Age-related hearing loss affects nearly half of all older adults, making it the third most prevalent chronic condition of aging, yet its molecular roots have remained stubbornly elusive. A new study published in Aging Cell now points the finger at an unexpected culprit: the tiny blood vessels that feed the cochlea, and specifically the pericyte cells that wrap around them. Researchers report that an age-driven decline in the hormone insulin-like growth factor 1, or IGF-1, sets off a chain reaction that destabilizes the blood-labyrinth barrier, the specialized vascular gatekeeper of the inner ear, ultimately eroding hearing itself.
The team, working with young and aged C57BL/6J mice, began by confirming what epidemiological studies had long hinted at. Auditory brainstem response testing showed that 85 percent of the aged animals failed to respond to sounds below 70 decibels, with click-evoked and frequency-specific thresholds markedly elevated across the 4 to 32 kilohertz range. Distortion product otoacoustic emissions were also impaired at high frequencies, indicating that the cochlea’s mechanical amplifier had faltered alongside its neural signaling. In short, these mice were a faithful model of human presbycusis.
To find out what was happening at the cellular level, the investigators isolated pericytes from the stria vascularis, the metabolically ravenous, ribbon-like structure that powers the cochlea and houses the blood-labyrinth barrier. Using fluorescence-activated cell sorting to purify pericytes marked by PDGFR-beta, they performed transcriptome sequencing on cells from young and aged mice. The results were striking: both Igf1 and Slc25a33, a gene encoding a mitochondrial nucleotide carrier, were significantly downregulated in the aged pericytes. Pathway enrichment analyses flagged the TGF-beta signaling pathway as one of the most differentially activated routes in the aging cells, alongside terms linked to cell junctions and the cytoskeleton.
Immunofluorescence staining of cochlear sections confirmed the story in tissue. IGF-1 and SLC25A33 proteins, which normally co-localize within the stria vascularis, showed a pronounced age-dependent decline, and the change was most dramatic in pericytes themselves. Critically, the levels of the IGF-1 receptor did not differ between young and aged pericytes, suggesting that the defect lies in the supply of the hormone rather than in the cell’s ability to sense it. When the researchers blocked IGF-1 signaling in cultured human brain vascular pericytes with the inhibitor NVP-AEW541, SLC25A33 messenger RNA and protein both fell; adding recombinant IGF-1 pushed them back up. Endothelial cells, by contrast, did not respond in the same way, marking pericytes as the specific cellular target of this regulatory axis.
Why would losing SLC25A33 matter so much? The protein is a mitochondrial carrier that helps sustain oxidative phosphorylation and redox balance. When the team silenced Slc25a33 with shRNA, flow cytometry using MitoSOX Red revealed a surge in mitochondrial reactive oxygen species leaking from the electron transport chain. The pericytes then began to change character. Alpha-smooth muscle actin, the signature of a contractile, myofibroblast-like state, rose sharply at both the messenger RNA and protein levels, while E-cadherin, a junctional protein associated with quiescent, barrier-stabilizing pericytes, dropped. The cells were undergoing a phenotypic switch from quiet vascular support cells into activated, fibrosis-prone contractile cells.
The mechanistic thread connecting these events proved to be TGF-beta signaling. In SLC25A33-deficient pericytes, TGF-beta messenger RNA and protein were elevated, and phosphorylated Smad2, the activated form of the transcriptional mediator, increased robustly. Total Smad2, Smad3, and Smad4 levels were unchanged, and phosphorylated Smad3 did not budge, indicating a selective engagement of the canonical Smad2 arm. When the researchers treated the deficient cells with MitoTEMPO, a mitochondrial antioxidant, the excess reactive oxygen species fell and TGF-beta, phospho-Smad2, and alpha-SMA all declined, placing mitochondrial oxidative stress upstream of the signaling cascade. Conversely, blocking the TGF-beta receptor with LY2109761 restored E-cadherin and suppressed the contractile markers, confirming that the pathway mediates the differentiation program.
The decisive test came in living animals. Delivering recombinant IGF-1 directly into the cochlea of aged mice through the round window membrane boosted SLC25A33 expression in the stria vascularis, while the IGF-1 inhibitor deepened its decline. Using adeno-associated virus vectors tailored for inner ear transduction, the team then overexpressed or knocked down Slc25a33 in the aged cochlea. Overexpression reduced alpha-SMA and TGF-beta signaling and raised E-cadherin; knockdown did the opposite. Transmission electron microscopy laid bare the structural consequences: in IGF-1-suppressed mice, pericytes showed abnormal morphology, loose associations with endothelial cells, and widened tight junctions, hallmarks of a leaky blood-labyrinth barrier. Exogenous IGF-1 preserved those intimate pericyte-endothelial contacts and restored tight junction integrity.
Most importantly for patients, the intervention worked functionally. IGF-1 supplementation significantly lowered click-evoked auditory brainstem response thresholds in aged mice, and at 12 kilohertz the treated animals heard markedly better than both untreated and IGF-1-suppressed controls. In mice whose Slc25a33 had been silenced by viral knockdown, treatment with the TGF-beta receptor inhibitor LY2109761 raised levels of the tight junction proteins Claudin-5 and Occludin in the stria vascularis, easing barrier disruption. The findings were further validated in an independent mouse strain, CBA/CaJ, where aged animals likewise showed reduced IGF-1 and SLC25A33 protein in the stria vascularis, indicating that the mechanism generalizes across genetic backgrounds.
The study thereby assembles a complete causal chain: aging lowers IGF-1, which suppresses the mitochondrial carrier SLC25A33 in strial pericytes; mitochondrial reactive oxygen species accumulate; the TGF-beta/Smad2 pathway activates; pericytes transform into contractile, pro-fibrotic cells; the blood-labyrinth barrier breaks down; and hearing deteriorates. This mirrors the pericyte-to-myofibroblast transitions documented at the blood-brain barrier, where elevated alpha-SMA similarly undermines vascular stability, and it echoes the ROS-driven epithelial-to-mesenchymal transitions long observed in other tissues. The cochlea, with its extraordinarily high metabolic demand and dense mitochondrial population, appears uniquely vulnerable to this failure mode.
Questions remain before the discovery can be translated into therapy. Whether IGF-1 acts directly on pericytes through its receptor or partly through paracrine networks will require cell-specific knockout models, and IGF-1 almost certainly regulates additional mitochondrial and cytoprotective genes that contribute to barrier stability. Species differences between human and mouse pericytes also warrant caution. Still, the identification of SLC25A33 as a biomarker and potential drug target, and the demonstration that both hormone supplementation and TGF-beta blockade can partially rescue barrier structure and auditory function in aged animals, opens a genuinely new frontier. If future work confirms the axis in humans, protecting the inner ear’s microscopic vasculature could become a strategy for preserving hearing in a rapidly aging world population.
Subject of Research: The IGF-1/SLC25A33 regulation of blood-labyrinth barrier pericytes in age-related hearing loss
Article Title: IGF‐1/SLC25A33 Maintains Blood‐Labyrinth Barrier Integrity by Suppressing TGF‐β/Smad2‐Mediated Pericyte Activation in Age‐Related Hearing Loss
Article References: Xu, R., Tang, J., Lin, H., Li, Q., Feng, Y., Zhang, X., Hu, X., Yang, J., Li, Y., & Bai, Y. (2026). IGF ‐1/ SLC25A33 Maintains Blood‐Labyrinth Barrier Integrity by Suppressing TGF ‐β/Smad2‐Mediated Pericyte Activation in Age‐Related Hearing Loss. Aging Cell, 25(10), Article e70712. https://doi.org/10.1111/acel.70712
Image Credits: AI Generated
DOI: 10.1111/acel.70712
Keywords: age-related hearing loss, IGF-1, SLC25A33, pericytes, blood-labyrinth barrier, TGF-beta, Smad2, mitochondrial ROS, stria vascularis, presbycusis, cochlea, Aging Cell
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Beatrice Stafford. (October 1, 2026). Aging Hormone Signal Reveals Hidden Trigger of Age-Related Hearing Loss. Scienmag. https://scienmag.com/aging-hormone-signal-reveals-hidden-trigger-of-age-related-hearing-loss/
Beatrice Stafford. “Aging Hormone Signal Reveals Hidden Trigger of Age-Related Hearing Loss.” Scienmag, 1 October 2026, https://scienmag.com/aging-hormone-signal-reveals-hidden-trigger-of-age-related-hearing-loss/. Accessed 1 October 2026.
Beatrice Stafford. “Aging Hormone Signal Reveals Hidden Trigger of Age-Related Hearing Loss.” Scienmag. October 1, 2026. https://scienmag.com/aging-hormone-signal-reveals-hidden-trigger-of-age-related-hearing-loss/
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Tags: age-associated cochlear degenerationage-related hearing lossAging Cellaging hormone signalingauditory system agingblood-labyrinth barrierblood-labyrinth barrier breakdowncochleacochlear blood vesselsIGF-1IGF-1 decline and hearinginner ear vascular healthmitochondrial ROSmolecular causes of hearing losspericyte cell dysfunctionpericytespresbycusispresbycusis mechanismsSLC25A33SMAD2stria vascularisTGF-betavascular contribution to hearing decline
