Replication induced senescence
Replication induced senescence
Normal somatic human cells in culture undergo a finite number of divisions before entering a state of irreversible growth arrest termed ‘‘replicative senescence”. This phenotype is characterized by the acquisition of flattened and enlarged cell morphology, presence of β-galactosidase activity at suboptimal conditions (i.e., pH 6), and absence of cell division in metabolically active cells. Replicative senescence is triggered by erosion and dysfunction of telomeres and is mediated by multibranched signaling processes. The DNA damage-triggered response is commonly called “stress-induced premature senescence” (SIPS). Unlike replicative senescence, SIPS is independent of telomere length or function.
The morphology of fibroblasts near the end of their replicative lifespan is mainly characterized by cellular enlargement and flattening with a concomitant increase in the size of the nucleus and nucleoli, an increase in the number of lysosomes and Golgi, appearance of vacuoles in the cytoplasm and endoplasmic reticulum and an increase in the number of cytoplasmic microfilaments. In addition to the morphological changes, populations of senescent cells exhibit an increase in the number of multinucleated cells. Cellular responses to environmental cues are mediated via activation of complex signaling cascades that invariably induce changes in gene expression. The impaired responsiveness of senescent fibroblast to environmental factors, particularly the lack of response to mitogens, suggests inappropriate transmission of signals. This hypothesis is supported by the observation that infection of senescent fibroblasts with Simian Virus-40 results in one more round of DNA replication indicating that, even though senescent cells fail to replicate their DNA in response to serum or growth factors, their replicative machinery is actually intact.
Telomeres are repetitive structures of the sequence (TTAGGG)n at the ends of mammalian chromosomes. It has been shown that the average length of telomere repeats in human somatic cells decreases by 20–200 base pairs with each cell division. One reason for this shortening is the so-called “end replication problem”: during the replication of the lagging strand, the RNA primer for the most distal Okazaki fragment cannot be replaced by DNA. On the basis of regular shortening, telomeres have been connected with replicative aging in vitro and in vivo and were characterized as a “mitotic clock”.
The regenerative potential of our body decreases upon aging. Regenerative tissues depend on specialized adult stem cells, thus aging in these tissues can be interpreted as signs of aging in somatic stem cells. The relationship between senescence and disease state throughout the lifetime can be modeled in several ways. In the first hypothesis, all individuals are expected to show similar inherited replicative capacities at the start of their lifespan. In subjects without cardiovascular disease, senescence is assumed to be the consequence of lifelong reparative cell divisions with advancing age. In subjects with cardiovascular disease, senescence may be thought to represent an acceleration of the biological ageing process, triggered by exposure to mitotic stress, oxidative stress or DNA damage, independent of chronological age. Those more prone to developing disease are, therefore, expected to exhaust their replicative potential at an accelerated rate compared to healthy individuals. An alternative hypothesis is that individuals differ in inherited replicative capacity at the start of their lifespan, but exhaust their replicative potential at a similar rate. Those more prone to developing disease are expected to start off with a lower replicative capacity.