Can we reset, reprogram, rejuvenate, or reverse the organismal aging process? Certain
genetic manipulations could at least reset and reprogram epigenetic dynamics beyond
phenotypic plasticity and elasticity in cells, which can be manipulated further into
organisms. However, in a whole complex aging organism, how can we rejuvenate intrinsic
resources and infrastructures in an intact and noninvasive manner? The incidence of
diseases increases exponentially with age, accompanied by progressive deteriorations
of physiological functions in organisms. Aging-associated diseases are sporadic but
essentially inevitable complications arising from senescence. Senescence is often
considered the antithesis of early development, but yet there may be factors and mechanisms
in common between these 2 phenomena to rejuvenate over the dynamic process of aging.
The association between early development and late-onset disease with advancing age
is thought to come from a consequence of developmental plasticity, the phenomenon
by which one genotype can give rise to a range of physiologically and/or morphologically
adaptive states based on diverse epigenotypes in response to intrinsic or extrinsic
environmental cues and genetic perturbations. We hypothesized that the future aging
process can be predictive based on adaptivity during the early developmental period.
Modulating the thresholds and windows of plasticity and its robustness by molecular
genetic and chemical epigenetic approaches, we have successfully conducted experiments
to isolate zebrafish mutants expressing apparently altered senescence phenotypes during
their embryonic and/or larval stages (“embryonic/larval senescence”). Subsequently,
at least some of these mutant animals were found to show a shortened life span, whereas
others would be expected to live longer into adulthood. We anticipate that previously
uncharacterized developmental genes may mediate the aging process and play a pivotal
role in senescence. On the other hand, unexpected senescence-related genes might also
be involved in the early developmental process and its regulation. The ease of manipulation
using the zebrafish system allows us to conduct an exhaustive exploration of novel
genes, genotypes, and epigenotypes that can be linked to the senescence phenotype,
which facilitates searching for the evolutionary and developmental origins of aging
in vertebrates.
Abbreviations:
SA-β-gal (Senescence-associated β-galactosidase), TERT (Telomerase reverse transcriptase)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: November 14, 2013
Accepted:
October 21,
2013
Received in revised form:
October 20,
2013
Received:
August 22,
2013
Footnotes
Conflicts of Interest: The author has read the journal’s policy on conflicts of interest and have none to declare.
The work of the author’s laboratory reviewed in this article was funded by research grants from The Ellison Medical Foundation, the Glenn Foundation for Medical Research, the A-T Children’s Project, and the National Institute of General Medical Sciences/National Institute on Aging/National Institutes of Health.
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Copyright
© 2014 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
