What was tested

Li, Yu, Yao, Tang, and colleagues at West China Hospital of Stomatology, Sichuan University, set out to find an in vivo driver of tooth aging. They combined human histology and a prospective case-control study with a panel of mouse genetic tools: Cre-based pulse-chase lineage tracing, Cre-driven ablation, conditional knockout combined with tracing, and the FUCCI cell-cycle reporter (Li et al. 2026, Stem Cell Reports, Summary and Results).

The work focuses on dental pulp mesenchymal stromal cells (MSCs), the resident repair population that must generate new odontoblasts and dentin after injury. The authors hypothesized that age-related loss of a specific pulp MSC population, rather than passive wear, might explain why older teeth lose regenerative capacity.

Human data: aged pulp loses structure and defensive capacity

The team collected healthy third molars from systematically healthy volunteers in two age groups, 18 to 40 years and 60 years or older, between January 2022 and December 2024 (Li et al. 2026, STAR Methods). Masson’s trichrome showed that aged pulp had lower cell density, depolarized odontoblasts, a disrupted fence-like odontoblast layer, more intercellular porosity, and more crosslinked fibers. Sirius red under polarized light showed more collagen fibers in pulp cores and more depolarized predentin than in young teeth (Li et al. 2026, Results, Figure 1).

In a separate prospective case-control study, teeth with deep caries were followed for one year to track progression to irreversible pulpitis. Under three logistic regression models, the aged group showed a statistically significant odds ratio for progression to irreversible pulpitis compared with the young group (Li et al. 2026, Results, Figure 1D and Tables S1-S2). The authors interpret this as evidence that tooth aging impairs the pulp-dentin complex’s ability to mount a protective repair response.

Mouse genetics: NFATC1-expressing pulp MSCs maintain the tissue

Using Nfatc1-CreER; tdTomato mice, the authors found that NFATC1-expressing cells in 3-month-old mouse molars were concentrated in pulp core MSCs and were barely present in odontoblasts. Lineage tracing showed that these NFATC1+ MSCs continuously replenished pulp mesenchyme and gave rise to new odontoblasts over 30 days. In 18-month-old mice, NFATC1+ cells were barely detectable, suggesting that loss of this population accompanies natural aging (Li et al. 2026, Results, Figure 2).

To test whether the cells are functionally required, the authors ablated NFATC1-expressing MSCs in young mice. Ablation reduced proliferating Pdgfra-high pulp MSCs, upregulated senescence-associated secretory phenotype markers IL-1alpha and TNF-alpha, and severely blocked generation of pulp core mesenchyme and odontogenic lineage cells. Histologically, young ablated teeth resembled aged teeth: lower pulp cell density, depolarized odontoblasts, disrupted odontoblast layer, and increased porosity (Li et al. 2026, Results, Figure 2).

Conditional knockout of Nfatc1 in Pdgfra-expressing pulp MSCs produced the same aging-like phenotype, including thinner predentin and an increased pulp volume to total root volume ratio under homeostasis. NFATC1 knockout completely halted generation of DSPP-positive odontoblasts in vivo (Li et al. 2026, Results, Figure 3).

Senescence is the mechanism, and injury repair collapses

Flow cytometry of CD45-negative pulp MSCs from knockout mice showed that 54.0% were SA-beta-galactosidase-positive, compared with 15.9% in controls. FUCCI cell-cycle reporting showed S/G2-M phase cells fell from 0.94% in controls to 0.36% in knockouts, while G1-phase cells rose from 0.80% to 1.33%, indicating cell-cycle arrest. Immunofluorescence for phospho-histone H3 and gamma-H2AX supported cycle arrest and genomic instability, and SASP factors were elevated (Li et al. 2026, Results, Figure 4).

In a dental injury model, Nfatc1 knockout mice had significantly less reparative dentin and root dentin thickening by micro-CT at 14 days post-injury. Quantification of double labeling showed daily dentin regeneration dropped to less than 0.5 micrometers of mineralized surface per micrometer in knockouts versus 1.5 in controls. After injury, knockout pulp MSCs showed reduced S/G2-M proportions (0.46% versus 0.83% in controls) and increased G1 proportions (3.58% versus 2.77%) (Li et al. 2026, Results, Figure 5).

Senolytic therapy rescues the phenotype

The authors treated mice with dasatinib plus quercetin (D+Q), a known senolytic combination. In aged mice, an intermittent “hit and run” regimen reduced the proportion of SA-beta-galactosidase-positive CD45-negative Pdgfra-positive pulp MSCs by 14.4%. In the Nfatc1 knockout injury model, D+Q restored the pulp canal to root volume ratio to control levels by 14 days post-injury and brought reparative dentin regeneration back to control levels. Histologically, D+Q restored reparative dentin and pulp cell density, reduced porosity, increased Ki67-positive proliferating cells, and lowered TNF-alpha expression (Li et al. 2026, Results, Figure 5).

What it means for pulp-dentin repair

For the pulp and dentin repair program, the paper reframes age-related regenerative failure as a stem-cell senescence problem driven by NFATC1 dysfunction, rather than as irreversible tissue exhaustion. It also provides a first proof of concept in mice that clearing senescent pulp MSCs with D+Q can restore reparative dentin formation. If the finding holds in larger models, it would suggest that regenerative endodontics in older patients may eventually be paired with senolytic preconditioning of the pulp niche.

What it does not show

The clinical case-control study links age to higher risk of irreversible pulpitis, but the exact odds ratio values are in supplementary tables and the precise effect size should be read from Figure 1D and Tables S1-S2. The senolytic rescue is in genetically induced, not naturally aged, mice, and all animal work is in a C57BL/6 background with small group sizes (n = 3 or 4 per group for most histological endpoints). D+Q has known off-target effects, and the study does not establish dosing, safety, or efficacy in humans. No human pulp regeneration or clinical senolytic trial data are reported.

Provenance: grounded in the open-access full text of Li F, Yu C, Yao L, Tang Y, Yang X, Wang Y, Liu J, Yin B, Wang H, Yu F. NFATC1 dysfunction-triggered MSC senescence induces tooth aging amenable to senolytic therapy. Stem Cell Reports. 2026;21(6):102925. doi:10.1016/j.stemcr.2026.102925, retrieved and verified against the PMC full text at PMC13261951. Method and sourcing standard at /method/.