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“Hayflick limit” in health and disease

Cellular senescence, a phenomenon also referred to as the “Hayflick limit”, is defined as a process limiting proliferation of normal human cells in culture. It was first described by Hayflick and Moorhead in 1961 in a seminal study on human fibroblasts. They identified one particular type of cellular senescence produced after extensive proliferation by the loss of telomeres following a significant drop in endogenous telomerase activity. Since then, the various stimuli and cellular contexts that induce senescence in multiple physiological and pathological processes have been studied in depth. It is now believed that the general biological purpose of senescence is to eliminate unwanted cells, a concept similar to apoptosis.


Senescence and apoptosis are important players in the elimination of damaged cells. This is particularly relevant with cancer cells, which are characterized by the accumulation of severe cellular damage and contrary to normal cells, an indefinite capacity to proliferate. Senescent cells differ from other non-dividing cells (e.g. quiescent or terminally-differentiated cells) by some morphological changes and several senescence-specific biomarkers. Proliferative markers such as Ki-67 are no longer expressed. Dimry et al. (1995) later proposed the existence of senescence-associated β-galactosidase (SA-β-gal) in senescent cells. Contrary to lysosomal β-galactosidase (β-gal) which activity is detectable at pH 4.0, SA-β-gal was identified when experiments were carried out at pH 6.0. This activity is based on the increased lysosomal content of senescent cells, which enables the detection of lysosomal β-gal at a sub-optimal pH (i.e. pH 6.0) and more than likely reflects the increased autophagy occurring in senescent cells and an enlargement of the lysosomal compartment.

Cellular senescence is a crucial anticancer mechanism preventing the growth of cells at risks of neoplastic transformation. Tumor cells are often regarded as an immortal entity with an irreversible loss of senescence response. They do, however, tend to retain this capacity and use it in response to a genotoxic stress. Senescent cells have been, for example, observed in primary tumors undergoing chemo- and/or radiotherapy. This accelerated senescence or pseudo-senescence is also considered a strategy to limit tumor growth. Indeed, the intensity of the oncogenic signaling flux progressively increases during the early stages of tumorigenesis until it reaches a threshold that activates the key tumor suppression pathways p16 and p53. Cells with premature senescent phenotype are in abundance in premalignant lesions in order to avoid tumor suppression. They are generally resistant to apoptosis and can serve as reservoirs of secreted factors with mitogenic and angiogenic activity associated with tumor recurrence. Senescence can therefore be seen as both beneficial and detrimental (D. Muñoz-Espin et al., 2014).

Great progress has been made in the past decade in understanding ever growing number of stimuli that induce senescence and linking these mechanisms to cancer protection and aging. Several signaling pathways are involved in this process with most ending up with the activation of p53 followed by the up-regulation of the cyclin-dependant kinases p15, p16INK4a, p16, p21CIP1 and p27. Eroded telomeres generate a persistent DNA damage response, which initiates and maintains the senescence growth arrest. Senescence can also be induced by the sudden increase in reactive oxygen species following chemotherapy, inhibition of tumor suppression and even oncogene activation. The latter was observed in vivo in a variety of tumor types and the list of oncogenes known to trigger senescence is constantly growing (D. Muñoz-Espin et al., 2014). Senescence also participates in tissue remodeling, embryonic development and morphogenesis. The long list of diseases associated with senescence and its implication in key biological processes represent an interesting opportunity to design targeted therapies and develop new tools for a better understanding of the process (R. Salama et al., 2014).

To that effect, the SA-β-gal assay developed by F. Debacq-Chainiaux et al. (2009) is a useful assay to identify senescent cells in a heterogeneous population and screen conditions or compounds capable of activating or inhibiting their appearance. Potential applications include determining the replicative potentials of normal cell populations in culture and determining the abilities of drugs or genetic manipulations to stimulate a senescence response both in vitro and in vivo. The limitation of the assay is that it is not entirely specific as increased SA-β-gal activity can also be found in cells held at confluence and in differentiated cells such as adult melanocytes. Some aspects of its physiological significance remain conjecture and several aspects of its regulation are enigmatic. However, it continues to be the marker of choice for the study of senescence especially when used in combination with the proliferation marker Ki-67 and a morphological phenotype analysis. As biologists further unravel the mysteries and build on the foundations of current knowledge of cellular senescence, it will be possible to decipher its complex role in health and disease.

Enzo Life Sciences has a very unique portfolio for researchers investigating senescence such as the Cellular senescence activity assay and the Cellular senescence live cell analysis assay. In addition, Enzo offers antibodies, immunoassays, live cell analysis kits, proteins and small molecules, some of which are listed below:

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References:

  1. L. Hayflick and P.S. Moorhead. The serial cultivation of human diploid cell strains. Exp. Cell. Res. (1961) 25: 585-621.
  2. G.P. Dimri, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. U. S. A. (1995) 92: 9363-7.
  3. D. Muñoz-Espin and M. Serrano. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell. Biol. (2014) 15: 482-96.
  4. R. Salama, et al. Cellular senescence and its effector programs. Genes Dev. (2014) 28: 99-114.
  5. F. Debacq-Chainiaux, et al. Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo. Nat. Protoc. (2009) 4: 1789-806.

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