The incidence of traumatic brain injury (TBI) increases dramatically with advanced age and accumulating evidence indicates that age is one of the important predictors of an unfavorable prognosis after brain trauma. Unfortunately, thus far, evidence-based effective therapeutics for geriatric TBI is limited. By using middle-aged animals, we first confirm that there is an age-related change in TBI susceptibility manifested by increased inflammatory events, neuronal death and impaired functional outcomes in motor and cognitive behaviors. Since thyroid hormones function as endogenous regulators of oxidative stress, we postulate that age-related thyroid dysfunction could be a crucial pathology in the increased TBI severity. By surgically removing the thyroid glands, which recapitulates the age-related increase in TBI-susceptible phenotypes, we provide direct evidence showing that endogenous thyroid hormone-dependent compensatory regulation of antioxidant events modulates individual TBI susceptibility, which is abolished in aged or thyroidectomized individuals. The antioxidant capacity of melatonin is well-known, and we found acute melatonin treatment but not liothyronine (T3) supplementation improved the TBI-susceptible phenotypes of oxidative stress, excitotoxic neuronal loss and promotes functional recovery in the aged individuals with thyroid dysfunction. Our study suggests that monitoring thyroid function and acute administration of melatonin could be feasible therapeutics in the management of geriatric-TBI in clinic.

Traumatic brain injury (TBI) in the elderly is frequently associated with worsened neurological outcomes and prolonged recovery, yet the age-specific molecular mechanisms driving this vulnerability remain poorly understood. Aging is characterized by increased oxidative stress and chronic neuro-inflammation, both of which may amplify the brain’s susceptibility to injury. In this study, we identify spermine oxidase (SMOX), a polyamine-catabolizing enzyme that produces reactive oxygen species, as a key mediator linking oxidative stress and neuro-inflammation to age-dependent TBI susceptibility. Using a mouse model of controlled cortical impact (CCI), we found that SMOX expression was significantly upregulated in aged brains, primarily in neurons and microglia, and this increase correlated with greater microglial activation, elevated pro-inflammatory cytokine expression, and widespread neuronal degeneration. Notably, SMOX upregulation also impaired astrocytic glutamate clearance by disrupting the membrane localization of the transporter GLT-1, contributing to excitotoxic stress. Importantly, analysis of postmortem human brain samples and transcriptomic data revealed a parallel age-related increase in SMOX expression, supporting its translational relevance. The pharmacological inhibition of SMOX with JNJ-9350 in aged mice reduced oxidative and inflammatory markers, preserved neuronal viability, and improved motor, cognitive, and emotional outcomes up to 30 days post-injury. These findings establish SMOX as a critical molecular driver of age-related vulnerability to TBI and highlight its inhibition as a promising therapeutic strategy for improving outcomes in elderly TBI patients.

Antibody-based therapeutics have transformed the management of several vision-threatening ocular diseases by enabling targeted modulation of pathological angiogenesis, inflammation, and disease-associated molecular pathways. However, their clinical effectiveness remains constrained by anatomical and physiological barriers that limit ocular tissue penetration, therapeutic durability, and treatment accessibility. This review provides a comprehensive overview of antibody and related biologic therapeutics across six major ocular disease domains: age-related macular degeneration (AMD), diabetic retinopathy (DR) and diabetic macular edema (DME), retinal vein occlusion (RVO), uveitis, glaucoma, and thyroid eye disease (TED). We first discuss the molecular mechanisms underlying their therapeutic actions, including inhibition of angiogenic signaling, modulation of inflammatory and immune pathways, complement inhibition, and regulation of apoptosis and fibrosis. We then summarize the clinical applications of established and emerging biologic therapies, highlighting their molecular targets, therapeutic outcomes, and limitations. Particular emphasis is placed on advances in antibody engineering and ocular drug delivery, including bispecific antibodies, Fc engineering, antibody–drug conjugates, sustained-release systems, and targeted delivery platforms. Despite substantial progress, repeated administration, variable therapeutic responses, and limited treatment durability remain important challenges. Integrating next-generation biologic platforms with innovative ocular delivery technologies may support more effective, durable, and individualized therapeutic strategies for ocular diseases.