a recent study found.
Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.
“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.
Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue ofThey looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.
The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).
In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).
Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.
When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).
In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.
Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).
“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.
“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.
The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.
The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
SOURCE: Ahluwalia A et al. CMGH. 2018 May 17.