“ Developmental senescence acts as a morphogenetic regulator whose activity must be tightly integrated with proliferative cues, differentiation programs, and tissue-specific signaling networks .”
BUFFALO, NY — September 29, 2026 — A new review was published in Volu m e 18 of Aging on September 8, 2026, titled “ Developmental senescence misregulation in congenital disorders: CHARGE syndrome as a candidate model .”
The article proposes that disruption of developmental senescence—a tightly controlled cellular program involved in embryonic tissue remodeling—may contribute to congenital abnormalities associated with CHARGE syndrome.
The review was led by co-first authors Álvaro J. Arana and Pablo Palau-Irisarri, who contributed equally. Arana is affiliated with the Departamento de Zoología, Genética y Antropología Física, Facultad de Veterinaria, Universidad de Santiago de Compostela, Spain , while Palau-Irisarri is affiliated with the Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Spain . Arana is also the corresponding author.
Cellular senescence is commonly associated with aging, cellular stress and tumor suppression, but it also occurs naturally during embryonic development. Unlike classical stress-induced senescence, developmental senescence is transient and restricted to particular tissues and developmental stages. These cells can contribute to tissue remodeling and patterning before being cleared, helping shape developing organs.
Because this process must occur at the right place and time, the authors propose that excessive, insufficient, prolonged or misplaced senescence could interfere with normal morphogenesis. CHARGE syndrome provides a particularly relevant model for investigating this possibility. The rare developmental disorder can involve coloboma, heart defects, choanal atresia, growth and developmental delay, genitourinary abnormalities and characteristic ear defects. Most patients with CHARGE syndrome carry pathogenic variants in CHD7, which encodes an ATP-dependent chromatin remodeler.
The authors identify anatomical overlap between tissues affected in CHARGE syndrome, regions where CHD7 is expressed during development and areas where developmental senescence has been observed. These include structures associated with the eye, inner ear, pharyngeal regions and nervous system. Although this overlap does not establish causality, it provides a framework for investigating whether CHD7 deficiency alters the timing, location or intensity of developmental senescence.
The inner ear provides one of the strongest examples. Developmental senescence contributes to remodeling of the developing inner ear, while CHARGE syndrome frequently involves hypoplasia or absence of the semicircular canals. Chd7-deficient mice also show major vestibular abnormalities. The authors therefore propose that altered senescence-related remodeling could contribute to characteristic inner-ear defects associated with CHD7 deficiency.
There are also molecular connections supporting further investigation. CHD7 intersects with pathways involved in cell-cycle arrest and senescence, including p53, p21 and TGFβ-related signaling. In zebrafish embryos, reduced chd7 expression causes cell-cycle arrest alongside increased expression of several cell-cycle inhibitors. In mouse models, inappropriate p53 activation can produce major CHARGE-like abnormalities, while partial reduction of Trp53 can rescue several developmental defects caused by Chd7 deficiency.
Evidence from other developmental models supports the broader idea that senescence must be precisely controlled during embryogenesis. Abnormal senescence has been implicated experimentally in models involving Six1 deficiency, valproic acid exposure, maternal diabetes and trisomy 21. Together, these findings suggest that developmental abnormalities may emerge when senescence occurs in the wrong location, at the wrong time or at an inappropriate level.
The review also considers whether senescence-related mechanisms could contribute to other congenital conditions, including Rett syndrome, Treacher-Collins syndrome, 22q11.2 deletion syndrome, Waardenburg syndrome and related SOX10-associated disorders, and Kallmann syndrome. Evidence varies considerably among these disorders, and whether the observed changes represent authentic developmental senescence or related cell-arrest states remains unresolved.
Importantly, the proposed connection between CHD7 and developmental senescence remains a working hypothesis. The available evidence is heterogeneous and often indirect, and direct experiments are needed to determine whether CHD7 deficiency alters developmental senescence in affected embryonic tissues.
“ The available anatomical, developmental, and molecular evidence does not yet demonstrate that CHARGE syndrome is a disorder of senescence misregulation. ”
Future studies could map senescence markers across CHD7-sensitive tissues and determine how CHD7 affects chromatin accessibility, cell-cycle control and senescence-associated signaling. Although senescence-modulating approaches have shown benefits in some experimental models, the authors emphasize caution because developmental senescence is itself a normal component of morphogenesis.
Overall, the review presents CHARGE syndrome as a candidate model for understanding how misregulation of a normally beneficial developmental program could contribute to congenital disease. The proposed framework connects CHD7-dependent regulation with senescence-related pathways and embryonic tissue remodeling, but establishing a causal role will require direct functional evidence, particularly in CHD7-sensitive structures such as the inner ear.
Paper DOI : https://doi.org/10.18632/aging.206396
Corresponding author: Álvaro J. Arana – alvaro.arana@usc.es
Keywords: aging, CHD7, morphogenesis, p53/p21 pathway, TGFβ signaling, congenital disorders
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Aging-US
Systematic review
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Developmental senescence misregulation in congenital disorders: CHARGE syndrome as a candidate model
8-Sep-2026
The authors declare that they have no conflicts of interest.