Fascinating new approach to diabetes cure: stopping cell senescence



This direction was fascinating to me because it is the first time I see it applied to diabetes—I also see some great potential!

This brand new study, also out of UCSF (the third in a week!), looks at a radically different approach. Rather than assuming that the immune system is at fault, it looked for (in mice bred for diabetes), and found, signs that beta cells get early DNA damage that, in turn, triggers cell senescence. This, in turn, they hypothesize, provokes an immune system reaction. So they administered a drug that destroys senescent cells, and were able to lower the rate of diabetes in these mice from 75% to 30%. To verify that what they saw with mice also applies to humans, they examined tissue from 6 diabetics and 6 patients testing positive to diabetes autoantibodies, and found the same senescence markers in beta cells. Here is the UCSF press release:

The new findings contrast sharply with the prevalent belief that T1 diabetes is caused by an overly aggressive immune system attacking healthy beta cells. The new data suggest instead that inherent problems with DNA repair in some beta cells triggers senescence, which patrolling immune cells first fail to recognize and clear out. As a result, these cells accumulate and spread so widely within the pancreas that by the time the immune system eventually recognizes the problem, it essentially has to raze the whole insulin-producing system, leading to the onset of diabetes. […]

The researchers found that well before immune cells began to attack the pancreatic islets where beta cells reside, the beta cells began exhibiting signs of “secretory senescence,” a type of cellular decline caused by DNA damage in which cells stop functioning properly and begin producing molecules that harm nearby cells and attract the attention of the immune system.

To test whether eliminating senescent beta cells could help prevent T1 diabetes, Bhushan’s group tested a drug called ABT-199 (Venetoclax) […]— a drug that selectively eradicates senescent cells. Remarkably, the researchers found that while 75 percent of control mice developed diabetes by 28 weeks of age, only 30 percent of mice who were given ABT-199 for two weeks prior to the onset of symptoms went on to develop the disease. The researchers showed that the drug had rapidly eliminated senescent beta cells in these mice, after which their immune systems (which were not directly affected by the treatment) left the remaining, healthy beta cells alone, avoiding the loss of insulin production that causes diabetes.

“These findings support the idea that senescent beta cells are like the bad apples that spoil the whole basket,” Shah said. “Here we show that eliminating the bad apples can save the rest, which brings a new therapeutic avenue for treating patients with T1 diabetes.” […]

In line with their animal findings, the authors identified clear signs of DNA damage and secretory senescence in the beta cells of six donors with early-stage T1 diabetes, compared to six non-diabetic donors. The researchers also found signs of beta cell senescence in six donors without a diabetes diagnosis, but whose blood showed early signs of an immune reaction against beta cells, corroborating the idea that senescence is an early part of the chain of events leading to the disease.

“Seeing this data was an incredible moment,” said Thompson. “Many results from these diabetic mouse lines have not panned out in humans, but the fact that we were seeing the very same markers of senescence in human pancreas tissue indicated that the same process is occurring in the human disease as well.” […]

Bhushan’s group hopes these findings will lead to a therapy that could forestall the onset of T1 diabetes in young people at risk of developing the disease – which can currently be assessed via blood tests – and preserve remaining beta cell function in people with a recent T1 diabetes diagnoses. The animal experiments suggest that patients might be able to take such a drug periodically to clear out any senescent beta cells, and then perhaps be healthy for years.

I am so interested in this new direction that I quoted much more than I normally quote in an article. This is truly new!

LInk to the article abstract: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30021-X

More discussion is FierceBiotech: https://www.fiercebiotech.com/biotech/abbvie-s-cancer-drug-venclexta-blocks-diabetes-mice-by-targeting-beta-cell-senescence (but I like the press release better)


I like this statement… Asking WHY…

Bhushan, who has long studied the biology of pancreatic beta cells, said that he has never been completely satisfied with the dominant model of the origins of type 1 diabetes: “Why does the immune system attack just those cells, while leaving neighboring cells of other types untouched?”

Which came from this link
Beta cell destruction

Thanks for sharing.


I liked that too: What a good way for a scientist to think!

The main drawback I see for this approach—not really a drawback if what they find is the truth, really, maybe a regret?—is that, so far, this approach can only lead to prevention and to, possibly, cure or delay for recently diagnosed T1s only.

But—it would be a tremendous step forward towards understanding the cause of T1 diabetes—if it is on the right track. Either way, an interesting direction to keep track of.


This is intriguing in light of some earlier cell-culture studies suggesting that the immune cells are responding to distress signals specifically sent out by the beta cells prior to the autoimmune attack starting. Those signals were more inflammatory distress signals, if I remember correctly.

I think it really strengthens the idea that these beta cells are sick or damaged somehow before the onset of T1, in at least a subset of people.

Downside: it’s using NOD mice. They get diabetes because they have a few key gene tweaks that make them more susceptible, but it certainly can’t mimic the number of gene mutations associated with T1 in humans – it’s a “mouse model” of the disease but it’s certainly not perfectly analogous.


You are totally right: the preventive part of the study is only on mice :frowning:

At the same time they do have that other part of the study that is looking for this weird DNA damage behavior that turns on cell senescence, and that part was done on humans as well:

“Seeing this data was an incredible moment,” said Thompson. “Many results from these diabetic mouse lines have not panned out in humans, but the fact that we were seeing the very same markers of senescence in human pancreas tissue indicated that the same process is occurring in the human disease as well.”

I was thrilled when I read that part. This is new knowledge! It may fizzle out, but right now it is new, hot and amazing: It could open many new directions. I don’t think I have seen anything in the past three years that appears to me to have as much potential.


I noted that in the paragraph, but I’m curious as to why. I’m ignorant on this question, but I’d like to know what residual capacity remains in the pancreas, and whether the presence of an outside source of insulin in effect finishes that off. I had read recently, but I don’t recall where, that even those with T1D over a period of a lifetime are found to have, post-mortem, some functioning and healthy beta cells inside the pancreas. Just not nearly enough to make a difference. Nonetheless, there may be hope from a number of angles.

I, too, like and find self-evident the idea that the immune system is not exactly going rogue.


So if this is correct, would it mean T1D is not an autoimmune disease? Don’t lots of other autoimmune diseases attack very specific types of cells while leaving nearby cells untouched? And don’t many people with T1D go on to develop other autoimmune conditions?


yeah I mean the genetic mutations associated with T1D are also often associated with many other autoimmune conditions.

I think this study is more asking people to potentially reconceptualize what it means for a disease to be autoimmune in nature. In other words, it’s not just that your immune system is hyperalert and attacking things willy-nilly – it’s that the body is unable to repair other damage until the immune system then has to step in.

But I am skeptical that this can explain all cases of T1D or autoimmunity. Because other lines of evidence suggest other interpretations.


I always wonder what the connection between allergies and autoimmunity is. Because, even if autoimmune conditions are caused by things like subtle DNA damage of some sort, allergies seem to be the immune system getting mixed up and targeting something that truly poses no sort of threat or problem. So clearly there are things that can legitimately “confuse” the immune system into attacking something even without a valid reason to do so.


Yes, it appears to be true for many T1Ds. Normally, this capacity appears to progressively go down with time. But some people theorize that all T1Ds still have some residual capability, however small.

From what I understood of the article, once the damage is done and the immune system has already ravaged practically all beta cells, it is not an issue of protecting what is left any more: so the patient must still be in honeymoon.

That said, this is all very hypotherical—until we see human results, pie in the sky really :slight_smile:


I think the rationale is partly that there’s a resident population of beta stem cells that are somewhat unkillable – and this population size may be tiny but always there for people. But my guess is it also has to do with cellular memory and how long the immune system keeps its “most wanted” list active, so to speak. For instance they find an exponential drop in beta cell number for the first 7 years of disease and then whatever you’re left with at 7 years tends to be pretty stable, from what I remember. To me that seems to suggest the immune system changes its focus over time.


well, allergies and autoimmunity involve different types of T-cells, so it’s possible the mechanism isn’t the same for both. But yeah, the immune system can get mixed up for sure. But for most people, I sort of think it’s not just getting mixed up for no reason, there’s something about the cells or whatever it’s targeting that is, so to speak, suspicious. (For instance, maybe the shape of the protein in an allergy is similar enough to something else that is harmful , etc.)


ahhhh yes… posted same sorry