Aging: altered responsiveness of gastric mucosa to epidermal growth factor

Abstract

The present investigation examines the responsiveness of the gastric mucosa to the growth-promoting action of epidermal growth factor (EGF) during advancing age. Two sets of experiments were performed. In the first set of experiments, groups of 4-, 8-, 16-, and 24-mo-old Fischer 344 rats were injected subcutaneously at 12-h intervals for 2 days with either EGF (10 micrograms/kg) in gelatin or the vehicle only (controls). The animals were killed 16-18 h after the last injection. The oxyntic gland mucosa was assayed for thymidine kinase and the rate of DNA synthesis in vitro (indicators of proliferative activity) as well as for tyrosine kinase (Tyr-k) activity. In control rats, the rate of DNA synthesis and thymidine kinase activity rose steadily between 4 and 24 mo of age. However, whereas Tyr-k activity in the gastric mucosal cytosol changed only marginally with age, activity of the enzyme in the membrane fraction rose steadily between 4 and 16 mo and then increased abruptly. EGF stimulated gastric mucosal DNA synthesis and thymidine kinase activity in 4- to 16-mo-old rats compared with the corresponding controls, but in the 24-mo-old animals, it caused a significant 40-50% inhibition. EGF had no demonstrable effect on Tyr-k activity in either cytosolic or membrane fraction. We postulated that Tyr-k activity might have returned to basal level 16-18 h after the last EGF injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging and cancer of the stomach and colon

“…Despite this decrease in proliferative activity between 4-5 wks of life, mucosal DNA content increased dramatically during this period, indicating an increase in total mucosal cells (43). In contrast, gastric mucosal proliferative activity in 20-24 month old Fischer rats was found to be higher than in their 4-5 month old counterparts (44) as reflected by increases in mitotic labeling( 13,45 ), rate of DNA synthesis ( 46,47), thymidine kinase activity (47,48 ), and ODC activity (43,48). More interestingly, however, the increased mucosal proliferative activity was not accompanied by a concomitant rise in mucosal growth, but rather aging resulted in atrophy as evidenced by decreased mucosal height as well as DNA and RNA content in older animals compared to their younger counterparts (13,45).…”

Age-associated loss of heterozygosity of tumor suppressor genes in the gastric mucosa of humans

“…ALTHOUGH EARLIER OBSERVATIONS in the mouse suggest that proliferative activity of the small intestine either decreases (16,24) or remains unchanged (17) with aging, recent morphological and biochemical studies from our own and other laboratories have demonstrated that in barrier-reared Fischer 344 rats, aging is associated with increased mucosal proliferative activity in the stomach and small and large intestines (3,14,21,22,(27)(28)(29). In both gastric and colonic mucosa, the age-related rise in proliferation could partly be attributed to enhanced transition from G 1 to S phase as well as progression through the S phase of the cell cycle (42,44).…”

Regulation of TGF-α-induced activation of AP-1 in the aging gastric mucosa

“…Therefore, a detailed knowledge of mucosal cell proliferation and regulation of this process is essential for a better understanding of the normal aging process as well as many gastrointestinal diseases that arise from dysregulation of growth. Although earlier observations in the mouse suggest that with aging, proliferative activity of the small intestine either decreases (7,18) or remains unchanged (9), recent morphological and biochemical studies from our own and other laboratories have demonstrated that in barrier-reared Fischer 344 rats, aging is associated with increased mucosal proliferative activity in various parts of the gastrointestinal tract, including that of the stomach (2,11,12,19,21,22).…”

“…epidermal growth factor receptor signaling processes; phosphatidylinositol kinase; Src kinase; transcription factor OVER THE PAST SEVERAL YEARS, results from this and other laboratories have demonstrated that in barrier-reared Fischer 344 rats, aging is associated with increased mucosal proliferative activity in various tissues of the gastrointestinal tract, including the oxyntic gland area of the stomach (2,11,12,21,19,22). In the oxyntic gland area (referred to as gastric mucosa), the agerelated rise in mucosal proliferative activity was demonstrated by increased labeling index, DNA synthesis, and thymidine kinase and orinithine decarcoxylase (ODC) activities (6,(19)(20)(21)23) Moreover, progression of gastric mucosal cells through G 1 into S phase was also shown to be increased in aged rats, as reflected by increased levels of cyclin E and the activity of cyclindependent kinase (Cdk2) (35) Although the responsible mechanisms for the agerelated rise in gastric mucosal proliferative activity are poorly understood, we have suggested that EGF receptor (EGFR)-induced signaling pathways may play a critical role in regulating this process (22,30).…”

“…In the oxyntic gland area (referred to as gastric mucosa), the agerelated rise in mucosal proliferative activity was demonstrated by increased labeling index, DNA synthesis, and thymidine kinase and orinithine decarcoxylase (ODC) activities (6,(19)(20)(21)23) Moreover, progression of gastric mucosal cells through G 1 into S phase was also shown to be increased in aged rats, as reflected by increased levels of cyclin E and the activity of cyclindependent kinase (Cdk2) (35) Although the responsible mechanisms for the agerelated rise in gastric mucosal proliferative activity are poorly understood, we have suggested that EGF receptor (EGFR)-induced signaling pathways may play a critical role in regulating this process (22,30). The basis for this postulation comes from our observation that increased gastric mucosal proliferative activity during aging in Fischer 344 rats is associated with a concomitant activation of EGFR, as evidenced by increased tyrosine kinase activity and tyrosine phosphorylation of the receptor (30,34).…”