Biology subjects

Kitto, E. S.

Publications and source records attributed to Kitto, E. S..

3 recordsLinked to original sources

bioRxiv2025

The hypoxic response extends lifespan through a bioaminergic and peptidergic neural circuit.

A coordinated response to stress is crucial for promoting the short- and long-term health of an organism. The perception of stress, frequently through the nervous system, can lead to physiological changes that are fundamental to maintaining homeostasis. Activating the response to low oxygen, or hypoxia, extends healthspan and lifespan in C. elegans. However, despite some positive impacts, negative effects of the hypoxic response in specific tissues prevent translation of their benefits in mammals. Thus, it is imperative to identify which components of this response promote longevity. Here, we interrogate the cell-nonautonomous signaling pathway downstream of genetic activation of the hypoxic response. We find that HIF-1-mediated signaling in ADF serotonergic neurons is both necessary and sufficient for lifespan extension. Signaling through the serotonin receptor SER-7 in the GABAergic RIS interneurons is necessary in this process. Our findings also highlight the involvement of additional neural signaling molecules, including the neurotransmitters tyramine and GABA, and the neuropeptide NLP-17, in mediating longevity effects. Finally, we demonstrate that oxygen- and carbon-dioxide-sensing neurons act downstream of HIF-1 in this circuit. Together, these insights develop a circuit for how genetic induction of the hypoxic response cell-nonautonomously modulates aging and suggests valuable targets for modulating aging in mammals.

physiology↗

bioRxiv2024

fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.

genetics↗

bioRxiv2024

Food touch limits lifespan through bioamine and neuroendocrine signaling.

In multicellular organisms, sensory perception affects many aspects of behavior and physiology. Sensory cues are frequently perceived by the nervous system, which in turn coordinates systemic changes that can modulate health. Here we find that the sense of touch interacts with nutritional state to modulate lifespan in C. elegans. Worms subjected to dietary restriction are shorter-lived when they perceive tactile stimuli that mimic bacterial food and protective soil. Touch modulation of dietary restriction requires primary mechanoreceptors, the neurotransmitters dopamine and tyramine/adrenaline, and the neuropeptides insulin and GnRH. Ultimately, the touch circuit regulates the longevity effectors DAF-2/IGF1R and FMO-2/FMO5. These results establish a physiological touch circuit and connect neural reward pathways to the growth and reproductive axes. Finding that gentle touch can modulate longevity suggests a role for physical comfort in healthspan and lifespan.

physiology↗