Our Research

As amyloid beta targeting has shown limitations and controversy remains around cytotoxic species, we are investigating whether metabolic dysfunction represents a key underlying risk factor for Alzheimer’s disease that could be modulated therapeutically. Evidence suggests metabolic abnormalities associated with aging, obesity, and lack of dietary restriction contribute to neurodegeneration and increased disease risk, warranting further study into metabolic dysfunction’s role and the potential for intervention.

CREB-regulated transcriptional coactivators (CRTCs), direct AMPK targets involved in diverse processes from metabolism to learning, were found to aberrantly cause diseases of nutrition when discovered in mammals. We identified the sole C. elegans ortholog CRTC-1 as a nutrient-responsive longevity switch downstream of AMPK, and are continuing exploration of its novel roles in aging, disease, and broader metabolic impact. 

Our work has demonstrated that the nutrient-responsive kinase AMPK extends lifespan by cell non-autonomously regulating the transcriptional cofactor CRTC-1 in neurons to modulate catecholamine signaling. Using C. elegans, we showed AMPK promotes healthy aging via CRTC-1 rather than mTOR, and that targeting energy perception rather than levels benefits aging via neural CRTC-1, uncoupling positive effects from pleiotropy. We continue exploring downstream targets of AMPK and molecular links between metabolism, signaling, and longevity.

Our research has revealed neural CRTC-1 drives mitochondrial fission cell non-autonomously, inhibiting metabolism and modulating lifespan, demonstrating a link between the dynamic state of mitochondrial networks and aging. We also showed the ancestral circadian regulator Bmal1/AHA-1 promotes C. elegans longevity by promoting mitochondrial fusion, establishing a connection between circadian rhythms, mitochondrial dynamics and healthspan.

Dietary restriction (DR) prolongs healthy lifespan across species by delaying age-related diseases while imposing side effects, motivating our aim to elucidate DR’s molecular mechanisms to develop therapeutics. Using model organisms, we determine genetic pathways governing DR’s benefits on pathology separately from detriments, informing multi-target drugs for human disorders by capitalizing on evolutionary conservation of the DR response. 

While the nervous system orchestrates whole-body metabolism, its role in regulating organismal aging is an emerging area of focus. A growing number of longevity factors like dietary restriction, sirtuins, insulin signaling and AMPK act through neuronal mechanisms, indicating the brain helps coordinate systemic aging. We study how neuronal energy and nutrient sensing integrates extrinsic and intrinsic signals to communicate with peripheral tissues and modulate the aging rate, establishing the nervous system as a promising therapeutic target for healthy aging and age-related diseases. 

Aging results from decreased cellular homeostasis, undermining the central dogma of DNA to RNA to protein. A key mechanism generating proteome complexity is alternative RNA splicing, producing protein variants from single genes, though vulnerable to age-related dysfunction. We study how splicing machinery deterioration drives aging and how longevity interventions like dietary restriction act partly by preserving splicing fidelity, maintaining the conversion of genetic information into functional proteins during aging.