Senescent Cells Mediate the Harmful Effects of Angiotensin II
Angiotensin II is used in many mouse models to induce hypertension and tissue damage, thereby accelerating the progression of a range of age-related conditions, including atherosclerosis. Researchers here show that an increased burden of senescent cells mediates these effects of angiotensin II, and that clearing senescent cells prevents the harms caused by increased angiotensin II levels. The near ubiquity of cellular senescence as an important mechanism linking forms of lower level molecular damage and dysregulation of metabolism to the development of disease continues to be surprising, even now.
Angiotensin II can cause oxidative stress and increased blood pressure that result in long term cardiovascular pathologies. Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a model that mimics long term tissue damage. We utilized the INK-ATTAC (p16Ink4a-Apoptosis Through Targeted Activation of Caspase 8) transgenic mouse model that allows for conditional elimination of p16Ink4a-dependent senescent cells by administration of AP20187.
Angiotensin II treatment for 3 weeks induced ATTAC transgene expression in kidneys but not in lung, spleen, and brain tissues. In the kidneys increased expression of ATM, p15, and p21 matched with angiotensin II induction of senescence-associated secretory phenotype genes MMP3, FGF2, IGFBP2, and tPA. Senescent cells in the kidneys were identified as endothelial cells by detection of GFP expressed from the ATTAC transgene and increased expression of angiopoietin 2 and von Willebrand Factor, indicative of endothelial cell damage. Furthermore, angiotensin II induced expression of the inflammation-related glycoprotein versican and immune cell recruitment to the kidneys.
AP20187-mediated elimination of p16-dependent senescent cells prevented physiologic, cellular, and molecular responses to angiotensin II and provides mechanistic evidence of cellular senescence as a driver of angiotensin II effects. In conclusion, the low dose, prolonged angiotensin II exposure is associated with the induction of senescence in kidneys and the promotion of an inflammatory microenvironment through both secreted factors and immune cells. Endothelial cells appear to be a major cell type impacted. The elimination of senescent cells in the INK-ATTAC transgenic model prevents these effects of angiotensin II and reveals a novel pathophysiologic mechanism amenable to targeting by senolytic drugs in development.
so...can we talk about the GOOD of senescent cells?
tell me what I'm getting wrong here:
The body has 2 ways to fight cancer: aptosis, and the ability to "senesce" (turn off? stop the 'cell lifecycle'?) cells. Great! so far so good. Any cell that has gone haywire (dna mutation, etc) can get cleared, or stopped by the body, and thus prevent that problem from replicating indefinitely, and thereby stop what will eventually turn into cancer.
But why the senesce ability? Why not just destroy and clean out the bad cell completely with aptosis, every time? There seems to be some usefulness to having a cell that's been switched off, but not destroyed... a senescent cell, sitting there, giving off the SASP, inducing inflammation. If you clear off all the senescent cells in a young body... you get bad effects, similar to someone with a very weak immune system that is unable to respond to diseases, metabolize, clear out arteries... etc (i think?). If you never clear out senescent cells, you get too much SASP and inflammation.
So... having too many senescent cells causes chronic SASP and inflammation, and that's bad... and too LITTLE senescent cells causes an inability for inflammation to occur at all, and that's also bad.
If all the things I just said are true, then....
Why is it that a 5 year old is able to fend off diseases, clear out their arteries, heal from wounds, and in general have an effective immune system? If senescent cells are needed to produce an appropriate level of inflammation and immune activity in the body, and senescent cells are created over time as we age... how do the young survive? Are they born with a number of senescent cells already?
I must getting something wrong here...
Maybe a better question is: what exactly is the GOOD of senescent cells?
PS: Also, in the future, if there seems to be a sweet spot for the number of senescent cells in the body... will this be a thing similar to the thyroid? You get tested, and if you are outside of the effective range, you get medication accordingly (hypo, or hyper thyroid).
Just because something exists doesn't mean that there's a benefit to it; quite often it's just because there's a lack of sufficient selective pressures against it. As for why we ended up with the two different mechanisms, well, the thing to note about senescent cells are that they are very apoptosis resistant, suggesting that senescence is the easiest, next best way of taking out cells that accumulate mutations that prevent apoptosis. As for why we just haven't evolved more robust ways of ensuring that damaged cells undergo apoptosis instead, there's just a lack of selective pressure to do so. By the time an organism has accumulated enough senescent cells to cause problem, that organism can expect to have long ago been eaten by a lion, died of infection, accidents etc. Senescence was just the easy, low hanging fruit way for evolution to take out apoptosis resistant cells - cellular senescence already existed for other functions (eg. wound healing), so it was easier to repurpose it for cancer prevention than to produce more foolproof apoptosis mechanisms.
Senescence is probably just an unfinished cell cycle that never reached apoptosis. The cells kinda get stuck and never signal the immune system to eat them by downregulation of CD47+ and somesuch.
"The senescence response" is to protect against cancer and means cycle arrest and marking the cell for disposal which the immune system usually does. Yet some cells survive this cleaning phase and turn into "lingering senescent cells". Lingering senescent cells are just a (partial) failure of this anti-cancer mechanism. But the evolution found in the mean time other 'good' uses for them, like to signal to create skin (in embryo phase) and to start re-creating skin (after being born) in wound healing (evolutionary pleiotropy :<). And last but not least to make hard and tall cliff on age graph after which every organism dies so nobody lives to 500 years. And worse, just sometimes the tissue they are in won't create replacement cells so it creates void that is more dangerous than their presence. Just 'cause of these cons' the best way to 'remove' them is to prevent them becoming senescent in the first place, at least in normal tissue operation and not in skin healing. Telomeres, mitochondria and many other forms of cells repair would be better than their removal. Just when they were created, they must be (sometimes) removed...
@SilverSeeker
some generic damage is inevitable. Those "damaged goods" should better be cleaned than risking cancer.
Lingering ScC wouldn't be much of a problem if they were inert akin scar tissue. The problem is SASP which is very inflammatory and damaging.
I think that the "good" functions of senescent cells require a different kind of senescence cells. Embryo simply doesn't have that much damage to accumulate , so the senescent cells there are of a different kind. They might have similar phenotype and look similar but on the inside are quite different. Anyway, distinguishing between "good" and "bad" ScC and targeted treatments are for generation II and IV of the senolytical therapies.
For now we need somebody to quickly push for human trials of gen II senolytics. For now we have very anemic gen I tests.
@Cuberat yes it's a painful tradeoff. The later we start, the worse. Yet SASP blocks telomerase, so it creates even more senescent cells and more SASP, it's just positive feedback loop gone wild that must be broken before it kills us.
For lack of a better place I will post this here. I am starting to strongly suspect that "senescent cells" is a misnomer, and that what we call "SCs" do divide, just less frequently, or in unique situations. How was it concluded that "SCs" don't divide?
@JohnD because when they divide they are called 'cancer cells' and frequently kill the host. Cancer cell that do not divide is called senescent cell, and senescent cell that divides is called cancer cell. Hence we know for sure that senescent cells do not divide.