ApoptoSENS

Removing cells that the body tries but fails to kill.

There are three main classes of cells that sometimes acquire a metabolic state that is damaging to their neighbours, and that accumulate in the body during aging:

1. Visceral fat cells
   Fat cells tend to grow and/or proliferate with age due to energy imbalance, and often replace the muscle mass that we lose with age. Their relative danger depends upon where they occur:
   • Interestingly, the most conspicuous fat – the "subcutaneous fat" that accumulates under the skin, making a person "pear shaped" – seems to be relatively harmless, unless of course it gets to the stage known as "morbidly obese" in which its sheer weight and the strain it puts on the heart and joints become a harmful stress on the body.
   • By contrast, "visceral" fat (the fat that accumulates around the organs of the gut, causing an "apple shape") seems to be really bad for us. It promotes the progressive loss of our ability to respond to nutrients coming in from the stomach; in particular, it causes us to develop insulin resistance. This means that there is a diminished effect of the insulin's signal to the cells to absorb and store sugar from the circulation. Eventually, this leads to Type II diabetes.
2. Senescent cells
   So-called "senescent" cells are those that have lost the ability to reproduce themselves. They appear to accumulate in quite large numbers in just one tissue (the cartilage in our joints), but even in these small numbers they appear to pose a disproportionate threat to the surrounding, healthy tissues, because of their abnormal metabolic state. Senescent cells secrete abnormally large amounts of some proteins that are harmful to their neighbours, stimulating excessive growth and degrading normal tissue architecture. These changes appear to promote the progression of cancer.

3. Immune cells
   The effect of the third type of cells is more complicated to explain. In brief, the total number of white blood cells in our bodies seems not to change very much with age, but some subsets of them become more numerous and others less. The third type of harmful cell accumulation occurs in some populations of immune cells ("memory cytotoxic T cells", especially those that are charged with defending us against infection by the ubiquitous cytomegalovirus). These cells tend to lose their effectiveness over time, and simultaneously stop properly responding to the body's signals to clear out of the way to make room in the limited immunological "space" for other kinds of immune cells, resulting in a condition called immunosenescence. Immunosenescence is thought to be largely responsible for the weakened immune responses of the elderly (and thus their greater vulnerability to infections such as pneumonia and influenza), and for the reduced effectiveness of vaccines in the same group.

   Hence, it is important to cull these cells back in order to make way for others to expand as needed – both young, healthy cells to defend us against cytomegalovirus, and also cells specialized in fighting other infections. Certain other types of immune cell seem also to become dysfunctional during aging, and again this may be because they've divided often enough that DNA damage responses are kicking in to stop them dividing much more, in order to prevent potentially cancerous cells from gaining a foothold.

The Solution

Getting rid of excess cells is a much simpler job than most of the other things we have to do as part of SENS. In the case of visceral fat, it's possible to deplete the extra cells through surgical removal, but that's unnecessarily risky and won't help us with the other two kinds of cells. There are two main alternatives:

1. Inject something that makes the unwanted cells commit suicide but doesn't touch other cells.
2. Stimulate the immune system to kill the target cells.

Both approaches involve making use of distinctive molecules on the surface of the target cells: luckily, different cell types tend to have different things on their surface, so this shouldn't be too hard. Preliminary work of this kind has been done in cancer, but it hasn't been done yet for these cell types, and not enough people are working on the problem; it needs much more attention. In the case of dysfunctional immune cells, much of this may be achieved indirectly as a result of the preferred anti-cancer therapy of SENS, WILT. WILT involves, among many other things, the genetic manipulation of blood stem cells, which are the cells that give rise to T cells. Thus, T cells can be made more controllable in terms of their willingness to die on demand, by additional genetic manipulations done to the stem cells, allowing us to clear them out more easily when necessary.

Our Work

An in-house project began in 2008 to develop a procedure for clearing aged T cells from the blood of mice. Additionally, we are funding one of the top professors in the immunosenescence field to investigate clearing these cells by other methods, in combination with therapies to reverse the other main component of immunosenescence, thymic involution.

Resources

Talks on this topic at IABG 10: Barzilai, Campisi

At SENS2: Unger, Kahn, Campisi, Swain, Pawelec

At SENS3: Akbar, Butler-Browne, Janda

Publications on this topic