Fight Aging!

Researcher Judith Campisi, known for her work on cellular senescence and its relevance to degenerative aging, here discusses the present state of knowledge regarding senescent cells. Senescent cells are constantly created throughout life, but with age these cells are no longer efficiently destroyed by the immune system, allowing their numbers to increase. Senescent cells disrupt normal tissue structure and function via their inflammatory secretions. Attempts to treat aging by clearing the age-related buildup of senescent cells are well on their way to the clinic, under development in many different biotech companies.

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. Cells with those characteristics increase with age. They're present at sites of age-related pathology in both humans and mice. We think that they're driving aging, and in the mouse, we've proven that. We have not proven it in humans yet.

That senescent cells appear in the brain is driving some neurodegenerative diseases. For example, if we take senescent astrocytes - so they're a support cell within the brain - and incubate them with neurons, healthy human neurons, those two cell types will exist - coexist just fine until we give a little bit of a signal that is common between neurons called glutamate. Senescent astrocytes but not non-senescent astrocytes down-regulate the transporters that get rid of excess glutamate. Excess glutamate kills neurons. We have shown that at senescence, the down-regulation of these proteins that get rid of excess glutamate will cause a neighboring neuron to die in the process of experiencing that glutamate. And that does not happen in a young brain because there are so few senescent astrocytes.

Low-level infiltration of certain immune cells into tissues is called inflammaging. So there are multiple causes of inflammaging, it is a general feature of aging and a general feature of aged tissues. Senescence is one of them. So the type of inflammation that's caused by senescent cells has been called sterile inflammation. There's no evidence for a pathogen. But the immune cells are there. And these immune cells are destructive. So many of them are part of the more primitive part of our immune system called the innate immune system. These guys evolved to get rid of pathogens. And they do it by initially secreting toxic molecules until the more sophisticated part of your immune system called the adaptive immune system can now make the antibodies the other types of proteins that we associate with sophisticated, immune function. So senescent cells attract mostly innate immune cells. But of course, these two immune systems talk to each other. So eventually, you get a full-blown inflammatory response.

There is a mouse where we had eliminated senescent cells. We can manipulate the genome of a mouse pretty well. And we've done that by causing one of these senescent marker genes to drive a foreign gene that is a killer basically but only in the presence of an otherwise benign drug. And so using that mouse, we've shared that mouse with many laboratories, all of them working on a different age-related disease. And they test the hypothesis. Do senescent cells make a difference? And if so, if we eliminate them, is the disease either postponed, which it often is, or ameliorated, meaning it's not so severe. And that often happens - that's why the list of diseases that we know can be driven by senescent cells is so long. And once in a while for a few diseases, it actually can reverse.

Link: https://www.buckinstitute.org/podcasts/understanding-senescence/