which organs age particularly fast? cell discovers hidden drivers of aging
2024-09-23
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▎edited by wuxi apptec content team as we age, the various tissues and organs that make up the body do not age synchronously. many people may see signs of aging from the skin and hair, but in fact some organs in the body age faster than the skin.for example, the liver, as the largest metabolic organ in the human body, is one of the organs that bear the brunt of the aging process.liverit presents typical aging phenomena such as increased inflammation and fibrosis, weakened regenerative ability, and reduced repair ability after injury, resulting in a decline in metabolic function and anti-stress ability.why some organs age faster has long been a puzzle for scientists. finding the answer to this question is likely to provide targeted intervention methods for delaying aging. recently, in the top academic journal cell, a research team composed of institutions such as the university of geneva and the university hospital of bern in switzerland found thatan overlooked factor: mutations hidden in noncoding regions of dnathese mutations are not easy to detect, but may explainwhy do organs such as the liver and kidneys age faster than other organs (such as the skin and intestines)?。in dna molecules, only a small part of them are protein-coding genes, and most of the rest belong to non-coding regions. non-coding regions were once considered useless "junk dna", but after in-depth exploration, scientists found that non-coding regions are involved in regulating or organizing gene expression, which is very important for when and where proteins appear correctly. today, with the advancement of sequencing technology, researchers can find mutations in non-coding regions and analyze their effects.when dna is damaged and mutations occur, the repair system prevents the accumulation of errors. errors in the coding region can be detected when the gene is transcribed into rna (that is, when the gene is activated). errors in the non-coding region are detected when the cell is renewed due to dna replication.
in organs such as the skin and intestines that are frequently in contact with the external environment, cells are easily worn out and are renewed very frequently, which is "weekly", and dna replication also occurs frequently. in contrast, the cell renewal frequency in tissues such as the liver and kidneys is much lower, generally only replicating a few times a year, and dna mutations in non-coding regions are not easy to detect.in this study, the authors used mouse livers as the research object and discovered the relationship between these hidden mutations and organ aging. the researchers performed partial liver resections on young and old mice and monitored the process of initiating dna replication in young and old livers during regeneration. the paper pointed out,this is the first in vivo experiment to examine the dynamics of dna replication under physiological conditions.。▲schematic diagram of this study (image source: reference [1])they found that in young mice,the origin firing sites are very clear and are located in the non-coding region of dna. most of them are 10-50 kb upstream or downstream of the relevant gene.this positional feature is also true in human cells. in old mice, although the location of the replication origin is the same, the efficiency of origin activation is greatly reduced and is accompanied by dna replication stress response.further analysis revealed that the non-coding dna of aged mice, including the replication start point, accumulated too many mutations, and when dna replication was needed,atr, a key kinase protein of the damage checkpoint, is triggered like an alarm system, preventing dna replication and thus preventing cell proliferation, leading to cell function degeneration and tissue aging.when the researchers used atr inhibitors to "relieve" the alarm and activated the dna replication starting points during liver regeneration in old mice, although the efficiency of initiating replication was restored, the proportion of liver cells entering the cell cycle did not increase to the level of young mice, and it also caused an inflammatory response in the liver.image source: 123rf
based on these results, the authors speculate that "if aging is caused by hidden dna damage-induced replication stress, this may explain why slowly proliferating organs such as the liver age faster than highly proliferative tissues such as the intestine." because in the liver, cells remain quiescent for a long time,excessive accumulation of hidden damage in noncoding regions, including sufficient accumulation of dna damage at the replication origin, puts the cell under increasing replication stress; on the contrary, if cells are renewed frequently, damage is not easy to accumulate, and the replication origin can better maintain efficiency.based on the above findings, the author further pointed out the idea of preventing aging. the author believes thatit's not the hidden dna damage itself that causes aging, but the cell's response to that damagecellular senescence can occur when cells attempt to replicate their dna under conditions of dna replication stress. therefore, repairing cryptic dna damage before initiating replication may help avoid senescence.
[1] Giacomo G. Rossetti et al., In vivo DNA replication dynamics unveil aging-dependent replication stress, Cell (2024). DOI: 10.1016/j.cell.2024.08.034.
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