title: Enhanced cell proliferation and biosynthesis mediate improved wound repair in refed, caloric-restricted mice.
abstract: Aged mice that have undergone long-term caloric-restriction (CR) have improved health and enhanced longevity in comparison to aged mice that are ad libitum-fed (AL). However, caloric-restriction does not benefit the impaired wound healing of aged mice. To test the hypothesis that CR mice have the capacity for enhanced wound repair, but require a short-term period of additional nutrient intake to show this advantage, we assessed wound healing in CR mice that had been refed (RF) an ad libitum diet for 4 weeks prior to wounding. Two strains of AL young (Y AL) (4-6 months), AL middle-aged (M AL) (15-17 months), and three different, matched cohorts of old mice (O) (30-33 months): O AL, O CR, and O RF were studied. Two full-thickness 4 mm diameter punch biopsy skin wounds were created on the dorsum of each mouse. Animals were sacrificed and wounds were harvested at 1,2,3,5, and 7 days post-wounding. Repair of wounds was slower in O AL and O CR mice compared to Y AL and M AL animals. In contrast, the O RF mice healed similarly to that of the Y AL and M AL mice, as assessed by measures of wound area and histologic criteria. O RF mice demonstrated enhanced synthesis of type I collagen mRNA in comparison to O AL and O CR mice. A greater number of endothelial cells and fibroblasts at the wound edge of the O RF mice exhibited replication in vivo as measured by uptake of BrdU. O RF mice had higher levels of insulin-like binding protein 3 (IGFBP-3). Furthermore, fibroblasts derived from the explant of the punch biopsy of O CR mouse skin revealed enhanced proliferation and contraction in vitro, in comparison to fibroblasts from the O AL mice. In conclusion, O RF mice demonstrate an enhanced capacity to undergo wound repair in comparison to O AL mice. This effect appears to be mediated, in part, by enhanced cell proliferation, contraction, and collagen biosynthesis. In addition, short-term refeeding induced an increase in the serum level of IGFBP-3, the major binding protein for IGF-1. These data confirm that cells from O CR animals have a preserved proliferative, biosynthetic, and contractile capacity, but that an adequate source of nutrients is necessary to demonstrate this advantage in wound healing.
authors.affiliation: Department of Medicine, University of Washington, Seattle 98195, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Reed
authors.forename: P E
authors.initials: PE
authors.lastname: Penn
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: R
authors.initials: R
authors.lastname: Birnbaum
authors.forename: R B
authors.initials: RB
authors.lastname: Vernon
authors.forename: T S
authors.initials: TS
authors.lastname: Johnson
authors.forename: W R
authors.initials: WR
authors.lastname: Pendergrass
authors.forename: E H
authors.initials: EH
authors.lastname: Sage
authors.forename: I B
authors.initials: IB
authors.lastname: Abrass
authors.forename: N S
authors.initials: NS
authors.lastname: Wolf
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002455:Cell Division / Q000502:physiology; D003094:Collagen / Q000235:genetics; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000096:biosynthesis; D014945:Wound Healing / Q000502:physiology*
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D003094:Collagen