An Overlooked Steroid Hormone as a Driver of Cognitive Resilience - PROJECT SUMMARY Aging is accompanied by progressive cognitive decline and is the greatest risk factor for Alzheimer’s disease and related dementias (AD/ADRD). Narrowing the healthspan–lifespan gap is a central goal of aging research, with cognitive decline a key indicator of healthspan deterioration. This exploratory proposal investigates the steroid hormone androst-5-ene-3β,17β-diol (ADIOL) as a novel regulator of cognitive capacity in mammals. Discovered in humans nearly a century ago, ADIOL remains largely overlooked, with poorly defined physiological roles. In C. elegans, we recently discovered that elevating ADIOL levels markedly enhances learning and memory, including in aged animals. Dietary restriction, which improves learning across species, increases ADIOL levels, yet ADIOL treatment alone does not extend lifespan, demonstrating that its cognitive benefits are independent of lifespan regulation. Mechanistically, ADIOL acts through estrogen receptor beta (ERβ) in the worm’s nervous system to suppress accumulation of kynurenine pathway (KP) metabolites, thereby enhancing activity of NMDA receptor–expressing neurons. The effects of KP metabolites on C. elegans learning parallel their roles in mammalian neural energetics, synaptic plasticity, and memory. In mammals, excessive KP metabolite accumulation contributes to age- and disease-related cognitive deficits, highlighting KP modulation as a promising therapeutic strategy. ADIOL’s ability to regulate this pathway is a novel mechanistic insight. We posit that ADIOL, acting via ERβ, promotes cognitive resilience by preventing harmful KP metabolite buildup. To test this, we will conduct mechanistic studies in mice and correlative studies in humans. In mice, we have shown that systemic ADIOL treatment accelerates acquisition of a cue–reward Pavlovian conditioning task in both sexes. Using ERβ pharmacology, fiber photometry, and two-photon calcium imaging, we will determine whether ADIOL’s effects require neural ERβ, modulate mesolimbic dopamine circuitry, and enhance NMDA- dependent neural activity. We will also test whether ADIOL reduces KP metabolite accumulation and whether fasting elevates endogenous ADIOL levels. In parallel, we will quantify ADIOL, related steroids, and KP metabolites in plasma from 80 deeply phenotyped, sex-balanced adults (ages 40–79) from the UCSF Hillblom Brain Aging Cohort using validated mass spectrometry assays. These samples have already been collected. Steroid hormones profoundly influence human physiology and cognition, yet ADIOL remains mostly unstudied. Given the paucity of interventions for cognitive decline, this work may uncover a previously unrecognized steroid-based mechanism to enhance cognitive healthspan and reduce vulnerability to AD/ADRD.
