Cellular Senescence and Aging

Cellular senescence is the state of irreversible cell cycle arrest in response to biological mechanisms and stresses. Causes include genotoxic stress (damage to the genome), telomere shortening, and inflammation by cytokine activity leading to the activation of tumor suppressor proteins p53 and p16 (cyclin-dependent kinase inhibitor). In vitro studies done on human fetal fibroblasts suggested that cells can stop dividing but still remain metabolically active and viable. The body’s natural cellular senescence mechanisms are thought to suppress tumor growth, inhibit tissue fibrosis, and facilitate wound healing however senescent cells may secrete or express harmful biological substances that may contribute to untimely aging, tissue remodeling, and age-related pathologies.

Senescent cells, unlike normal cells, are able to secrete and express certain biologically active molecules including senescence-associated beta-galactosidase, beta-galactosidase, growth factors, cytokines, and tumor suppressor protein p16. Scientists use beta-galactosidase as a marker for cellular senescence in vivo and in vitro whereas cytokines and growth factors - collectively referred to as SASP (Senescence Associated Secretory Phenotype) - contribute to tumorigenesis and malignant development through the activation of paracrine signaling pathways such as the epithelial-mesenchymal transition (EMT). The cellular senescence mechanism, therefore, serves as a double edged sword in the pathogenesis of cancer.

Cellular senescence is triggered by telomere erosion, DNA damage, oncogene activation, mitogen signals, tumor suppressor activation, epigenomic damage as well as the disruption of mitochondrial homeostasis. Acute cell senescence mechanism is normally induced to initiate a response to stress and stimuli consequently facilitating tissue homeostasis whereas chronic cell senescence is a result of the accumulation of senescent cells and is associated with aging and age-related pathologies.

Telomere erosion is a hallmark of cellular senescence. Telomeres consist of DNA bases that are repetitive in nature. Together with protein complexes they provide protective structures that maintain chromosomal stability and genome integrity. Telomere erosion exposes chromosomes to DNA damage and degradation. Continuous DNA degradation initiates cellular senescence. It inhibits replication and promotes the production of senescent cells. Accumulation of senescent cells induces aging and age-related ailments.

DNA damage activates the tumor suppressor p53 pathway. P53 activation upregulates the expression of pro-apoptotic genes and cyclin-dependent kinase to initiate cell cycle arrest. Increased levels of cyclin-dependent kinase p21 inhibit cyclin A/cdk2 and cyclin E/cdk2 kinases activity thereby halting cell cycle progression. The upregulation of pro-apoptotic genes induces apoptosis, a process that is essential in acute senescence. Cellular senescence is achieved when a permanent cell cycle arrest takes place as a result of DNA damage. An increase in the number of senescent cells brings forth the senescent phenotype and enables the development of age-related pathologies as well as premature aging.

Disruption of mitochondrial homeostasis is also a cause of cellular senescence. When mitochondrial homeostasis is impaired, cells produce more reactive oxygen species, resulting in increases in oxidative stress and DNA damage. The DNA damage triggers acute senescence at the cellular level, a mechanism that serves to limit the bad effects of DNA damage. An increase in the level of DNA damage induces permanent cell cycle arrest and thereby cellular senescence and a senescent phenotype. Loss of mitochondrial homeostasis is thus one of the hallmarks of cellular senescence, and it is associated with untimely aging and age-related maladies.

Epigenetic dysregulation and altered gene expression may lead to cellular senescence. Epigenetic errors can be corrected spontaneously by acute senescence, but chronic senescence leads to irreversible cell cycle arrest. Impairment of normal cell reproduction results in the accumulation of senescent cells and the consequent rise of senescent phenotypes such as tissue degeneration, aging, and age-related diseases.

Mutations and changes to proto-oncogenes give rise to oncogene-induced cellular senescence. The upregulation of oncogenes facilitates tumorigenesis hence activating the overexpression of tumor suppressor genes, consequently propagating senescence at the cellular level. The Ras proteins act on the Guanosine-5'-triphosphate, one of the building blocks of RNA. In vitro studies done on fibroblasts in human lungs, found that oncogenic spontaneous changes in Ras generated cellular senescence. In vivo studies on mammary epithelial cells suggested that the overexpression of Ras induced the activation of tumor suppressor genes and permanent cell cycle arrest thus initiating senescence at the cellular level. Oncogene induced signaling may trigger the activation of paracrine signaling pathways such as the epithelial-mesenchymal transition (EMT) and thereby propagate cancer.

Chromatin is the genetic material (DNA and proteins) that condense to form chromosomes before and during cell division. The formation of chromatin structures is important in processes such as cell differentiation, cell cycle progression, cellular senescence, and biological aging. Chromatin landscape changes and structural alterations induce replicative cellular senescence . Chromatin structural changes that result in the formation of heterochromatin foci promote cellular senescence and epigenetic alterations. When there are more senescent cells in a tissue, there is more likely to be tissue degeneration and pathogenesis of age-related illnesses.

Accumulation of senescent cells makes a body "old", in some sense. Studies in mice have shown that the clearance of senescent cells extends lifespan and reduces incidence of age-related disease. Senescent cells are a research area of interest and studies are being done to see if therapeutic interventions targeting senescent cells can reverse aging.