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What is the lethal threshold for molecular damage in humans?

Image credit: Krysko 2011 https://www.cell.com/trends/immunology/fulltext/S1471-4906(11)00014-7

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 19, 2020
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Necessity

Is the problem still unsolved?

Conciseness

Is it concisely described?

If and when humanity solves the longevity problem, another equally difficult (probably) problem of accumulation of lethal levels of molecular damage awaits. Here, I would like to address the questions - whether organisms have a lethal threshold? If yes, how do we determine the lethal threshold for humans?

According to Blagosklonny, although accumulation of DNA mutations correlates with age, it does not necessarily cause aging. Mutations accumulate with time as a measure of time itself. Other than premature aging syndromes, there is little direct evidence that aging is caused due to accumulation of molecular damage. However, although not aging but accumulated molecular damage causes deterioration sooner or later. Currently, an organism may not live long enough to reach that “lethal threshold” of molecular damage. In the future, we might need to know the lethal threshold for humans and ways to overcome it.

[1]Blagosklonny M V. Aging: ROS or TOR. Cell Cycle [Internet]. 2008 Nov 5;7(21):3344–54. Available from: http://www.tandfonline.com/doi/abs/10.4161/cc.7.21.6965

[2]Khrapko K, Kraytsberg Y, de Grey AD, Vijg J, Schon EA. Does premature aging of the mtDNA mutator mouse prove that mtDNA mutations are involved in natural aging? Aging Cell [Internet]. 2006 Jun;5(3):279–82. Available from: http://doi.wiley.com/10.1111/j.1474-9726.2006.00209.x

[3]Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS, Prolla TA, et al. Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet [Internet]. 2007 Apr 4;39(4):540–3. Available from: http://www.nature.com/articles/ng1988

[4]Wakayama T, Yanagimachi R. Mouse cloning with nucleus donor cells of different age and type. Mol Reprod Dev [Internet]. 2001 Apr 1;58(4):376–83. Available from: https://onlinelibrary.wiley.com/doi/10.1002/1098-2795(20010401)58:4%3C376::AID-MRD4%3E3.0.CO;2-L

[5]Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, et al. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics [Internet]. 2003 Dec 16;16(1):29–37. Available from: https://www.physiology.org/doi/10.1152/physiolgenomics.00122.2003

[6]Lanza RP. Extension of Cell Life-Span and Telomere Length in Animals Cloned from Senescent Somatic Cells. Science (80- ) [Internet]. 2000 Apr 28;288(5466):665–9. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.288.5466.665

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Creative contributions

Change as a sign of reaching the threshold

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J
Juranium Sep 04, 2020
When a nuclear reactor reaches temperatures or power that are too high, it automatically shuts down. If the damage is too big and they continue to rise, Chernobyl happens. The best would be to detect the damage earlier and fix/replace the reactor. Translated to your topic, I would say that the lethal threshold for molecular damage is reached when a drastic change in cells' faith is reached. If the damage gets detected, cells go apoptotic or senescent (automatic shutdown). If they somehow avoid being detected, they "go wild" and become tumor cells. Therefore, I would not describe the longevity problem without molecular damage. I would say it is one of the roadblocks we have to cross on the road to longevity. But we could use it as a biomarker of tissue fitness (e.g. tissue rate of senescence) and then enrich it with new stem cells (when we figure out how) if needed.
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