University of Kentucky UKnowledge Biology Faculty Publications Biology 1-21-2013 Revisiting the relationship between regenerative ability and aging Ashley W. Seifert University of Kentucky, [email protected] S. Randal Voss University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/biology_facpub Part of the Biology Commons Repository Citation Seifert, Ashley W. and Voss, S. Randal, "Revisiting the relationship between regenerative ability and aging" (2013). Biology Faculty Publications. 33. https://uknowledge.uky.edu/biology_facpub/33 This Response or Comment is brought to you for free and open access by the Biology at UKnowledge. It has been accepted for inclusion in Biology Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Revisiting the relationship between regenerative ability and aging Notes/Citation Information Published in BMC Biology, v. 11, 2. © 2013 Seifert and Voss; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Digital Object Identifier (DOI) http://dx.doi.org/10.1186/1741-7007-11-2 This response or comment is available at UKnowledge: https://uknowledge.uky.edu/biology_facpub/33 Seifert and Voss BMC Biology 2013, 11:2 http://www.biomedcentral.com/1741-7007/11/2 COMMENTARY Open Access Revisiting the relationship between regenerative ability and aging Ashley W Seifert1,2 and S Randal Voss1,3,* See research article: http://www.biomedcentral.com/1741-7007/10/103 to regenerate, and understanding these limits may be the Abstract key to understanding why humans cannot regenerate Contrary to the longstanding view that newts whole organs. Although examples of tissue regeneration (Notophthalamus viridescens), but not axolotls are rare among birds and mammals, tissue regeneration (Ambystoma mexicanum), can regenerate a lens, a occurs in amphioxus, the most basal living chordate [2]. recent report in BMC Biology by Panagiotis Tsonis and This suggests that humans likely share mechanisms that colleagues shows axolotls indeed possess this ability are used by salamanders and other vertebrates to re­ during early larval stages. In contrast, they show that generate organs. Salamanders provide a good stepping­ zebrafish never posses this ability, even as embryos. off point for considering factors that limit regenerative This underscores the importance of comparing ability because they present a basal tetrapod condition regenerative ability across species and reinforces the that most closely approximates ancestral lineages leading need to consider organ regeneration in the context of to amniotes. evolution, development, and aging. Regenerative potential is generally higher during early life stages New insights in regenerative biology will continue to To understand why and how regenerative ability varies arise from studies of animal models that present a across ontogeny and phylogeny requires a comparative diversity of regenerative responses. To better leverage approach that evaluates regeneration of homologous these models, it will be important to consider re genera­ structures throughout development, preferably using tive ability within the context of evolution, life history, species that diverged from a common ancestor. Unfortu­ physiology, and development [1]. Here we highlight a nately, few rigorous studies have examined regeneration long­standing problem, the loss of regenerative ability as throughout development. Still, ontogenetic changes in an organism ages. Considering this fundamental relation­ regenerative potential have been described for a few ship between aging and regeneration in naturally re­ species and several lines of evidence support the idea that generating systems may help translate new discoveries embryos, larvae, and juveniles of many species have into effective applications in regenerative medicine. greater potential for tissue repair and regeneration than While humans possess varied and diverse mechanisms adults (Figure 1). Frogs and mice, for example, are for physiological regeneration ­ regeneration to maintain capable of regenerating skin during early life stages but and renew organ functions throughout life ­ this renewal lose this ability later in development, while axolotls retain declines with age; furthermore, we possess a very limited the capacity for skin regeneration even after metamor ­ ability for the regeneration of tissues following injury. phosis ([3] and references therein). Similarly, the ability Enviously, we watch flawless regeneration of limbs, lens, of zebrafish to regenerate pectoral fins and frogs to retina, spinal cord, brain, heart, and neuro­sensory cells, regenerate limbs is reduced in older animals, while heart seemingly throughout life, by distant vertebrate relatives. regeneration appears unaffected even in very old fish There are, however, limits to the ability of any organism ([1,4] and references therein). Adding to these studies, a report by Suetsugu­Maki et al. [5] now shows that axolotls can regenerate a lens during early life stages, *Correspondence: [email protected] while most vertebrates cannot regenerate lenses at all. 1Department of Biology, University of Kentucky, Lexington, KY 40506, USA And yet, newts are capable of lens regeneration through­ Full list of author information is available at the end of the article out life and if the progenitor cells that restore lenses in © 2013 Seifert and Voss; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Seifert and Voss BMC Biology 2013, 11:2 Page 2 of 4 http://www.biomedcentral.com/1741-7007/11/2 puberty (a) metamorphosis puberty (b) spinal cord, heart, brain spinal cord, heart, brain 5 5 skin, digit, newt lens pectoral n limb 3 pectoral 3 n lens axolotl lens 0 0 embryolarva juvenile adult embryolarva juvenile adult metamorphosis puberty (c) puberty (d) 5 5 Regenerative ability Regenerative 3 3 heart digit digit skin spinal cord, heart, brain, skin, spinal cord, limb, brain, lens 0 lens, limb 0 embryolarva juvenile adult embryo juvenile adult Developmental stage Figure 1. Reparative regeneration as a function of developmental stage among vertebrate models of regeneration. Panels depict how the regenerative ability of homologous structures varies across ontogeny for the primary vertebrate models of regeneration. Regenerative ability is presented on a 0 to 5 scale; fi ve represents perfect regeneration and zero no regeneration. Major ontogenetic stages are represented as embryo, larva, juvenile and adult with metamorphosis, puberty or both indicated for each species. (a) Zebrafi sh exhibit lifelong regenerative capacity of spinal cord, brain, and heart. They cannot regenerate a lens at any time in development and while pectoral fi ns (homologous to tetrapod limbs) regenerate in juveniles, their regenerative capacity is reduced following puberty, with females retaining a higher capacity for complete regeneration. (b) Salamanders and newts are the archetypical tetrapod regenerator, retaining near perfect regeneration of most organs and appendages well into adulthood (although almost no studies have tested these abilities in old animals). They do, however, experience a decline in limb regeneration following metamorphosis, which usually manifests as patterning defects and loss of limb elements. Axolotls can only regenerate lenses as early stage larvae. (c) Although most frogs exhibit some degree of regeneration as larvae, with the exception of limited digit and very restricted limb regeneration in some species, they do not exhibit regenerative ability as adults. (d) Mammals exhibit some regenerative capacity as embryos but lose almost all of this ability before or shortly after birth for the structures listed. non­regenerating species, including humans, are cultured these examples suggest that even in some salamanders in vitro, cells with lens phenotypes diff erentiate [6]. Th us, with boundless regenerative abilities, constraints im­ while the potential for lens regeneration is apparently a posed by aging, either at the physiological or cellular shared derived trait of vertebrates, that potential is level, work to limit regenerative capacity in organ­ and restricted during development in most species. Together, species­specifi c manners. Seifert and Voss BMC Biology 2013, 11:2 Page 3 of 4 http://www.biomedcentral.com/1741-7007/11/2 What limits regenerative ability during aging? Many animals undergo post­embryonic growth and Understanding how aging changes cells, tissues, and developmental phases that commence in response to physiological systems is key to identifying mechanisms circulating hormones that are released at relatively that limit regenerative ability. During both development specific times during ontogeny. In the case of amphibian and regeneration, relatively undifferentiated cells become metamorphosis, thyroid hormone (TH) reprograms specified to form organs that then undergo tremendous juvenile