The Impact of Insulin-like Growth Factors and Insulin-like Growth Factor Receptors on Aging 

By  Juan Vallin

 

Insulin-like growth factor (IGF-1) and the IGF-1 receptor play essential roles in metabolic cellular activities.  The liver synthesizes IGF-1 usually during times of rapid growth.  The IGF-1 and insulin receptors are generally grouped together due to their similar structure and the binding of insulin and IGF-1 to either receptor.  As age takes hold IGF-1 receptors decrease, which reduces the affects of IGF-1 in the body.  Since old age reduces IGF-1 receptors, research is being done to determine what can be done to minimize the problem. 

 

IGF-1 receptor is important in many aspects of cellular activity.  The IGF-1 receptor not only performs an essential role in several essential cellular actions which consist of the growth of cells, multiplication and separation, but it also serves to regulate cell transformation, enhanced tumorgenicity and inhibition of programmed cell death (6). Many biological aspects of aging are correlated to IGF-1 and the IGF-1 receptor.

 

When the liver releases IGF-1 it signals the body to begin to grow.  Since the IGF-1 signals the body to grow, puberty is a time period when this occurs.  IGF-1 was once referred to as somatomedin-C because IGF-1, not growth hormone(gh), is the instant stimulus for development of the body (1).  Growth hormone activates the liver to synthesize IGF-1, which is released from the liver and binds to the IGF-1 receptor.  A large number of cells have receptor sites for IGF-1, particularly cells in the cartilaginous growing areas of the long bones in the bone marrow (1).  When IGF-1 binds to a receptor it stimulates the cell towards mitosis, after several changes to the cell (1).

 

The time period when IGF-1 is in its highest concentration in the blood is obviously puberty, which is the time period when humans grow at a rapid rate (1).  Between the ages of 12 and 15 years old is when the highest concentration of IGF-1 is found in the body, which is shown in Table 1.  From figure 1 we see that before the age of 12 there is an increasing build up of IGF-1 in both females and males.  After the age of 15 there is a decrease in the concentration of IGF-1 right on past 55 years of age.

 

 

TABLE 1: IGF-1 concentrations by age

AGE	MALE	FEMALE
2 months-5 years	17-248 ng/ml	17-248 ng/ml
6-8 years	88-474 ng/ml	88-474 ng/ml
9-11 years	110-565 ng/ml	117-771 ng/ml
12-15 years	202-957 ng/ml	261-1096 ng/ml
16-24	182-780 ng/ml	182-780 ng/ml
25-39	114-492 ng/ml	114-492 ng/ml
40-54	90-360 ng/ml	90-360 ng/ml
55 years and older	71-290 ng/ml	71-290 ng/ml

 

Table 1 from reference 2

Children are sometimes born with inherited mutant genes for the growth hormone receptor, which leads to underdeveloped growth (1).  This has been successfully treated with recombinant human IGF-1 (1).

 

Human growth hormone, along with nutritional intake, regulates the release of IGF-1 from the liver.  Growth hormone is released from the anterior lobe of the pituitary and travels to the liver, which has a high concentration of growth hormone receptors (1).  With age, the growth hormone concentration has been shown to decrease, but has shown an increase in the concentration growth hormone receptors in the liver.  As stated earlier, the growth hormone binds to the receptor on the surface of the liver cells it stimulates the synthesis and release of IGF-1 from the liver (1).

 

When IGFs enter the blood plasma they are more than likely to attach to a binding protein.  There have been six Insulin-like Growth Factor Binding Proteins, or IGFBPs, identified with a high affinity for IGFs as shown in figure 1.

 

FIGURE 1: IGFBP-3 binding of IGF-1

Figure 1 from reference 8

 

 

Five out of the six IGFBPs favor binding to IGF-1 over IGF-2, which is also a growth factor(3).  No more than 1% of the IGFs circulating are free flowing (3).  Over 90% of IGFs form a complex with IGFBP-3, a binding protein, and the acid labile subunit, which form a 150-kDa complex (3).  This complex raises the half-life of IGF-1 from 10 min to about 15 h (3).  IGFBP-3 is the most abundant of the IGFBPs and the complex it forms with IGFs adjust the total of bioavailable IGF (3).  The binding of IGFBPs has growth reduction properties because when IGFBPs bind to IGFs this is in competition with the IGF receptors (3).  While IGFBPs have inhibitory properties they can also augment the IGFs properties by releasing IGFs gradually for receptor interactions and at the same time shielding the receptor from desensitization (3).

 

 Both IGF-1 and insulin receptors have similar structural and functional characteristics. The IGF-1 receptor is a glycoprotein made up of two peripheral a subunits and two transmembrane b subunits with an intracellular tyrosine kinase domain.  The insulin receptor is also transmembrane glycoprotein made of two a and two b subunits covalently attached by a disulfide bond (4).  The similarity of the two receptors indicates that their ligands can bind to either one, but they do so typically in high concentrations.  Just as the insulin receptor, the IGF-1 receptor is in the tyrosine kinase class of receptors, which includes a tyrosine kinase domain on the intracellular side of the membrane.

 

One study showed the binding of insulin did not use the insulin receptor to initiate its effects.  It was found that when insulin wields it mitogenic effects on rat arterial endothelial cell, it does so using the IGF-1 receptor (4).  An inhibitor of the IGF-1 receptor was used to show that insulin was binding to the IGF-1 receptor and not to the insulin receptor.  The inhibition of the IGF-1 receptor caused the inhibition of the growth promoting effects of insulin.  Although several studies have stated that IGF-1 can imitate particular metabolic actions of insulin, there has been debate as to whether the metabolic effects of IGF-1 are exerted through insulin or IGF-1 receptor or through insulin/IGF-1 hybrid receptors (5).  Although there has been controversy on how both receptors are activated, most of the studies have generally indicated the use of insulin and IGF-1 receptors and not a hybrid receptor. So in general the receptors can be stimulated by either insulin or IGF-1.   

 

As age progresses IGF-1 receptor protein levels in cardiac and skeletal muscle have been shown to decrease in mice.  In the skeletal and cardiac muscle, IGF-1 receptor content was reduced in cardiac receptors to 20% of controls(Fig 2).

 

FIGURE 2: IGF-1 receptor protein content vs. age (months)

Figure 2 is from reference 7.

 

 

 

The mice used where 5, 12, 17, 22.5, 25, and 29 months of age.  Relative to the 5-month control group the 12-25 month old animals lost IGF-1 receptor protein content 77% to that of the control group (7).  From 25 to 29 months the loss was even more dramatic.  The IGF-1 receptor protein levels fell to 25% of the control group (7).  The IGF-1 receptor protein content of skeletal muscle tissue decreased to a larger extent than the cardiac tissue of the aldult and older mice (7).

 

Although IGF-1 receptors decrease as we get older, some research has given us clues on what can be done.  Once we pass the teen years the production of IGF-1 drops off as the production of growth hormone is reduced (8).  For the young the production of IGF-1 can be stimulated with exercise (8).  Work done by Parkhouse’s lab has shown that the availability of IGF-1 in the elderly can be increased by exercise (8).  They also showed that exercise increases the number of IGF-1 receptors along with their affinity for IGF-1 (8).  Research for the effects caused by reduction in IGF-1 and IGF-1 receptors as the result of old age has given us options to reduce the impact by exercise.   

References:  

1.   http://www.ultranet.com/~jkimball/BiologyPages/L/LiverHormones.htm date retrieved: 4/17/01. 1 pg.

2.   http://www.aruplab.com/guides/clt/tests/clt_ij16.htm date retrieved: 4/17/01 11 pgs.

3.   Grimberg A., Cohen P.  Role of Insulin-Like Growth Factors and Their Binding Proteins in Growth Control and Carcinogenesis. Journal of Cellular Physiology 183 (2000) 1-9.

4.   Avena R., Mithchell M., Carmody B., Arora S., Neville R., Sidawy A. Insulin-like Growth Factor-1 Receptors Mediate Infragenicular Vascular Smooth Muscle Cell Proliferation in Response to Glucose and Insulin Not by Insulin Receptors. The American Journal of Surgery vol. 178 Aug. 1999 156-161.

5.   Baudry A., Lamothe B., Bucchini D., Jami J., Montarras D., Pinset C., Joshi R.L. IGF-1 receptor as an alternative receptor for metabolic signaling in insulin receptor-deficient muscle cells. FEBS letters 488 (2001) 174-178.

6.   http://www.gradstudies.musc.edu/Pharm/sar.html date retrieved: 4/17/01.  2 pgs.

7.   Martineau L., Chadan S., Parkhouse W.  Age-associated alterations in cardiac and skeletal muscle glucose transporters, insulin and IGF-1 receptors, and PI3-kinase protein contents in the C57BL/6 mouse. Mechanisms of ageing and development 106 (1999) 217-232.

8.   http://www.css.sfu.ca/update/vol8/8.1-muscles.html date retrieved: 4/17/01 3 pgs.