Revisiting the relationship between regenerative ability and aging
© Seifert and Voss; licensee BioMed Central Ltd. 2013
Received: 2 January 2013
Accepted: 18 January 2013
Published: 21 January 2013
Contrary to the longstanding view that newts (Notophthalamus viridescens), but notaxolotls (Ambystoma mexicanum), can regenerate a lens, a recent report in BMC Biologyby Panagiotis Tsonis and colleagues shows axolotls indeed possess this ability during earlylarval stages. In contrast, they show that zebrafish never posses this ability, even as embryos.This underscores the importance of comparing regenerative ability across species and reinforces theneed to consider organ regeneration in the context of evolution, development, and aging.
See research article: http://www.biomedcentral.com/1741-7007/10/103
New insights in regenerative biology will continue to arise from studies of animal models thatpresent a diversity of regenerative responses. To better leverage these models, it will be importantto consider regenerative ability within the context of evolution, life history, physiology, anddevelopment . Here we highlight a long-standing problem, the loss of regenerative ability as anorganism ages. Considering this fundamental relationship between aging and regeneration in naturallyregenerating systems may help translate new discoveries into effective applications in regenerativemedicine.
While humans possess varied and diverse mechanisms for physiological regeneration - regenerationto maintain and renew organ functions throughout life - this renewal declines with age; furthermore,we possess a very limited ability for the regeneration of tissues following injury. Enviously, wewatch flawless regeneration of limbs, lens, retina, spinal cord, brain, heart, and neuro-sensorycells, seemingly throughout life, by distant vertebrate relatives. There are, however, limits to theability of any organism to regenerate, and understanding these limits may be the key tounderstanding why humans cannot regenerate whole organs. Although examples of tissue regenerationare rare among birds and mammals, tissue regeneration occurs in amphioxus, the most basal livingchordate . This suggests that humans likely share mechanisms that are used by salamanders and othervertebrates to regenerate organs. Salamanders provide a good stepping-off point for consideringfactors that limit regenerative ability because they present a basal tetrapod condition that mostclosely approximates ancestral lineages leading to amniotes.
Regenerative potential is generally higher during early life stages
What limits regenerative ability during aging?
Understanding how aging changes cells, tissues, and physiological systems is key to identifyingmechanisms that limit regenerative ability. During both development and regeneration, relativelyundifferentiated cells become specified to form organs that then undergo tremendous growth, but theoverall process differs between the two. Regeneration is activated in response to injury, dependsupon tissue-specific progenitor cells, and occurs under physiological conditions and within anextracellular environment that differs from the embryonic state. Embryonic cells have greatpotential for cellular reprogramming, and cellular reprogramming through epigenetic modificationsand changes in transcription are associated with regenerative responses . During development, cells exhibit changes in transcription that limit signaling pathwaysassociated with cellular plasticity. For example, cells differentiate and lose the ability to enterthe cell cycle, both of which must be reversed for limb regeneration to occur in salamanders. Themaintenance of plastic cellular states and cell-cycle re-entry are likely associated with theactions of tumor suppressor proteins like retinoblastoma protein (RB), the levels and activationstates of which are known to vary during regeneration in salamanders and across developmental stagesin mammals [8, 9]. Taken together, studies suggest that the abundances of key regulatory molecules arepermissive for cell cycle re-entry from a quiescent state in young life stages, but restrictive asan organism ages, and this limits regenerative ability. Future studies that quantify levels of suchmolecules in young and old salamanders may shed new light on progenitor cell activation,regenerative ability, and potentially, diseases of aging such as cancer.
How do systemic factors affect regenerative ability?
Early, heightened cellular plasticity in response to injury reflects not only local but alsosystemic factors that are difficult to disentangle without ontogenetic perspective. The importanceof systemic factors is dramatically shown in studies of parabiotic mice that differ in age but sharethe same circulatory system. Serum from young animals stimulates older muscle to regenerate andserum from old individuals decreases the regenerative capacity of young muscle . A similar phenomenon was noted in the ability of a young systemic milieu to rejuvenateaged oligodendrocyte precursor cells and promote remyelination of axons in old mice . While these studies provide further support for the idea that regenerative potentialcorrelates negatively with aging, they also show that regeneration is not simply a local property ofcells and tissues. Instead, regeneration also depends upon blood cells and serum factors that havebroad access to tissues and progenitor cell niches - and the properties of these cells and factorschange during development.
Many animals undergo post-embryonic growth and developmental phases that commence in response tocirculating hormones that are released at relatively specific times during ontogeny. In the case ofamphibian metamorphosis, thyroid hormone (TH) reprograms juvenile cells and activates adultprogenitor cells, and this brings about the conversion of tadpole aquatic larvae into moreterrestrial adults. Interestingly, while newts always undergo metamorphosis, axolotls rarely dounless treated exogenously with TH . Future studies that use hormones to induce metamorphosis at different times duringontogeny may be able to disentangle the effects of aging from intrinsic regenerative ability, as ithas already been shown that prolonging the larval state enhances regenerative ability compared tosame-aged animals that have undergone metamorphosis .
Regeneration insight from comparative approaches
In coming years, we envision a new, golden age in regenerative biology. Animals present adiversity of regenerative responses that vary across organs, developmental stages, and phylogeny.Increasingly, advances in genetic and genomic technologies will make it possible to compareregenerative responses within and among animal models to identify factors that cause regenerativeability to change with aging.
We thank Megan Seifert for helpful comments on the manuscript and figure. We apologize to authorswhose work was not cited due to space constraints.
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