Aging, Senescence and Insulin-Like Growth Factors

One approach to understanding the senescent growth arrest is to examine the factors that are required for the division of young cells and to determine whether the senescent cells are able to respond to these factors. Any defect in their response would presumably shed light on the mechanism of the growth arrest. In virtually all cell types, cell division is regulated by the presence of growth factors. Growth factors are small proteins that bind to specific receptors on the surface of cells. The receptors for growth factors contain intrinsic enzymatic activity that is activated by growth factor binding. The activation of these receptors produces a cascade of enzymatic events within the cells to drive a number of events, including DNA synthesis to produce a replicate copy of the genome, increased protein synthesis, and an increase in cell size and cell division.

Understanding the factors that drive cell division in general was an area of great interest in the 1960s through the 1980s. Investigators used the fibroblast cell as the model system of choice due to the reproducible way in which these cells would divide following a period of nutrient deprivation. Fetal bovine serum, added in small quantities to a nutrient medium, was found to contain the strongest mix of factors for fibroblast cell division. Laborious work identified the key factors contained in fetal serum that are required for initiating cell division as a growth factor known as platelet-derived growth factor and two closely related proteins known as insulin-like growth factors. As its name implies, platelet-derived growth factor is released by platelets during the clotting process and is contained in serum but is absent from plasma. The insulin-like growth factors are two closely related proteins, insulin-like growth factor 1 and insulin-like growth factor 2. The insulin-like growth factors are produced by the liver and other tissues under the control of growth hormone.

Over time, a number of growth factors have been isolated. They can be grouped into two classes based upon their role in regulating cell division. The first class of growth factors, termed initiation factors, which includes platelet-derived growth factor, is required for initiating cell division in resting cells. The function of these growth factors in terms of cell division (it should be mentioned that the growth factors regulate many aspects of cell behavior such as motility in addition to regulating cell division) is to move a cell out of the resting or quiescent state. The quiescent cell is performing differentiated functions producing proteins specific to its class, and the initiation factors serve to shift the cell away from these differentiated functions and toward cell division. But they are not sufficient to drive cell division on their own.

The second class of growth factors, collectively known as progression factors, includes the insulin-like growth factors and is required at a later stage for the initiation of DNA synthesis and cell division. In general, cells require the addition of two growth factors, one initiation factor and one progression factor, to divide. The specific growth factor that regulates division in a specific cell type is dictated by the cell surface receptor that the cell produces. Like a lock and key, only the right growth factor will activate a specific receptor. For example, no other growth factor can substitute for platelet-derived growth factor in terms of activating the platelet derived growth factor receptor. Thus, a cell expressing the platelet-derived growth factor receptor and the insulin-like growth factor receptor will respond to this specific combination.