A research team investigating the mechanisms of regeneration has assembled the TiRe (Tissue Repair) database, a catalog of genes known to be involved in skin healing in a variety of mammals. There are several hundred such genes at this point, indicative of the complexity of the processes involved. Among the questions explored in this open access paper is whether or not more rapid healing corresponds with greater longevity in, for example, genetically varied lineages of laboratory mice: is there any overlap in the genes known to be relevant in healing and aging, and what exactly do those relationships mean?
Wound healing is an inherent feature of any multicellular organism and recent years have brought about a huge amount of data regarding regular and abnormal tissue repair. Despite the accumulated knowledge, modulation of wound healing is still a major biomedical challenge, especially in advanced ages. Some species from diverse taxa (such as salamander, axolotl, hydra, and several others) and early mammalian embryos are able to fully regenerate damaged tissues/organs. In mammals, however, this ability is drastically reduced after birth and continues to decline with age. For most organs, this reduced regenerative capacity is in fact a normative response, favoring speed over functional restoration, so that regular tissue repair results in scar formation. Deviations from regular tissue repair may lead to diverse pathological conditions, from slow or ineffective wound healing to hyper-fibroproliferative responses, both of which are often observed in advanced ages. Thus, factors that govern tissue repair are strongly associated with aging and age-related pathologies, and as such are potential targets for intervention in aging.
Is accelerated wound healing "good" for longevity? In an attempt to address this question, we have compared the list of wound healing-associated genes (WHAGs) with those reported as being involved in the control of lifespan. The comparison yielded 17 genetic mouse models of extended lifespan (longevity phenotype), or reduced lifespan (premature aging phenotype), which were also tested for skin wound healing. It is important to note that many studies used the rate of skin wound closure as a biomarker, assuming a priori that slower skin wound healing is indicative of an aging phenotype. Yet, our analysis shows that a slower or faster skin wound healing is indicative of an aging or longevity phenotype, respectively, only when assessed in advanced ages, but not in the young. For example, Agtr1a knockout resulted in slower wound healing in young mice but also in an extended lifespan. In contrast, Cav1 knockout, which accelerated wound closure, was accompanied by reduced longevity.
This means that pro- or anti-longevity effects of genetic interventions manifest in accelerated or delayed skin wound healing only in advanced ages, but not in young animals. Moreover, it seems that the association between the rate of wound healing 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 wound healing capacity up to an old age (at least 25 months). In this unique model, 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 wound healing. Overall, the results emphasize that the age factor should be taken into account when evaluating the links between skin wound healing, aging and longevity.
To better understand these links, including older animals in the analysis is encouraged while using only young animals might yield confusing or misleading results. In particular, the opposite effect between the rate of skin wound healing in young age and the effect on life span could be explained by the links between wound healing and cancer, and the role of cancer in the determination of mouse longevity. Indeed, cancer has been considered as "an overhealing wound". This could be especially relevant to mice as cancer is the main cause of death for a variety of murine strains. For example, Tert overexpression in the young leads to accelerated wound healing, a high incidence of cancer, and increased mortality. Another example is the tumor suppressor gene Pten, known to negatively regulate the activity of the PI3K/mTOR pathway, which is involved in various cancers. Knockout of this gene resulted in accelerated wound healing in young age but a decreased lifespan, which is most likely associated with increased tumorigenesis.