Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression. — VialBase Research

Summary

This study investigated the role of senescent cells in pulmonary hypertension using human pulmonary arterial hypertension (PAH) lung tissue alongside several animal models, and reached a conclusion that runs directly against the prevailing senolytic-as-anti-aging narrative. Patients with PAH showed high lung p16, p21, and γ-H2AX protein levels relative to controls, with abundant vascular cells costaining for p16, γ-H2AX, and 53BP1; hypoxia likewise increased senescence and DNA-damage markers, senescence-associated secretory phenotype (SASP) components, and p16 staining of pulmonary endothelial cells (P-ECs) and pulmonary artery smooth muscle cells in mice. The investigators then removed senescent cells by four independent routes — a p16 promoter-driven suicide gene in p16-ATTAC mice, the senolytic drug ABT263, the cell-permeable FOXO4-p53 interfering peptide FOXO4-DRI, and p16 inactivation. Rather than protecting the pulmonary vasculature, senescent cell clearance increased right ventricular systolic pressure and the hypertrophy index, increased vessel remodeling, and markedly decreased lung P-ECs. Specifically, SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI developed pulmonary hemodynamic alterations and P-EC loss compared with relevant controls. In monocrotaline-treated rats, ABT263 modestly reduced pulmonary hypertension severity at 1 week but aggravated it by 3 weeks, again with P-EC loss. The authors concluded that eliminating senescent pulmonary endothelial cells with senolytic interventions may worsen pulmonary hemodynamics, and explicitly invited caution about the pulmonary vascular impact of any strategy aimed at controlling cell senescence.

Key Findings

• Patients with PAH exhibited elevated lung p16, p21, and γ-H2AX protein compared with controls, with abundant vascular cells costained for p16, γ-H2AX, and 53BP1 — confirming senescent cells are present in diseased human pulmonary vasculature
• Hypoxia increased thoracic bioluminescence in p16-luciferase (p16LUC/+) knock-in mice and raised lung senescence markers, DNA-damage markers, SASP components, and p16 staining of pulmonary endothelial cells and pulmonary artery smooth muscle cells
• Pulmonary endothelial cells represented approximately 30% of lung senescent cells under normoxic conditions
• Senescent cell elimination by suicide gene or ABT263 increased right ventricular systolic pressure and the hypertrophy index, increased vessel remodeling (higher dividing PCNA-stained vascular cell counts in both normoxia and hypoxia), and markedly decreased lung P-ECs
• FOXO4-DRI specifically: SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI showed pulmonary hemodynamic alterations and lung P-EC loss versus relevant controls — the same adverse pattern as the other senolytic modalities
• Pulmonary hemodynamic alterations and P-EC loss also occurred in older p16LUC/LUC mice and in wild-type mice exposed to Sugen or hypoxia+Sugen
• In monocrotaline-induced pulmonary hypertension in rats, ABT263 decreased severity slightly at 1 week but aggravated it at 3 weeks, with loss of P-ECs
• Stated conclusion: elimination of senescent P-ECs by senolytic interventions may worsen pulmonary hemodynamics

Relevance to Foxo4-DRI

This is the single most important safety document in the current evidence base, because it tests Foxo4-DRI by name and reports harm rather than benefit. The senolytic premise sold to consumers — that clearing senescent cells is broadly rejuvenating — does not hold in the pulmonary vasculature, where roughly a third of senescent cells under normal conditions are endothelial cells that the vessel wall apparently needs. Removing them with FOXO4-DRI or ABT263 produced hemodynamic deterioration and endothelial loss across multiple independent models, and the monocrotaline rat data show the effect can look protective early and turn harmful with continued exposure. Anyone reading the enthusiastic senescent-Leydig-cell and senescent-chondrocyte findings should read this alongside them: the same mechanism that selectively kills senescent cells in a culture dish is not organ-neutral in a living animal, and there are no human trials of FOXO4-DRI that would tell us whether this pulmonary signal translates. This paper should be treated as an active argument for caution, not as one more entry on a list of FOXO4-DRI research.

Citation

Born E, Lipskaia L, Breau M, et al. Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression. Circulation. 2023;147(8):650-666. doi:10.1161/CIRCULATIONAHA.122.058794.

See Also

• Parent compound: Foxo4-DRI