How Exactly Is Cellular Aging Activated?

The circle is now closing. The cellular senescence of stem cells appears to be the root of the problems in our nearly perfect self-repairing organism. If we lose our functional stem cells, the repair mechanisms will be severely limited. To prevent this, we need to understand how it works in detail. Which molecules are degraded, and which processes are disrupted?

Adding extracellular vesicles produced by senescent cells (P5 EVsG93A or P5 EVsWT) increases DNA damage (β-Gal+ cells). This is due to the effect of misfolded, oxidized superoxide dismutase (SOD1).

Research on Alzheimer's disease may help. I’ve mentioned the issue of cognitive impairment related to this serious disease several times before. The most interesting was a study on a mouse model, tracking metabolic changes linked to enzyme acetylation and the availability of acetyl-CoA molecules in the cytoplasm. Back then, I didn’t realize that cellular pseudohypoxia is a manifestation of cellular senescence — cellular aging. This leads us to further connections and studies.  

Neural stem cells become more senescent in the presence of misfolded human superoxide dismutase (hSOD) after each cycle of oxidative stress (P1 to P5). Labeling with the CT4 protein (AAV-CT4) removes misfolded hSOD molecules, preventing senescence (markers P53 and P16).

Let’s look at a study on neuronal stem cells and their aging. The study states that the pathological amyloid-β protein significantly worsens the senescence of neuronal stem cells. This leads to DNA damage and suppression of the deacetylase SIRT1, so therapies boosting SIRT1 activity appear very promising. We already know that acetate/vinegar works by activating SIRT1 — we’ll see if human studies emerge in time.

But I still haven’t mentioned what kind of damage likely occurs. Another study helps with this. It actually brings me back to the beginning of this entire investigation — to the origin of the superoxide O2⁻, a molecule with immense oxidative power that forms when electrons from food find an alternative target: the O2 molecule. As you probably know, the energy of hydrogen electrons bound to carbon is higher than that of hydrogen electrons bound to oxygen. This is the basis of life’s energy cycle. The usual products of fuel oxidation are carbon dioxide and water. Superoxide is a byproduct and is immediately dismutated into hydrogen peroxide, a signaling molecule that is then used and converted into water and other signaling molecules. If this doesn’t happen, rising hydrogen peroxide levels in the cell trigger an adaptation to oxidative stress.

Superoxide and hydrogen peroxide are produced as byproducts of oxidative phosphorylation — energy production, especially during fat burning — or as a primary offensive product of the immune system against invaders (NOX2). They can oxidize almost anything: phospholipids in mitochondrial membranes, enzymes in the cytoplasm — anything prone to oxidation. And one such oxidized, misfolded enzyme, superoxide dismutase (SOD1), has been identified by researchers as a possible culprit in oxidative stress-induced senescence. Not only that, but senescent cells communicate with their surroundings via extracellular vesicles containing proteins, lipids, DNA, etc. These membrane-bound vesicles, carrying oxidized SOD1, are taken up by neighboring cells, which then also become senescent.

However, when researchers removed the oxidized enzyme from the vesicles, leaving only functional SOD1, senescence did not spread. A fascinating finding. This explains why antioxidant protection — adequate levels of NADPH and GSH — is so crucial to preventing or suppressing senescence.

The method for detecting the amount of misfolded, oxidized SOD1 is interesting because researchers attached CT4 molecules to mark them for removal. Then, they simply measured how many undamaged SOD1 enzymes remained. Senescence was induced in cycles P1 to P5. Each cycle increased the ratio of oxidized to functional SOD1, but removing the oxidized SOD1 prevented cellular senescence.

Oxidative stress can thus damage one of the cell’s most important antioxidant enzymes, leading to cellular senescence as a protective response. Removing damaged SOD1 molecules restores normal stem cell function and, in the case of neural stem cells, counteracts Alzheimer’s disease while improving cognitive abilities.

Overall, this research suggests that the senescence of neural stem cells is caused by insufficient SOD1 activity — meaning the oxidative activity of superoxide O2⁻, which likely damages genetic information or DNA repair enzymes, leading to cellular senescence. Oxidized SOD1 cannot fold into a functional enzyme, and the nonfunctional enzyme accumulates in the cell. SOD1 oxidation is carried out by hydrogen peroxide (possibly also peroxides or aldehydes derived from omega-6 PUFAs), which accumulates when antioxidant defenses fail — for example, in the presence of amyloid plaques and reduced SIRT1 deacetylase activity (due to G6PD enzyme acetylation and disrupted NADPH production). Excessive oxidative stress thus destroys antioxidant defenses — a vicious cycle. A permanent cellular state. But there is a solution: restoring SIRT1 activity can revive antioxidant defenses and suppress cellular senescence.

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References:

Alzheimer’s Amyloid-β Accelerates Cell Senescence and Suppresses SIRT1 in Human Neural Stem Cells

Oxidized SOD1 accelerates cellular senescence in neural stem cells