Hallmark of Aging 8 - Cellular Senescence

July 01, 2024

Hallmarks of Aging 8 - Cellular Senescence


We are up to eight Hallmarks! Two to go! Cellular senescence caught my curiosity. The fact that there is now an international organization dedicated to studying cellular senescence speaks to the seriousness that people are now giving this topic. Every tissue makes senescent cells, at wildly different rates. "Endothelial" cells, the lining of organs and arteries, fibroblasts, what holds tissues together, and immune cells are the most common sources of senescent cells. Brain and heart tissue hardly have any senescent cells at all, unless you examine our politicians.

The best argument for the recognition of senescent cells' damaging role is the prolongation of life and wellness in multiple experimental models of aged mice, by the elimination of those senescent cells by pharmacological means.


Healthy, functional cells are called "quiescent" meaning they are alert, alive, and ready to go when needed. The best analogy is a squadron of soldiers in parade uniform, at ease and all lined up in parade formation. They are ready to go.


Now, imagine those same soldiers back in the barracks playing poker in their underwear and having their third beer. They are inviting you to join their poker game. They aren't doing their assigned function. Senescent cells are like zombie cells, infecting their neighbors and spreading their own maladaptions.

Therein is the problem. Senescent cells damage the cells around them with increasing levels of messaging that nudges the cells to act older. What do you mean by "act older"? Well, we aren't so sure, just yet. We believe the complex portfolio of mRNA molecules, coding for hundreds of different seemingly unrelated chemicals and compounds all have a complementary influence on aging. We see that in the use of exosomes from older mice injected into younger mice. Harvest their exosomes (tiny packets of 100-300 mRNA) molecules circulating in the blood of all animals, including humans) that are the organism's method of coordinating the whole organism to similar behavior. Harvest those exosomes and inject them into younger mice. Presto, chango. They become much older. Reverse it and they become much younger. When it comes to me, please make sure you get the right vial.


In case you thought the topic was that simple, consider just one quote about one feature of senescence. "Another important event during senescence is the depletion of lamin B1 from the nuclear envelope. This results in the loss of lamin-associated heterochromatin and de novo formation of heterochromatin rich in H3K9me3, a process that can be visualized as HP1α foci or senescence-associated heterochromatin foci (SAHFs)." It's not simple and parsing out the details is a challenge for the ages. But a good start is naming it, and beginning to devise means of studying it.


There is no single marker of senescence yet identified but there are some features when taken together are enough make a working list: (1) lysosomal expansion, detectable by SABG; (2) upregulation of CDK inhibitors, particularly p16 and/or p21; (3) loss of LMNB1 from the nuclear envelope; (4) loss of the chromatin component HMGB1 from the nucleus and its extracellular release as an alarmin; (5) heterochromatic foci, visualized as HP1γ nuclear foci or SAHFs; (6) high levels of ROS; (7) exacerbated DNA damage, visualized as γH2AX nuclear foci; and (8) high levels of SASP factors, notably IL-6, TGF-β, PAI1, and others.

My eyes glazed over before I got to 7. This is hard-core cellular biology.


www.What will Work for me? There continues to be interest in some sort of senescent strategy for our individual lives. The taking of Sirolimus, an analog of Rapamycin (an antibiotic produced by an actinomycete bacteria found at the foot of one of the monoliths on Rapa Nui, (Easter Island)) is popular in the high-end range of anti-aging efforts. It's probably just as beneficial to have you include some sort of ketosis strategy and growth hormone inducement by peptides. Those are the three things that I do. I'm still alive.


References: Cell, Cell,


Pop Quiz


1. What is cellular senescence?                        Answer: The slow accumulation of damage from various sources.


2. What is the problem with senescent cells?                        Answer: They are zombies and don't do their function properly. Moreover, they recruit neighbors to be just as dysfunctional.


3. Do we have good proof of the concept?                        Answer: No, the research is pretty nuanced and our best crack at it is the prolongation of life induced in aged mice with various senescent cell-killing strategies.


4. Are there other strategies that may help that shift?                       Answer: Yes, growth hormone, exercise, fasting, and ketosis all play a part.


5. Are there clear markers of senescent cells?                         Answer: No. It appears to be a subtle continuum. All cells start as quiescent. Somewhere along the line they fall off the cliff and get reprocessed - "autophagy". I suspect that subtle degradation has to include loss of plasmalogens in the membranes. I could find no mention of that anywhere, but it is the only way one can square the evidence of plasmalogen functionality and the philosophical construct of senescence. If I were a starting out PhD student, this would be my consideration for a thesis.

 

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