The appearance of wrinkles and age spots is associated with old age, which is accompanied by feelings of fear of the future, death and even rejection. But is old age necessarily bad? What happens in our body over the years and why do our cells age?

Cellular senescence or cellular aging

Cellular senescence is an irreversible cessation of cell growth and proliferation that occurs in response to various endogenous and exogenous stresses, and those are most commonly telomere erosion, DNA damage, oxidative stress and oncogenic activation. It is irreversible because no known physiological stimuli can trigger senescent cells to re-enter the cell cycle. The loss of cell function occurs at a molecular, cellular, tissue and organic level and is a feature of all aging organisms. It is responsible for processes such as tumor suppression, tissue repair, embryogenesis and aging of the organism. These cells show high metabolic activity, remain viable and actively suppress apoptosis, and differ from other cells in their morphological and molecular characteristics. Hallmarks of cellular aging include: prolonged cell cycle arrest, changes in transcription, acquisition of a bioactive secretome known as the senescence-associated secretory phenotype (SASP), macromolecular damage and changes in chromatin organization and gene expression.

Although cellular senescence is normally a defense mechanism against tumor development, the presence or persistence of large numbers of senescent cells can promote tumor progression due to inflammation, tissue disruption and growth signals due to SASP. The burden of senescent cells is low in young individuals, but increases with aging in several tissues, including adipose tissue, skeletal muscles, kidneys and skin. Accumulation of senescent cells can occur due to various chronic illnesses associated with aging, oxidative stress, developmental factors, chronic infections (e.g. human immunodeficiency virus [HIV]), certain drugs (chemotherapy or certain HIV protease inhibitors) and exposure to radiation. Degenerations that cause accumulations of senescent cells are sarcopenia, atherosclerosis, heart failure, osteoporosis, pulmonary insufficiency, kidney failure, neural degeneration and other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.

Biomarkers that indicate aging

A major limitation in the field of aging is the lack of unique, universal or model-specific biomarkers for identification of cellular aging in cell culture or tissue samples. Currently, the identification of senescent cells relies on a combination of multiple markers that can, when present simultaneously, distinguish stably arrested senescent cells from quiescent or differentiated counterparts. The first and still most commonly used biomarker for detection of senescent cells in cultured cells and fresh tissue samples is the accumulation of a lysosomal enzyme called senescence-associated β-galactosidase (SA-β-gal). Another characteristic of senescent cells is an abnormally enlarged and flat cell morphology with a disproportionate increase in the ratio of cytoplasm to nucleus.

What after DNA damage?

To preserve the integrity of the genome, cells respond to DNA damage by engaging in a signal amplification cascade called DDR (DNA damage response) in order to block cell cycle progression and promote DNA damage repair. If the damaged sites in proliferating cells are properly fixed, the cell cycle will resume rapidly. Otherwise, unrepaired damage can lead to prolonged DDR activation, which eventually translates into irreversible cell cycle arrest (senescence) or programmed cell death (apoptosis).

Cell cycle

The growth arrest of senescent cells is thought to occur by blocking the cell cycle in the G1 phase to prevent the initiation of DNA replication in damaged cells. However, they can also arrest in the G2 phase in order to block mitosis in the presence of DNA damage. As this cell cycle arrest is initiated to ensure that damaged or transformed cells do not spread mutations, its maintenance must be strictly controlled.

Telomere shortening

One of the first and best described mechanisms of cellular senescence induction is telomere shortening. As the standard DNA replication machinery cannot fully duplicate the ends of chromosomal DNA, in the absence of telomere maintaining mechanisms such as telomerase expression or inter-telomeric recombination, telomeres shorten with each round of DNA replication. Below a certain length, loss of telomere capping factors or protective structures renders critically short telomeres similar to DNA damage and thus DDR is triggered. One or several DDR signaling telomeres are sufficient to initiate cellular senescence.

Mitochondrial dysfunctions and cellular aging

Increased oxidative stress in aged cells is associated with the accumulation of dysfunctional mitochondria. Indeed, aged cells are characterized by changes in mitochondrial mass, membrane potential and mitochondrial morphology. Dysfunctional mitochondria may play an important role in the establishment of aging, as depletion of mitochondrial sirtuins, a group of evolutionarily conserved proteins that regulate aging across species, as well as selective chemical inhibition of mitochondrial function, trigger aging.

Cellular aging in Alzheimer’s disease

It is believed that cellular senescence, a state of permanent cell growth arrest, contributes significantly to aging and aging-related illnesses, including Alzheimer’s disease. Senescent astrocytes, microglia, endothelial cells and neurons have been detected in the brains of patients and animal models with Alzheimer’s disease. The removal of senescent cells genetically or pharmacologically ameliorates neuropathologies induced by β-amyloid peptide and tau-proteins and improves memory in mouse models, indicating a central role of cellular senescence in the pathophysiology of Alzheimer’s disease. Although gathered evidence supports a role of cellular senescence in the disease, the mechanisms that promote cellular senescence and how senescent cells contribute to the neuropathophysiology of Alzheimer’s disease remain largely unknown.

Cellular senescence – a necessary process for survival

As the name itself suggests, aging can prompt us to think about the lived past and the end of our lives. However, aging in the body helps us with tumor suppression and understanding various diseases. Although the concept of cellular senescence is not yet sufficiently researched, it is likely to have a promising approach in the future for the effective treatment of aging-related illnesses.

Translated by: Nina Šlopar

 

Literature

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Photography source

Image by Arek Socha from Pixabay