By: Una Choi
With age comes a bevy of age-related diseases and tissue deterioration. Cellular senescence heavily impacts this process and describes the final, irreversible period during which cells — most often fibroblasts or connective tissue cells — flatten and cease to undergo mitosis after around fifty rounds of replication (1). Senescent cells are at the heart of cataracts, wrinkles, and other forms of tissue aging. After ceasing proliferation, senescent cells emit cytokines, which act in concert with other growth factors emitted by the senescence-associated secretory phenotype (SASP) to help maintain senescent cells’ static state (2). Cytokines and SASP help initiate age-related tissue degeneration via the immune system. Furthermore, senescent cells themselves exhibit increased expression of genes encoding peptides that can later be presented by major histocompatibility complex molecules as markers for degradation (3).
Cellular senescence, however, is not solely linked with advanced age; senescent cells have been identified in embryos and are thought to hold a pivotal role in regulating organogenesis (2). In addition, senescence holds implications in areas outside of age; cells often become senescent after accumulating extensive DNA damage or telomere decay, revealing that senescence may help prevent replication of cells with potentially harmful mutations (2). Oncogene-induced senescence (OIS) can thereby contribute to tumor suppression, as the retinoblastoma (RB) tumor-suppressor networks active in senescent cells suggest. Although cellular senescence involves changes on the cellular scale, its effects extend to both the tiny, developing embryos and the fully formed, aging tissues present in adults.
Cellular Senescence: Causes
Unrepaired DNA single-strand breaks (SSBs) have been linked to cellular senescence (1). Diminished poly(adenosine diphosphate-ribose) polymerase-1 (PARP1) expression permits the accumulation of SSBs and can eventually result in the creation of atypical XRCC1 foci. Consequently, p16 expression increases and triggers the transition to cellular senescence.
Oxidative stress and telomere erosion can also activate the p16/RB pathway. Oxidative stress, or an imbalance of reactive oxygen species, can trigger an accumulation of SSBs, thus promoting cellular senescence. Telomeres, the DNA-protein complexes present at the ends of chromosomes, shorten after each round of cell division. Once telomeres are shortened, they are subject to incorrect DNA repair machineries that can cause chromosome breakage (4).
Cellular Senescence and Aging
Although senescent cells release cytokines to trigger their own destruction, this process can be slow and can result in painful inflammation as the senescent cells accumulate in aging tissues. This inflammation contributes to age-related frailty syndrome, symptoms of which include increased vulnerability to stresses, fat tissue loss, and muscle deterioration (5). Reactive products released from inflammatory cytokines can also lead to tissue degradation. These cytokines can also trigger angiogenesis, which contributes to chronic inflammation, and can disrupt cell-cell communication in surrounding tissue (6).
Consequently, scientists are focusing on eliminating cellular senescence as a means to prevent multiple age-related diseases. In 2011, scientists at the Mayo Clinic demonstrated the beneficial effects of eliminating senescent cells (5). Dr. Darren J. Baker and colleagues constructed the INK-ATTAC transgene for the destruction of p16Ink4a, a biomarker required for the survival of senescent cells. They induced the activation of INK-ATTAC using AP20187, a synthetic drug. p16Ink4a destruction delayed age-related degradation of the eye, skeletal muscle, and adipose tissue. When given the drug at weaning age, the mice with the INK-ATTAC transgene were larger, exhibited greater muscle retention, and were able to travel farther distances during treadmill exercise tests.
The same group then activated the transgenic INK-ATTAC in 5-month-old mice. Although the irreversible cataracts remained, the older mice still exhibited increased muscle fiber diameters and improved ability to complete treadmill exercise tests.
The overall survival of the INK-ATTAC mice, however, was not extended; this may be due to the prevalence of cardiac failure in both the control and experimental groups of mice. Because INK-ATTAC is not significantly expressed in the heart and aorta, senescent cells in those organs could persist. A later study, however, experienced greater success in eliminating senescent cells and consequently reported a 20-30% extension of the rodents’ lifespan (7).
Cellular Senescence and Embryogenesis
Although cellular senescence is most often associated with age, a group at the Weizmann Institute of Science found senescent cells in the syncytiotrophoblast (epithelial covering of the placental villi) (8). Another group at the Center for Genomic Regulation in Spain found senescent cells in mouse and chick embryos, further emphasizing the role of cellular senescence in early development (2). Biologist Mekayla Storer and colleagues took advantage of the characteristic activation of the senescence-associated beta-galactosidase (SAβ-gal) enzyme in senescent cells in order to detect the presence of cellular senescence in embryos. Staining embryos with SAβ-gal, a substrate which the SAβ-gal enzyme cleaves to form a colored product, revealed senescent cells along the neural roof plate and apical ectodermal ridge (AER), two regions closely associated with signaling during embryogenesis. The neural roof plate dictates development of the central neural system while the AER, a region of the ectoderm, secretes growth factors regulating the growth of limbs.
Dr. William Keyes, a member of the group that discovered senescent cells in the murine embryo, posits that cellular senescence plays a critical role in dictating the development of the embryo, as the non-proliferative behavior of senescent cells guarantees a short-lived signal.9 Further supporting the potential role of senescent cells in regulating embryogenesis, staining was not constant throughout the development of the embryo. At embryonic day 9.5 (E9.5), Dr. Storer’s group found that staining at the far end of the limb bud (2). By E13.5, staining was visible in the growing area between the toes. By E16.5, the staining had vanished, revealing that the senescent cells, having most likely completed their role in directing development, had been destroyed by the immune system.
Interestingly, many common birth defects are concentrated in the areas exhibiting the most staining for senescent cells, suggesting that these are critical areas for ensuring proper development of the embryo. When murine embryos were deficient in p21, a gene whose expression is essential for inhibiting the cell cycle and for protecting against apoptosis, the impaired cellular senescence increased cell death (2). In the AER, p21-deficient mice had impaired expression of FGF4 and FGF8, vital signals which trigger the proliferation of mesenchymal and limb cells.
Although the senescent cells found in the mouse and chick embryos shared many characteristics with the previously mentioned oncogene-induced senescence, the embryonic senescent cells lacked p16 and DNA damage. The group at the Center for Genomic Regulation posits that this phenomenon may be due to the simpler nature of embryonic senescence; oncogene-induced senescence requires more elaborate control.
Cellular Senescence and Cancer
Because cellular senescence most often halts the proliferation of damaged fibroblasts, it is thought to contribute to the lack of sarcomas, or fibroblast-originating tumors, in humans (1). Indeed, sarcomas represent less than 1% of all human cancers. The activation of the p16INK4a/ pRB tumor suppressive pathway involved in triggering cellular senescence negatively regulates cell cycle progression (4).
Carcinomas, in contrast, originate in epithelial cells and are the most common human cancers (1). Interestingly, carcinoma occurrence increases with age. While cellular senescence is often tied to tumor suppression, Dr. Joe Nassour and colleagues found that, unlike fibroblasts, epithelial cells are unresponsive to DNA damage and can spontaneously leave senescence. Once these damaged cells resume replication, the cells are more likely to become cancerous. These cells exhibit diminished PARP1 expression, which in fibroblasts would cause the cell to enter senescence. In these epithelial cells, however, the diminished PARP1 expression does not reinforce their senescent state. Indeed, another group, found that PARP1 deficient mice exhibited accelerated aging and more prevalent carcinomas (1).
Similarly, senescent cells increase production of matrix metalloproteinase-3 (MMP3), an enzyme that stimulates tumor cell invasion (4). Senescent cells secrete factors like TIMP-1 that protect surrounding cancer cells.
Implications of Cellular Senescence
Because senescent cells cause chronic inflammation and other phenotypes tied to aging, the targeted destruction of these cells can, as Dr. Baker and colleagues demonstrated, delay and even reverse the consequences of aging. This may provide a new method of alleviating arthritis and other conditions exacerbated by senescent cells.
Further research is needed on the mechanisms behind the initiation of cellular senescence. While diminished PARP1 expression is linked to senescence in fibroblasts, the same characteristic has no effect in epithelial cells. This may also aid in clarifying the role of senescent cells in embryogenesis.
In addition, the significance of transient senescence versus chronic senescence requires further investigation. The immune system may destroy senescent cells (4). Chronic senescence, however, can aggravate inflammation and other phenotypes tied to aging.
Una Choi ‘19 is a freshman in Greenough Hall.
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