby progenitor cells to repopulate the tissue with nonsenescent, more functional cells. In other cases, the removal of senescent cells may enable nearby motile cells to enter into the area. In adults, senescence can enable the removal of nonfunctional tissues and their replacement by more functional cells. However, as an animal ages, random events (epigenetic and genetic changes) may make more cells senescent and put strains on the immune system to clear them away. If the senescent cells persist, their SASP may create a chronic inflammation and basement membrane lysis that leads to tissue malfunction and the symptoms of old age. Indeed, a recent report (Baker et al 2016) has shown that if one genetically manipulates mice so that senescent cells are immediately removed from their respecytive organs, the lifespan of the mouse is increased, and it leds a healthier life for a longer time. Moreover, the senescent cell removal also delayed the appearance of cancers. The removal of these cells did not, however, prevent memory or muscle deterioration.

Figure 1

Figure 1 The hypothesized senescence pathway leading to the aging syndrome. The central node is the protein p21, which inhibits cyclin-dependent kinases, blocking cells in the G1 phase of the cell cycle, through the function of the retinoblastoma protein. This leads to the senescent phenotype, characterized by specific secretion products (SASP). These proteins recruit immune system macrophages and lymphocytes, leading to inflammation. If the inflammation is transient, the senescent cells are removed, the tissue can be remodeled, and stem cells can restore more functional cells to the tissue. If the senescent cells are not removed, the inflammation can become chronic, in which case tissue degradation and the symptoms of aging can occur. In adults, this is thought to arise from oncogenic stress, and it is used as a way of removing senescent cells. In the embryo, senescence of cells happens normally in development of organs, such as in the placenta, ear, and limbs. (After Muñoz-Espin et al. 2013; Muñoz-Espin and Serrano 2014; Tchkonia et al. 2014.)

Literature Cited

Baker, D. J. and twelve others.  2016. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530: 184 – 189.