SCOPE: It is known that a decline in food intake occurs with aging. In this 
study, we investigated changes in parameters associated with food intake in 
response to aging, and whether orexigenic peptides stimulated food intake after 
peripheral administration even in aged mice.
METHODS AND RESULTS: Food intake and body weight of 27-month-old male C57BL/6N 
mice were lower than those of 15-month-old mice. Epididymal and mesenteric fat 
mass, blood glucose, triglyceride, and leptin levels were also decreased. 
Meanwhile, the hypothalamic mRNA expression of endogenous orexigenic peptides 
such as neuropeptide Y (NPY) and agouti-related protein, also called 
agouti-related peptide, was increased. Next, we tested responsiveness to 
exogenously administered orexigenic peptides coupled to NPY in aged as well as 
young mice. Orally administered rubiscolin-6, a δ opioid agonist hexapeptide 
derived from a major green leaf protein Rubisco, stimulated food intake in 
27-month-old mice. In contrast, ghrelin was ineffective after intraperitoneal 
administration to aged mice, suggesting that the NPY system downstream of 
ghrelin but not δ opioid receptors might be impaired in aged mice.
CONCLUSION: Orally administered rubiscolin-6 stimulates food intake in aged mice 
with ghrelin resistance.