With filters and editing tools at our fingertips, we are able to play with our appearances to predict what we’ll look like in the future or attempt to change what’s already there. However, at one point or another, we hit those points of no return, such as an amputation or poor healing abilities in old age. Regardless of the preventive measures we take, helmets, creams, and procedures can only help us so much.
On the other hand, organisms like salamanders and zebrafish never have to worry about these things. Like us, they have “aging cells” that essentially “fix” their bodies when needed, allowing them to return to their daily routines. Yet, the simple bodies of these organisms allow for high plasticity (the ability of cells to change physical characteristics without genetic mutations) and regenerative abilities that we could only dream of [1].
Another organism, a close relative of jellyfish and corals, Hydractinia symbiolongicarpus, never ages due to extremely powerful regenerative abilities that allow it to grow a whole new body from a tissue fragment as small as a portion of its mouth [2]. This tubelike animal that lives on shells occupied by hermit crabs [3] brought to question the role of cellular senescence, an adaptive response induced by multiple stressors that results in a permanent stop to the cell cycle [4], due to its potential in aiding treatments for age and tissue-related diseases.
Research published in June 2023 in Cell Reports and the National Institutes of Health demonstrates that senescence, the biological aging process, in Hydractinia can induce the reprogramming of neighboring cells to drive whole-body regeneration [5]. This mechanism found in such an ancient organism has long interested scientists, as cellular senescence in modern mammals can compromise tissue repair and regeneration, thus contributing to aging. The mechanism has both beneficial and detrimental effects on our bodies, as it can prevent the reproduction of potentially cancerous cells [6]. However, like a moldy piece of fruit that ruins the rest of a serving, a small number of these “aging cells” can prevail and spread inflammation that damages neighboring cells [7].
Moreover, when studying the Hydractinia species, the researchers discovered that this animal could regrow a lost head within three days post-amputation [5]. This head regeneration is driven by pluripotent migratory stem cells, also known as i-cells. Though normally restricted to the lower extremities of the animal, these i-cells migrate to the injury site after amputation to regrow the head. Led by an RNA sequence pointing to senescence that was comparable to the aging genes in humans, these i-cells were able to migrate and develop new “aging cells” because of one of the comparable genes being “turned on” [2]. When the gene was turned off, the researchers found that new stem cells couldn’t be regenerated. Though these cells pose a malignant risk in humans, the roles of these aging genes in Hydractinia further allow the organism to avoid these harmful effects by ejecting these “aging cells” out of its mouth.
The amputated oral tips of the heads, known as hypostomes, can regenerate into a fully functional animal containing i-cells, despite not having them immediately post-amputation [5]. These new i-cells that regenerated were recognized as “secondary i-cells” as opposed to primary i-cells generated during embryogenesis, the developmental stage of an animal embryo, and provided an increased reproduction of stem cell descendants.
By studying our most distant relatives, like Hydractinia, we unravel secrets that can advance the field of medicine. Through strong evidence for a role for senescence signaling in cellular reprogramming, the researchers were able to speculate that with cell fate stability and complexity found in modern mammals came a “trade-off” in which these organisms experienced side effects that evolved later in the evolution of these lineages [5]. Placing the spotlight onto unusual organisms like Hydractinia, intertwined with biological processes of healing and aging, provides great potential for novel insights into human biology as questions for the cell reversal theory persist [8].
While regeneration can already be visualized, deciphered, and manipulated, there's still room for improvement. Over the past decade, there have been key advances for approximating human tissue regeneration, which include cell type-restricted injuries, retrospective fate-mapping techniques, and imaging platforms [3]. Additionally, gene knockdown methodologies such as RNA interference, morpholinos, and CRISPR have supported the hypothesis of the specific gene of interest involved in an observed phenotype presented in Hydractinia studies [1]. However, as discoveries progress, functional genomic experiments are crucial in moving forward to better understand the genetics and dynamics of regenerating cells at individual and population levels.
References:
Mokalled, M. H., & Poss, K. D. (2018, November 5). A Regeneration Toolkit - PMC. NCBI. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373444/
U.S. Department of Health and Human Services. (2023, June 30). Scientists discover clues to aging and healing from a squishy sea creature. National Institutes of Health. https://www.nih.gov/news-events/news-releases/scientists-discover-clues-aging-healing-squishy-sea-creature
Grosberg, R., & Plachetzki, D. (2017). Marine Invertebrates: Genetics of Colony Recognition. In Reference Module in Life Sciences (pp. 381-388). University of California, Davis. https://www.sciencedirect.com/science/article/abs/pii/B9780128096338011638
Senescence Signaling. (2019, September). Cell Signaling Technology. https://www.cellsignal.com/pathways/senescence-signaling-pathway?_requestid=1280680
Salinas-Saavedra, M., Febrimarsa, Krasovec, G., Horkan, H. R., Baxevanis, A. D., & Frank, U. (2023, June 30). Senescence-induced cellular reprogramming drives cnidarian whole-body regeneration. https://www.cell.com/cell-reports/fulltext/S2211-1247(23)00698-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124723006988%3Fshowall%3Dtrue
Kumari, R., & Jat, P. (2021). Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Frontiers in Cell and Developmental Biology, 9, 645593. https://doi.org/10.3389/fcell.2021.645593
Does cellular senescence hold secrets for healthier aging? (2021, July 13). National Institute on Aging. https://www.nia.nih.gov/news/does-cellular-senescence-hold-secrets-healthier-aging
Carvalho, J. (2020, April 15). Cell Reversal From a Differentiated to a Stem-Like State at Cancer Initiation. NCBI. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174973/