Hypothesis

Corneal mechanical sensitivity, when adjusted for tear‑borne neuroinflammatory signals, serves as a more sensitive readout of systemic biological age than sensitivity alone.

Rationale

• Aging reduces corneal nerve density and raises mechanical detection thresholds, reflecting structural changes such as collagen glycation and keratocyte senescence[1][2][3][4].
• However, in inflammatory ocular states (e.g., dry eye) the cornea becomes hypersensitive despite ongoing structural degeneration, indicating a uncoupling of nerve function from matrix integrity[5].
• This uncoupling parallels systemic inflammaging: elevated pro‑inflammatory cytokines in tears (IL‑6, TNF‑α, IL‑1β) correlate with leukocyte telomere attrition and clonal hematopoiesis[6][7].
• Mitochondrial dysfunction in circulating leukocytes predicts both increased pain perception and reduced vagal tone, linking cellular energy status to neuro‑immune communication[8].

Novel Mechanism

We propose that senescent keratocytes release a senescence‑associated secretory phenotype (SASP) that modulates corneal nerve growth factor (NGF) and brain‑derived neurotrophic factor (BDNF) levels. Simultaneously, tear cytokines reflect the systemic SASP spillover, creating a composite signal where:

• High threshold (hyposensitivity) indicates predominant matrix stiffening and nerve loss.
• Low threshold (hypersensitivity) amid high tear cytokines signals SASP‑driven nerve sensitization despite matrix decay. Thus, the ratio of threshold to tear inflammatory load captures the balance between structural aging and neuroimmune dysregulation, a balance that mirrors whole‑body inflammaging and mitochondrial health.

Testable Predictions

1. In a cohort of adults aged 30‑80, individuals with discordant corneal sensitivity (e.g., low threshold but high tear IL‑6/TNF‑α) will show accelerated GrimAge acceleration compared with age‑matched peers who show concordant high threshold and low tear inflammation.
2. The composite index (corneal threshold ÷ (1 + tear IL‑6 + tear TNF‑α)) will correlate more strongly with longitudinal change in GrimAge (β > 0.45, p < 0.001) than threshold alone (β < 0.20) or tear cytokines alone (β < 0.25).
3. Pharmacologic reduction of tear inflammation (e.g., topical corticosteroid) in dry‑eye subjects will increase thresholds toward age‑expected values without altering corneal structure, thereby normalizing the composite index and predicting slowed GrimAge change over six months.

Experimental Design

• Recruit 200 participants, stratify by age decade.
• Measure: corneal mechanical detection threshold (non‑contact esthesiometry), tear IL‑6, TNF‑α, IL‑1β (ELISA), circulating leukocyte mtDNA copy number, heart‑rate variability (RMSSD) as vagal tone proxy, and baseline GrimAge.
• Follow 12 months, repeat GrimAge and ocular measures.
• Analyze using linear mixed models, adjusting for sex, BMI, smoking.
• Falsification: if the composite index fails to improve prediction of GrimAge change over threshold alone (ΔR² < 0.02, p > 0.05), the hypothesis is rejected.

Implications

A simple office‑based esthesiometry combined with point‑of‑care tear cytokine assay could yield a low‑cost biological‑age readout that captures neuroimmune aging missed by current clocks.

References

[1] https://pubmed.ncbi.nlm.nih.gov/36730377/ [2] https://escrs.org/channels/eurotimes-articles/how-ageing-can-affect-the-cornea [3] https://iovs.arvojournals.org/article.aspx?articleid=2737202 [4] https://pmc.ncbi.nlm.nih.gov/articles/PMC12609739/ [5] https://pmc.ncbi.nlm.nih.gov/articles/PMC4771192/ [6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710972/ [7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12609739/ [8] https://pubmed.ncbi.nlm.nih.gov/11080534/