Wound healing and longevity: Lessons from long-lived αMUPA mice

Abstract

Does the longevity phenotype offer an advantage in wound healing (WH)? In an attempt to answer this question, we explored skin wound healing in the long-lived transgenic αMUPA mice, a unique model of genetically extended life span. These mice spontaneously eat less, preserve their body mass, are more resistant to spontaneous and induced tumorigenesis and live longer, thus greatly mimicking the effects of caloric restriction (CR). We found that αMUPA mice showed a much slower age-related decline in the rate of WH than their wild-type counterparts (FVB/N). After full closure of the wound, gene expression in the skin of old αMUPA mice returned close to basal levels. In contrast, old FVB/N mice still exhibited significant upregulation of genes associated with growth-promoting pathways, apoptosis and cell-cell/cell-extra cellular matrix interaction, indicating an ongoing tissue remodeling or an inability to properly shut down the repair process. It appears that the CR-like longevity phenotype is associated with more balanced and efficient WH mechanisms in old age, which could ensure a long-term survival advantage.

Middle age has a significant impact on gene expression during skin wound healing in male mice

“…Gene expression during wound healing As expected (for example, see Grose and Werner 2003;Yanai et al 2015), for all groups examined, we consistently observed an overexpression of genes related to the extracellular matrix (ECM) including ECM organization, ECM-receptor interaction, collagen metabolism, and focal adhesion (Online Resource 5). Accordingly, the combined score which reflects both the fold enrichment and the statistical significance, was the highest for these categories in all groups and time points (Online Resource 5).…”

“…Likewise, castration of male mice extends their life span and improves wound repair. In our previous study on female FVB/N mice (Yanai et al 2015), we found clear differences in the rate of head skin wound closure and gene expression between young and old females. It would be interesting to examine if our observations are relevant for middle-aged C57BL/6 female mice as well.…”

Tissue repair genes: the TiRe database and its implication for skin wound healing

“…Moreover, it seems that the association between the rate of WH and longevity is primarily attributed to an overall effect of the target gene on organismal aging rather than to its skin-specific action. This assumption is strongly exemplified by our study on the long-lived αMUPA mice, which preserve their skin WH capacity up to an old age (at least 25 months) [10, 27]. In this unique model [28], the uPa transgene is expressed in the ocular lens and the brain stem but not in the skin, thus excluding the gene-specific effects on WH.…”

Identification of functional networks associated with cell death in the retina of OXYS rats during the development of retinopathy

“…26 For example, in old aMUPA mice the apoptosis are regulated after full wound closure and none is differentially expressed in the intact skin, whereas the WT mice exhibited significant age-related differences in gene expression of apoptosis both in intact animals and in the course of skin wound healing. 27 Construction of association networks should help to identify crucial components of the pathophysiology. During construction of such networks by means of topological analysis, we detected central or most important nodes: the genes that probably play essential roles in the relevant biological systems.…”

“…29 Suppression of the system of repair of single-strand and double-strand breaks in DNA is characteristic of many neurodegenerative diseases including AMD 30 and Alzheimer disease. 27,31 , There is evidence that mice with the defective NHEJ pathway undergo accelerated senescence. 32 It is also known that mutations in the Lig4 gene are a cause of severe immunodeficiency.…”