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| aging [2026/04/16 12:27] – [why do we age?] gary1 | aging [2026/04/16 12:28] (current) – [why do we age?] gary1 |
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| * key factor is the aging of the spleen with functional deterioration of splenic red pulp macrophages leads to the accumulation of iron deposits and toxic by-products in the spleen creating an oxidative environment that damages T cells, in response, T cells, partly via IRP2 downregulation to resist ferroptosis, reduce their iron uptake and sequester the iron already present within the cell in protein complexes that lower its availability but as available iron is essential for T-cell activation, their ability to respond is significantly weakened(([[https://www.nature.com/articles/s43587-025-00981-4|2025: Heme and iron toxicity in the aged spleen impairs T cell immunity through iron deprivation]])) | * key factor is the aging of the spleen with functional deterioration of splenic red pulp macrophages leads to the accumulation of iron deposits and toxic by-products in the spleen creating an oxidative environment that damages T cells, in response, T cells, partly via IRP2 downregulation to resist ferroptosis, reduce their iron uptake and sequester the iron already present within the cell in protein complexes that lower its availability but as available iron is essential for T-cell activation, their ability to respond is significantly weakened(([[https://www.nature.com/articles/s43587-025-00981-4|2025: Heme and iron toxicity in the aged spleen impairs T cell immunity through iron deprivation]])) |
| * aging hematopoietic stem cells (HSCs) lose their effectiveness in generating a balanced mix of blood cells | * aging hematopoietic stem cells (HSCs) lose their effectiveness in generating a balanced mix of blood cells |
| * stress-induced MLKL activation appears to be transient and localized to mitochondria, where it causes direct damage, reducing membrane potential, altering mitochondrial structure, and impairing energy production, in turn, these changes lead HSCs to exhibit hallmark features of aging | * stress-induced MLKL activation appears to be transient and localized to mitochondria, where it causes direct damage, reducing membrane potential, altering mitochondrial structure, and impairing energy production, in turn, these changes lead HSCs to exhibit hallmark features of aging but this pathway seems to have the potential to be blocked (([[https://www.nature.com/articles/s41467-026-71060-4|2026: Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging]])) |
| * **epigenetic drift** | * **epigenetic drift** |
| * in the intestine, colorectal cancers become more common as we age partly due to a specific form of epigenetic aging - known as ACCA drift - accumulates in intestinal stem cells. This leads to the shutdown of key genes through hypermethylation. The drift spreads across the intestinal crypts and is caused by a combination of age-related inflammation, weakened Wnt signaling, and impaired iron metabolism, which affects the activity of DNA-modifying enzymes. Older intestinal cells absorb less iron but release more iron at the same time. This reduces the amount of available iron (II) in the cell nucleus, which serves as a cofactor for the TET (ten-eleven translocation) enzymes. These enzymes normally protect from the excess DNA methylations, but if the cell doesn't have enough iron, they can't do their job properly. Excess DNA methylations are no longer broken down.(([[https://www.nature.com/articles/s43587-025-01021-x|2025: Iron homeostasis and cell clonality drive cancer-associated intestinal DNA methylation drift in aging]])) | * in the intestine, colorectal cancers become more common as we age partly due to a specific form of epigenetic aging - known as ACCA drift - accumulates in intestinal stem cells. This leads to the shutdown of key genes through hypermethylation. The drift spreads across the intestinal crypts and is caused by a combination of age-related inflammation, weakened Wnt signaling, and impaired iron metabolism, which affects the activity of DNA-modifying enzymes. Older intestinal cells absorb less iron but release more iron at the same time. This reduces the amount of available iron (II) in the cell nucleus, which serves as a cofactor for the TET (ten-eleven translocation) enzymes. These enzymes normally protect from the excess DNA methylations, but if the cell doesn't have enough iron, they can't do their job properly. Excess DNA methylations are no longer broken down.(([[https://www.nature.com/articles/s43587-025-01021-x|2025: Iron homeostasis and cell clonality drive cancer-associated intestinal DNA methylation drift in aging]])) |
