Dr Jan van Deursen, Mayo Clinic
Most cell types in our body are being constantly replenished, but we still get old. A sub population of cells are said to undergo senescence – chemical controls kick in and stop them from dividing to produce new cells. When we’re young, these are then cleared out by the immune system, but as we age they start to build up in our tissues.
Now, researchers at the Mayo Clinic in Rochester suggest that these cells may play an important role in diseases of old age, as Meera Senthilingam found out when she spoke to Jan van Deursen…
Jan - So we basically set out to test whether senescent cells, which are really cells that accumulate in some mammalian organisms over time were suspect of contributing to age-related disease. So we wanted to test whether that was really the case. All we did essentially was design an animal model in which we could clear these so-called senescent cells. We have two approaches – one approach was to do it lifelong, start at an early age and keep doing it for the rest of the life of the animal and then the other way was to first have the animal age so that the age related disabilities and disorders would be present and then clear the cells, and see whether there would be any beneficial effect of their clearance.
Meera - And whereabouts are these cells actually found? Are they throughout the body?
Jan - Yeah, they're found in most tissues and organs. They are really thought of as cells that are accumulating as a result of an anti-cancer defence mechanism. So if a cell becomes damaged to a degree that it is likely to develop into a tumour cell, this process of cell senescence is activated. And basically, what it is, it makes these cells stop proliferating as a way to prevent the formation of tumours. The side effect is that you start accumulating these cells in tissues and organs, and they're not just innocent bystanders at that point. This process of senescence really changes the profile of proteins that these cells produce. They start producing and secreting inflammatory cytokines, growth factors, proteases that chew up parts of the surrounding cells. So basically, the secretory components of senescent cells make the life of neighbouring cells much more difficult. So although the senescent cells are relatively small in numbers, maybe a couple of percentage of the total number of cells in a tissue or organ, their negative effects are quite widespread.
Meera - And how did you set about removing these cells?
Jan - We took advantage of the knowledge that tumour suppressor gene p16 is really expressed in most of these senescent cells. It actually is thought to play a role in the conversion of a normal cell to a senescent cell. So we use that to make an artificial gene, kind of a suicide gene driven by that same p16 promoter. So whenever p16 is expressed, we would also express this suicide gene. But the suicide gene is present but it needs to still be activated by a drug. So, senescent cells that express this suicide gene will still not die until we would expose the cells to a synthetic drug.
Meera - And what were your key findings then with regard to the presence of these cells and their effect on particular age-related disorders and which disorders did you see an effect with?
Jan - We needed to test this experimental system and we did that on a so-called progeroid mouse model. This is basically mice that have low amounts of this protein BubR1 and they age about five times faster than a normal mouse. So now the phenotypes in this accelerated ageing mouse that display ageing related disorders are sarcopenia, which is basically muscle wasting, also the loss of fats, both fat deposits in the body and subcutaneous fat, and the subcutaneous fat loss typically gives us the wrinkled skin. The third hallmark of ageing was formation of cataracts which is seen in about 25% of people above 65. So we looked at these three aspects because we know that in those ageing processes the gene p16 was expressed, indicating that in those age-related processes, perhaps p16 positive senescence cells will play a role. We saw that lifelong clearance really can either prevent or delay those age-related disabilities. But when we treat late in life, when those disorders were already present. We could hold them or slow them down from that moment on.
Meera - What are the hoped applications of this then?
Jan - A lot of work needs to be done, but this mouse model can be used to really try to figure out what would be the best strategy of removing these cells. Would that be continuous or would that be once every or once every so often? Would it be advantageous to do it late in life? We agree that lifelong treatments are not really desirable but could also imagine that this is more like a spring cleaning that you do every so often.