There is a good Buck Institute podcast interview with Judy Campisi that has just become available. There is also a full transcript of the interview on the same page as the podcast (scroll down) if you’d prefer to read vs. listen.
Judy: So, a senescent cell is a cell that has entered a state — a new state. And that state has three compartments. The first compartment is the cell doesn’t divide anymore. So it starts out where it can divide if it wants to. But now, it’s blocked. And it will never divide again so far as we know. The second is: the cells resist dying. They stick around both in vivo and also in culture when we study these things in human and mouse cultures. And the third thing, which we think is even most important, is they start secreting a lot of molecules that affect their neighbors. We call this a tripartite phenotype, three parts to what the cells are all about. And that defines the senescent cell. Cells with those characteristics increase with age. They’re present at sites of age-related pathology in both humans and mice. Uh, we think that they’re driving aging, and in the mouse, we’ve proven that. We have not proven it in humans yet.
Gordon: So, these cells are accumulating during normal aging.
Gordon: Let’s talk about inflammation.
Gordon: So it seems like this the senescent cells are producing inflammatory factors — which I think you coined the-the secretory phenotype of the — the SASP. Uh, so talk about the relationship with that process with the general picture of inflammation in aging and disease. I know it’s a huge topic. You could probably speak on that for a couple of hours.
Judy: Yes. But just to remind you, m — also, many, many years ago, an Italian scientist, Claudio Franceschi coined this term: inflammaging. And his point was, if you take a 16-year-old and do a liver biopsy and you take a 60-year-old and do a liver biopsy and then you give those biopsies blinded to a pathologist, the pathologist doesn’t really need to do very much. The pathologist will pretty much tell you, “This is young. This is old.” And what the pathologist will look for is low-level infiltration of certain immune cells. And that’s what Claudio called inflammaging.
Judy: And it is a general feature of aging and a general feature of aged tissues. It is not all driven by senescent cells. There are drivers that are senescent cells because they’re producing molecules that call these cells to the tissue. But there are other things that will cause, in — for example, a leaky gut will release certain fractions of bacteria. And that will attract immune cells. And that will cause inflammation. So there are multiple causes of inflammaging. Senescence is one of them. We think it’s a pretty important one. But it’s not the only one.
a) I think senescence occurs frequently because stem cells that should differentiate fail to do so. That is why you find patches of senescence in areas which renew more frequently.
b) I think there is a a process of dedifferentiation which occurs which is short of senescence, but results in cells which a partially senescent in that they don’t fully function.
c) I think that IL-10 as part of SASP causes a) and b) to some extent.
d) I think that Rapamycin in improving mitochondrial health mitigates against a) and b). I do not think Rapamycin kills off senescent cells. I think it assists to get some cells to function in a better manner and not be senescent.f
In essence that is what I am saying. As a result of autophagy stimulated by Rapamycin cells differentiate properly and don’t turn senescent. Actually I think there is a dynamic equilibrium the balance of which is shifted by autophagy (amongst other things). I think it is a mistake to think of cells as being configured to be in a static state. A better view point is a shifting dynamic equilibrium where if you wish to change the state of the cell you need to shift where the balance is.
I am such a fan of hers. Here’s another great podcast where she affirms the point that rapamycin may operate by reducing secretions from senescent cells for a period of time, but does not eliminate them.
In improving the mitochondria the levels of Acetyl-CoA in the nucleus are increased so longer genes do get transcribed and stem cells don’t get forced into senescence. There is evidence that telomeres are consequential rather than causal. (in vivo)