Role of autophagy in aging: The good, the bad, and the ugly is a really good review into the function of autophagy (eating yourself) which is how cells tidy themselves up by getting rid of dysfunctional mitochondria and creating new ones. Autophagy is a good thing because it makes cells work better. That almost certainly ups the Acetyl-CoA levels in the nucleus which readers of this blog will know is a *Good Thing. [Incidentally if you have the time its worth reading all of the review]
I will extract part of the review:
Unfortunately, the protection afforded by autophagy is progressively erased with age. For instance, Atg5, Atg7, and Beclin 1 are down-regulated in the normal aging brain, whereas, in osteoarthritis, the levels of ULK1, Beclin 1, and LC3 fall (Rubinsztein et al., 2011). In hepatocytes of aged rats, alongside the increase in cytosolic Hsc70, and coordinate with decreased binding and lysosomal uptake of cargo, there is a significant rise in degradation and hence reduced half-life levels of LAMP2A in lysosomal membranes (Cuervo and Dice, 2000, Kiffin et al., 2007). Indeed, under basal conditions, the half-life of LAMP2A in early passage fibroblasts is reduced from 38 to 26 h once the senescence settles (Kiffin et al., 2007).
Now I would think that this sounds like something that results from long genes and low levels of acetylation of the histone. So lets have a look:
Beclin1 is a protein encoded by the gene BECN1 (these things are often quite consistent). I have linked to the Gene Card. this is the actual gene. It has 14151 bases.
In a similar manner ULK1 has 5322 bases. MAP1LC3A (which encodes LC3) is 999 bases, ATG5 is 3185 and ATG7 is 5333.
Is a table from the very good paper Age- or lifestyle-induced accumulation of genotoxicity is associated with a generalized shutdown of long gene transcription
This table identifies genes that have a problem being transcribed as people get older as having lengths in excess of log(10) 4. Viz over 10,000. Which fits with Beclin 1's gene of BCLN1.
Why is this important?
In a sense given the knowledge that genes over 10,000 in length have a problem being transcribed as people get older is known this year and therefore not news.
However, this explains why Senolytics don't have the magic effect on the effects of aging. There is, as readers of this blog will know, a reinforcing impact on Acetyl-CoA levels via NF Kappa B and the Janus Kinase in that Senescent Cells issue a Cytokine (IL-10) that causes a reduction in the level of Acetyl-CoA. This, however, is not the only thing that impacts on the level of Acetyl-CoA. The efficiency of the mitochondria and the non-canonical TCA cycle also called SLC25A1 also impacts on nuclear Acetyl-CoA levels. Hence we have a second feedback mechanism driving down gene expression as people get older. Most importantly, however, reducing the number of senescent cells in itself will not improve the mitochondria that much. There will remain the impact of autophagy and particularly the downregulation of Beclin 1 (BCLN1).
Because it runs through the same pathway as the IL-10 process this will feed into the same Gompertz formula, but it explains the impact of aging on younger people who don't have many senescent cells. It also demonstrates the central importance of Autophagy and the role of HIF 1 alpha and other things that encourage autophagy.
Edit 24/12/2022
Thinking further on this. This will act in a reinforcing manner in a particular cell, but until the cell becomes senescent it will be restricted to that cell.
Edit 31/12/2022
*When I say Good Thing, I don't mean increasing Acetyl-CoA to the level at which there is a substantial amount of non-enzymatic acetylation. That would be a Bad thing.
Edit 24/4/2023
Looking further at the issue it appears that at times the blockage for gene expression is the translation of mRNA into protein. This may be more linked to the ATP/O efficiency of mitochondria and shortage of ATP than limits on Acetyl-CoA, but in one sense this does not matter if the solution to either problem is to have more efficient mitochondria. At times, however, the mRNA can be found, but the protein is still deficient.
Edit 5/6/23
Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis is one of a number of papers that highlight ribosome pausing as part of aging. Obvious causes of this are a shortage of ATP and/or other metabolites (probably acetyl-CoA is part of this).
Edit 24/7/23
A comprehensive atlas of the aging vertebrate brain reveals 2 signatures of progressive proteostasis dysfunction looks also at the failure to create protein from mRNA
I will extract part of the review:
Unfortunately, the protection afforded by autophagy is progressively erased with age. For instance, Atg5, Atg7, and Beclin 1 are down-regulated in the normal aging brain, whereas, in osteoarthritis, the levels of ULK1, Beclin 1, and LC3 fall (Rubinsztein et al., 2011). In hepatocytes of aged rats, alongside the increase in cytosolic Hsc70, and coordinate with decreased binding and lysosomal uptake of cargo, there is a significant rise in degradation and hence reduced half-life levels of LAMP2A in lysosomal membranes (Cuervo and Dice, 2000, Kiffin et al., 2007). Indeed, under basal conditions, the half-life of LAMP2A in early passage fibroblasts is reduced from 38 to 26 h once the senescence settles (Kiffin et al., 2007).
Now I would think that this sounds like something that results from long genes and low levels of acetylation of the histone. So lets have a look:
Beclin1 is a protein encoded by the gene BECN1 (these things are often quite consistent). I have linked to the Gene Card. this is the actual gene. It has 14151 bases.
In a similar manner ULK1 has 5322 bases. MAP1LC3A (which encodes LC3) is 999 bases, ATG5 is 3185 and ATG7 is 5333.
Is a table from the very good paper Age- or lifestyle-induced accumulation of genotoxicity is associated with a generalized shutdown of long gene transcription
This table identifies genes that have a problem being transcribed as people get older as having lengths in excess of log(10) 4. Viz over 10,000. Which fits with Beclin 1's gene of BCLN1.
Why is this important?
In a sense given the knowledge that genes over 10,000 in length have a problem being transcribed as people get older is known this year and therefore not news.
However, this explains why Senolytics don't have the magic effect on the effects of aging. There is, as readers of this blog will know, a reinforcing impact on Acetyl-CoA levels via NF Kappa B and the Janus Kinase in that Senescent Cells issue a Cytokine (IL-10) that causes a reduction in the level of Acetyl-CoA. This, however, is not the only thing that impacts on the level of Acetyl-CoA. The efficiency of the mitochondria and the non-canonical TCA cycle also called SLC25A1 also impacts on nuclear Acetyl-CoA levels. Hence we have a second feedback mechanism driving down gene expression as people get older. Most importantly, however, reducing the number of senescent cells in itself will not improve the mitochondria that much. There will remain the impact of autophagy and particularly the downregulation of Beclin 1 (BCLN1).
Because it runs through the same pathway as the IL-10 process this will feed into the same Gompertz formula, but it explains the impact of aging on younger people who don't have many senescent cells. It also demonstrates the central importance of Autophagy and the role of HIF 1 alpha and other things that encourage autophagy.
Edit 24/12/2022
Thinking further on this. This will act in a reinforcing manner in a particular cell, but until the cell becomes senescent it will be restricted to that cell.
Edit 31/12/2022
*When I say Good Thing, I don't mean increasing Acetyl-CoA to the level at which there is a substantial amount of non-enzymatic acetylation. That would be a Bad thing.
Edit 24/4/2023
Looking further at the issue it appears that at times the blockage for gene expression is the translation of mRNA into protein. This may be more linked to the ATP/O efficiency of mitochondria and shortage of ATP than limits on Acetyl-CoA, but in one sense this does not matter if the solution to either problem is to have more efficient mitochondria. At times, however, the mRNA can be found, but the protein is still deficient.
Edit 5/6/23
Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis is one of a number of papers that highlight ribosome pausing as part of aging. Obvious causes of this are a shortage of ATP and/or other metabolites (probably acetyl-CoA is part of this).
Edit 24/7/23
A comprehensive atlas of the aging vertebrate brain reveals 2 signatures of progressive proteostasis dysfunction looks also at the failure to create protein from mRNA
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