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Brainstorming session
Darko Savic Jul 26, 2020
Shubhankar Kulkarni Jul 28, 2020 
Antonio Carusillo Sep 08, 2020
What mechanisms are responsible for telomere shortening in non-dividing cells?
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Necessity
Is the problem still unsolved?
Conciseness
Is it concisely described?
Do we know what mechanisms are responsible for the telomere shortening in post-mitotic (non-dividing) cells? Especially neurons, since they have been studied in more detail than other cell types in this regard.
If it's still not known, could we come up with experiments to find out?
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Creative contributions
Re-induction of cell cycle and oxidative stress
A number of mechanisms for cell cycle-independent telomere shortening have been proposed:
1. In post-mitotic neurons, the observation of a variation in the DNA content suggested that there might be cell-cycle re-induction in about 10-20% of the neurons. Studies I found were speculative and we currently do not know the actual proportion of neurons (or other cells that were previously known to be non-dividing) that are (or can be, under certain circumstances) re-induce their cell cycle. This number can be greater than 20%, significant enough to observe telomere shortening at the tissue level.
Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286833/
2. Secondly, oxidative stress leads to telomere shortening in non-replicative cells.
Do check Figure 1 from (https://www.mdpi.com/2073-4425/7/9/58/htm)
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Telomeres deprotection and shortening in post mitotic cells : a puzzle yet to be solved
First of all, it is necessary a clarification: Cellular senescence can be defined as a permanent non-dividing cellular state triggered by numerous types of stress (DNA Damage, ROS, genotoxic agents ) and characterized by profound changes in cellular morphology, chromatin structure, metabolism and gene expression, including a senescence-associated secretory phenotype (SASP)—the expression and secretion of inflammatory cytokines, growth factors, proteases and other molecules. Cellular senescence is distinct from other non-dividing cellular states such as the quiescence that is a reversible absence of proliferation and the terminal differentiation corresponding to the acquisition of a functional specialization by cells that are often irreversibly cell-cycle arrested and therefore named post-mitotic (1).
One of the hallmarks of cellular senescence is telomeres (TL) shortening. TL consist of the long stretch of 5´-TAGGG-3´ repeats around 5 kb long in human cells, their function is to hide the chromosome ends from being recognized as double-strand DNA damage through recruitment of shelterin, alteration of their structure and compaction of telomere chromatin. These protection mechanisms are based on the maintenance of telomere length. However, TL progressively shortens with cell division. When a critical TL length is reached, shelterin will lose its binding site and telomeric DNA cannot form a protective secondary structure, thus triggering shelterin senescence.
Cell senescence activated by shortening it is also defined as replicative senescence. Thus, telomeres are regarded as the ‘‘molecular clock’’ of cells which goes off when telomerase is shut down during mid-embryogenesis in most cells of the human body. The protective function of the telomeres is lost and replicative senescence is triggered through DNA damage associated pathways (2).
On the other hand, a different kind of cellular ageing process interests the terminally differentiated long-lived post-mitotic cells (LLPMCs), such as myofibers and neurons, whose function can decline with age with no clear sign of cellular senescence. For instance, ageing neurons progressively show a decline in axonal transport, focal accumulations of cytoplasmic and membrane proteins, synaptic transmission alteration, impaired synaptic plasticity, and altered calcium homeostasis(3). Also, myofibers – as they age – will shoe altered muscle-specific mechanisms, loss of fast fibres and loss of organization at the level of neuromuscular synapses (4).
If stem cell division can be considered a rejuvenation mechanism, the situation is different for LLPMCs, which mostly rely on their intracellular capacities of repair and renewal (e.g., autophagy and mitophagy). It is generally accepted that an increase in reactive oxygen species (ROS) production by dysfunctional mitochondria and the age-dependent decrease in the efficiency of the cellular mechanisms. renewing, removing and repairing damaged molecules are responsible for the functional decline observed in LLPMCs during ageing (Bua et al., 2006; Fritzen et al., 2016; Kraytsberg et al., 2006; Linnane et al., 1989; Loos et al., 2017; Rubinsztein et al., 2011; Sakuma et al., 2015) (Terman et al., 2010) (Fig. 1B). However, the cascade of age-related events that trigger these changes and its link to LLPMC senescence is unclear.
As stated above, TL shortening is a clear hallmark in ageing cells. However this doesn’t seem to be the case of LLPMCs as TL are shortened at each round of replication, but LLPMCs do not undergo replication anymore. Although a growing body of shreds of evidence reporting TL shortening in different low-proliferating tissues: retina, cardiomyocytes and locates, these results are challenged by the fact that in the tissues analysed renewing cells – characterized by TL shortening – are also present. Thus they may act as confusing elements as it is hard to isolate LLPMC-like cells from proliferative cells where this mechanism is taken for granted(5).
From proliferating tissues, we know that oxidative stress can lead to TL shortening in dividing cells by interfering with telomere DNA replication and telomerase activity (6). A similar consequence has been also observed in isolated skeletal muscle fibers and adipocytes which showed telomere shortening upon ROS release, paving the hypothesis that indeed a replication-independent, oxidative stress-dependent mechanism of TL shortening exists(7). Another suggested mechanism has been a reduction in the expression of genes codifying for the shelterin complex, TRF1 and TRF2 whose role is to “mask” the telomeres ends and their functions may also regulate mitochondrial physiology (8, 9). This is supported by the fact that in human biopsies from individuals of different ages, TRF2 protein level showed a marked decrease (9). Thus deregulation of TRF1 and TRF2 seems to contribute to LLPM ageing by telomere deprotection. This can be assessed by co-localization studies of key factors involved in the DNA-Damage Response like the phosphorylated form of the H2AX histone as well as 53BP1 at the telomeric ends, marking breakage points(10). Accumulation of DNA Damage Response (DDR) factors have been reported for different LLPMCs: cardiomyocytes in mouse and human, mouse oocytes, human melanocytes and mouse retinal ganglion cells(5).
This opens the question to what engages the LLPMCs clock if any is present. A possible theory may come from what we said before: in the same tissue, both proliferating cells and LLPMCs co-exist. What we know is that proliferating cells entering senescence undergo different changes, among this, we know that senescent cells secrete many factors, including pro-inflammatory cytokines and chemokines, growth modulators, angiogenic factors, and matrix metalloproteinases (MMPs), collectively termed the senescent associated secretory phenotype (SASP) or senescence messaging secretome (SMS). The SASP factors mediate developmental senescence and tissue plasticity and also contribute to persistent chronic inflammation (known as inflammaging)(11.
A question would be whether senescent cells by releasing SAPS factors may also influence the neighbouring LLPMCs promoting, for example, ROS release and telomeres deprotection.
References:
1- Terzi MY, Izmirli M, Gogebakan B. The cell fate: senescence or quiescence. Mol Biol Rep. 2016;43(11):1213-1220. doi:10.1007/s11033-016-4065-0
2- Telomeres and Aging, Geraldine Aubert and Peter M. Lansdorp, Physiological Reviews 2008 88:2, 557-579
3- Milde S, Adalbert R, Elaman MH, Coleman MP. Axonal transport declines with age in two distinct phases separated by a period of relative stability. Neurobiol Aging. 2015;36(2):971-981. doi:10.1016/j.neurobiolaging.2014.09.018
4- McCormick R, Vasilaki A. Age-related changes in skeletal muscle: changes to life-style as a therapy. Biogerontology. 2018;19(6):519-536. doi:10.1007/s10522-018-9775-3
5- Maria Sol Jacome Burbano, Eric Gilson, Long-lived post-mitotic cell aging: is a telomere clock at play?, Mechanisms of Ageing and Development, Volume 189, 2020, 111256, ISSN 0047-6374,
https://doi.org/10.1016/j.mad.2020.111256.
6- Coluzzi E, Colamartino M, Cozzi R, et al. Oxidative stress induces persistent telomeric DNA damage responsible for nuclear morphology change in mammalian cells. PLoS One. 2014;9(10):e110963. Published 2014 Oct 29. doi:10.1371/journal.pone.0110963
7- Jackson MJ, McArdle A. Age-related changes in skeletal muscle reactive oxygen species generation and adaptive responses to reactive oxygen species. J Physiol. 2011;589(Pt 9):2139-2145. doi:10.1113/jphysiol.2011.206623
8- Walker JR, Zhu XD. Post-translational modifications of TRF1 and TRF2 and their roles in telomere maintenance. Mech Ageing Dev. 2012;133(6):421-434. doi:10.1016/j.mad.2012.05.002
9- Robin, JD, Jacome Burbano, M‐S, Peng, H, et al. Mitochondrial function in skeletal myofibers is controlled by a TRF2‐SIRT3 axis over lifetime. Aging Cell. 2020; 19:e13097. https://doi.org/10.1111/acel.13097
10-DNA damage response at functional and dysfunctional telomeres. Martina Pia Longhese, Gen Dev. January 15, 2008 22: 125-140; doi: 10.1101/gad.1626908
11-Nicolás Herranz, Jesús Gil J Clin Invest. 2018;128(4):1238-1246. https://doi.org/10.1172/JCI95148.
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