Researchers here discuss what is know of mechanisms surrounding telomere shortening in old tissues. Telomeres are the caps of repeated DNA at the ends of chromosomes. Their length is reduced a little with each cell division, and when too short, cells become senescent or self-destruct. This acts as a part of the limiting mechanisms that prevent normal somatic cells from dividing indefinitely, the Hayflick limit that ensures turnover of cells in tissues. Stem cells can continue to replicate and produce replacement daughter somatic cells with long telomeres via use of telomerase to lengthen their telomeres.
The body is thus divided into a small set of privileged cells and the majority of limited cells, a way in which evolution keeps cancer risk low enough for species survival. Average telomere length is shorter in older tissues arguably primarily because stem cell activity is lowered, and thus fewer replacements with long telomeres are introduced.
The above is a perhaps overly simplistic overview at the high level. The reality on the ground when cells begin to exhibit shorter telomeres is, as is usually the case in cellular biochemistry, much more complicated. Today's open access paper discusses some of the details. This is relevant to older tissues in which many more cells than is the case in young tissues are close to the Hayflick limit. There will be dysfunction that is more subtle than simply an increase in senescent cell creation.
Telomeres are the genomic portions at the ends of linear chromosomes. Telomeric DNA in vertebrates is made of TTAGGG repeats bound by a set of proteins that modulate their biological functions and protect them from being recognized as DNA damage that triggers a DNA damage response (DDR). As standard DNA polymerases cannot fully replicate linear DNA templates in the absence of telomerase, a DNA-template-independent DNA polymerase, and because of nucleolytic processing, DNA replication results in the generation of chromosomes with progressively shortened telomeres. As telomeres reach a critical length, they become unable to bind enough telomere-capping proteins and are sensed as exposed DNA ends, which activates the DDR pathways that, through the induction of the cell cycle inhibitors p21 and p16, arrest proliferation.
Such short telomeres, however, retain a sufficient number of telomere-binding proteins to inhibit DNA repair and avoid fusions, and consequently fuel a persistent DNA damage signal that enforces a permanent DNA damage-induced proliferative arrest. This initiates and maintains cellular senescence, a key contributor to organismal ageing and multiple age-related diseases. Activation of the DDR at telomeres (termed tDDR hereafter) results in the formation of telomere-associated DDR foci (TAFs) or telomere-induced DNA damage foci (TIFs), which are markers of cellular senescence in cultured cells and tissues. Following telomere dysfunction, some cell types may also undergo cell death by apoptosis or autophagy.
In addition to irreversible cell cycle arrest, cellular senescence is characterized by changes in chromatin, gene expression, organelles and cell morphology. Importantly, senescent cells secrete a complex set of pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This alters the composition of the extracellular matrix, impairs stem cell functions, promotes cell transdifferentiation and can spread the senescence phenotype to surrounding cells, thereby causing systemic chronic inflammation. SASP is both promoted by DDR and can promote DDR and TAF formation in an autocrine and paracrine fashion.
Although conceptually appealing to explain proliferative exhaustion and cell ageing, telomere shortening is inadequate to explain ageing in non-proliferating, quiescent or terminally differentiated cells. Nevertheless, TAFs and senescence have been reported in ageing post-mitotic cells, including cardiomyocytes, adipocytes, neurons, osteocytes, and osteoblasts. These observations can be explained by an evolutionary perspective by which telomere-binding proteins inhibit DNA repair to maintain the linear structure of chromosomes and to prevent fusions. As a consequence, DNA damage that occurs within telomeric repeats (tDD) resists repair, which causes persistent tDDR signalling and TAF formation also at long telomeres. Endogenous or exogenous DNA damage is constantly generated, and the fraction that occurs at telomeres, which is less efficiently repaired, thus accumulates and induces a senescence-like phenotype.
Therefore, persistent tDDR activation is the shared causative event of both replicative cellular senescence caused by critically short telomeres and the senescence-like state caused by damaged telomeres in non-replicating cells. Although these events may be mechanistically distinct in origin, DNA damage at long telomeres may cause, within the time frame of organismal ageing, degradation or loss of the terminal portions of telomeres, therefore leading to telomere shortening. In the broader context of organismal ageing, the notion that DNA is the only irreplaceable component of the cell makes a strong argument in favour of an apical role of DNA integrity in ageing. The irreparability of telomeres makes it more so.