Yellow spotted salamander

Health

A salamander’s amazing secret for staying young: Destroy senescent cells

By Juman Hijab

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Original date: February 3, 2023  

Updated: February 10, 2023

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Yellow spotted salamander

jeri leandera. Yellow spotted salamander. Flickr.com, Sept 15, 2007.

Salamanders and staying young

Salamanders and newts are related to frogs (1, 2). Their head looks like that of a frog, but their body looks more like a lizard. 


Impressive longevity and high regenerative abilities 

Salamanders are a very long-lived species - for their size (3): they are relatively small from 8 grams  (1/4 ounce) - 110 gram (3.8 ounces). Salamanders can live 20 - 30 years - even in the wild (4). Some exceptional creatures (Proteus or cave Olm) can live more than 100 years (3) . 


Not only do salamanders live longer than other similarly-sized creatures, they show resistance to aging. They seem to stay young for most of their life (5). Some authors suggest that the negligible senescence experienced by salamanders is probably due to their remarkable regenerative capacity (4, 5). Salamanders are able to regenerate most of their organs and appendages  almost perfectly, even as adults (6, 7). Moreover, salamanders have a low body temperature, which is known to be related to unusual longevity

Presence of youthful (stem) cells = Youth

A salamander's power in maintaining youthfulness is related to three elements:

  • The presence of adult stem cells in their body
  • An innate ability to transform specialized adult cells into immature cells. 
  • The ability to create a niche that is very conducive to regeneration

This means that - for salamanders - most of their specialized adult cells are an extensive treasure trove of cells that can be used to regenerate new tissues ((6, 7, 8, 9). 

Thus, experiments have been done where the lens of a Japanese Newt was removed. The newt was able to regenerate a new lens using retinal epithelial cells (7). Even old newts retained the ability to form new lenses. 

Dall-e representation of a stem cell; senescent cells

A DALL·e-representation of a stem cell, Feb 2, 2023,

Retaining the capacity for "stemness"

Stem cells are immature cells that have the ability to transform into new tissues. Interestingly, after a cell specializes or ages, the ball game is not lost.

Even in mammals, aged or specialized cells seem to have the ability to revert back to immature cells that display regenerative and reproductive abilities.


Giving an old cell new life

The trick is to give the nucleus of an old cell the appropriate youth stimuli. With that, an old cell can revert back to an immature state and regain the capacity for regeneration. For example,

  • Dolly - the cloned sheep - was produced by putting an old nucleus into the cytoplasm of an enucleated fertilized ovum (8, 10).  
  • Adding immaturity-inducing transcription factors to an old cell's nucleus (Yamanaka factors) can revert the cell back into a multi-functioning stem cell (811)
  • Vision loss was reversed in a mouse model of glaucoma by adding nuclear transcription factors (12)
  • Parabiosis experiments (combining an old and a young mouse surgically to produce a single, shared physiological system) induced youthfulness in aged mice (13)

In each of those situations, an older cell is reprogrammed or encouraged to become youthful again. Young cells are the key to staying young.

Young salamanders

Black yellow spotted-fire salamanders, courtesy of Dalle-e 2, Feb 1, 2023

Senescent cells beget senescent cells

Unfortunately, when stem cells age (or die and and are not replaced), the tissue/organism ages.

For example, geriatric muscle stem cells lose the ability to divide so that they can replace diseased muscle cells (6).  If that weren't enough, when cells become senescent, they create a "senescent" milieu around them. The nucleus changes its internal architecture and starts secreting proinflammatory proteins and encourages the extracellular matrix to remodel itself into an aged phenotype (6, 14). 

Unfortunately, this induces the nearby cells to become senescent. It is those changes that are thought to produce tissue degeneration, atherosclerosis, and loss of regenerative ability. (6).

Destroying senescent cells to maintain youth

Here's where the salamander has one up on  other animals. In mice and humans, senescent cells accumulate as the tissues age (3). Given that senescent cells beget more senescence, the development of aging-related conditions (atherosclerosis, loss of muscle mass, and  neurodegeneration) ensues.


Salamanders, on the other hand do not tack on senescent cells as they grow older. In fact, they have a highly active system to destroy senescent cells (14). The importance of getting rid of senescent cells to maintain youthfulness cannot be overstated. Experiments have shown that elimination of senescent cells decreases age-related pathology and leads to improved longevity in mice (15, 16). 


 These experiments have set the stage for multiple potential fountain of youth therapies in the rapidly expanding field of senotherapeutics. Clinical studies include the use of small molecules that target senescent cells (senolytics), drugs that delay the progression of young cells to senescent cells (senomorphics), and the use of the immune system to clear senescent cells from tissues (17, 18).

References

  1. Zardoya R, Meyer A. On the origin of and phylogenetic relationships among living amphibians. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7380-3. doi: 10.1073/pnas.111455498. Epub 2001 Jun 5. PMID: 11390961; PMCID: PMC34677.Wake DB, Koo MS. Amphibians. Curr Biol. 2018 Nov 5;28(21):R1237-R1241. doi: 10.1016/j.cub.2018.09.028. PMID: 30399342.
  2. Wake DB, Koo MS. Amphibians. Curr Biol. 2018 Nov 5;28(21):R1237-R1241. doi: 10.1016/j.cub.2018.09.028. PMID: 30399342.
  3. Yun MH. Salamander Insights Into Ageing and Rejuvenation. Front Cell Dev Biol. 2021 Jun 7;9:689062. doi: 10.3389/fcell.2021.689062. PMID: 34164403; PMCID: PMC8215543.
  4. Warburg M. R. (2007). Longevity in Salamandra infraimmaculata from Israel with a partial review of life expectancy in urodeles. Salamandra 43 21–34.
  5. Cayuela H, Olgun K, Angelini C, Üzüm N, Peyronel O, Miaud C, Avcı A, Lemaitre JF, Schmidt BR. Slow life-history strategies are associated with negligible actuarial senescence in western Palaearctic salamanders. Proc Biol Sci. 2019 Aug 28;286(1909):20191498. doi: 10.1098/rspb.2019.1498. Epub 2019 Aug 28. PMID: 31455192; PMCID: PMC6732381.
  6. Yun MH. Changes in Regenerative Capacity through Lifespan. Int J Mol Sci. 2015 Oct 23;16(10):25392-432. doi: 10.3390/ijms161025392. PMID: 26512653; PMCID: PMC4632807.
  7. Sousounis K, Qi F, Yadav MC, Millán JL, Toyama F, Chiba C, Eguchi Y, Eguchi G, Tsonis PA. A robust transcriptional program in newts undergoing multiple events of lens regeneration throughout their lifespan. Elife. 2015 Nov 2;4:e09594. doi: 10.7554/eLife.09594. PMID: 26523389; PMCID: PMC4739772. 
  8. Tweedell KS. The urodele limb regeneration blastema: the cell potential. ScientificWorldJournal. 2010 May 31;10:954-71. doi: 10.1100/tsw.2010.115. PMID: 20526526; PMCID: PMC5763810.
  9. Londono R, Sun AX, Tuan RS, Lozito TP. TISSUE REPAIR AND EPIMORPHIC REGENERATION: AN OVERVIEW. Curr Pathobiol Rep. 2018 Mar;6(1):61-69. doi: 10.1007/s40139-018-0161-2. Epub 2018 Feb 4. PMID: 29967714; PMCID: PMC6025457.
  10. Alberio R, Wolf E. 25th ANNIVERSARY OF CLONING BY SOMATIC-CELL NUCLEAR TRANSFER: Nuclear transfer and the development of genetically modified/gene edited livestock. Reproduction. 2021 Jun 11;162(1):F59-F68. doi: 10.1530/REP-21-0078. PMID: 34096507; PMCID: PMC8240728.
  11. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006 Aug 25;126(4):663-76. doi: 10.1016/j.cell.2006.07.024. Epub 2006 Aug 10. PMID: 16904174.
  12. Lu Y., Brommer B., Tian X., Krishnan A., Meer M., Wang C., et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 2020 588: 124–129. 10.1038/s41586-020-2975-4
  13. Conese M, Carbone A, Beccia E, Angiolillo A. The Fountain of Youth: A Tale of Parabiosis, Stem Cells, and Rejuvenation. Open Med (Wars). 2017 Oct 28;12:376-383. doi: 10.1515/med-2017-0053. PMID: 29104943; PMCID: PMC5662775.
  14. Yun M. H., Davaapil H., Brockes J. P. Recurrent turnover of senescent cells during regeneration of a complex structure. Elife 2015 4:e05505. 10.7554/eLife.05505
  15. Baker D. J., Wijshake T., Tchkonia T., LeBrasseur N. K., Childs B. G., van de Sluis B., et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011 479: 232–236. 10.1038/nature10600
  16. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016 Feb 11;530(7589):184-9. doi: 10.1038/nature16932. Epub 2016 Feb 3. PMID: 26840489; PMCID: PMC4845101.
  17. van Deursen JM. The role of senescent cells in ageing. Nature. 2014 May 22;509(7501):439-46. doi: 10.1038/nature13193. PMID: 24848057; PMCID: PMC4214092.
  18. Tabibzadeh S. From genoprotection to rejuvenation. Front Biosci (Landmark Ed). 2021 Jan 1;26(1):97-162. doi: 10.2741/4890. PMID: 33049666.

Tags

aging, longevity, salamander, stem cell, young


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