The Impact of Aging on Mechanisms of Mammalian Epimorphic Regeneration

Abstract

Aging is associated with a significant decline of tissue repair and regeneration, ultimately resulting in tissue dysfunction, multimorbidity, and death. Salamanders possess remarkable regenerative abilities and have been studied with the prospect of inducing regeneration in humans and counteracting regenerative decline with aging. However, epimorphic regeneration, the full replacement of amputated structures, also occurs in mammals. One of the best studied models is digit tip regeneration, which is described for mice, and occurs in humans in a comparable manner. To accomplish regeneration, the amputated digit tip has to undergo three interdependent, overlapping steps: (i) wound healing without formation of a scar; (ii) formation of a blastema, a highly proliferative cell mass; and (iii) spatiotemporally regulated differentiation to generate a pattern similar to the original structure. Aging likely interferes with each of these steps. In this article, we provide an overview of the critical signaling pathways for regeneration, as revealed by investigating mammalian digit regeneration, the possible impact of aging on these pathways, and approaches to induce regeneration in the elderly. We hypothesize that with aging, increased Wnt signaling, NF-κB and tumor suppressor activity, and loss of positional information hampers regeneration. Knowledge about the impact of aging on regenerative mechanisms will enable us to safely activate endogenous regeneration in the elderly, and to generate a regeneration-permissive environment for cell therapies.

Basics of Self-Regeneration

“…One relevant aspect of the study of regeneration is the influence of aging on the regenerative abilities of some species. Older zebrafish regenerate their fins poorly when compared to younger specimens (Anchelin et al 2011), and mammals show substantial decreases in both physiological and restorative regeneration over time (Brunauer and Muneoka 2018;Yun 2015). Specific examples of age-limited mammalian regeneration have been documented in mice.…”