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Cellular stress is an ever-present aspect of aging and a primary driver of many common age-associated diseases such as cancer, diabetes, or neurodegenerative diseases. As we age, stress-induced damage accumulates over time, along with reduced efficacy of stress response pathways at combatting such damage. Molecular stress response pathways are well studied in the context of individual stressors, but there is a lack of understanding of how these responses change when multiple stressors are encountered at the same time. The goal of our work is to explore the impact of multiple simultaneous stressors on health and survival, and to investigate the underlying molecular pathways involved. To accomplish this, we utilize the nematode Caenorhabditis elegans to monitor lifespan changes in response to various stressors. We simultaneously exposed C. elegans to high concentrations of sodium chloride and cadmium chloride, known to induce osmotic and heavy metal stress, respectively. We found that lifespan is drastically decreased by the combined stress, significantly more so than the reduction in lifespan caused by either individual stress. Our results show that glycerol levels, which are normally increased in response to osmotic stress, are significantly lowered when the two stresses are combined compared to levels detected for osmotic stress alone. This suggests that the presence of cadmium may sensitize worms to sodium and other osmotic stressors by blunting cells’ ability to mount an appropriate molecular response. In ongoing work, we will continue to dissect the mechanisms through which cadmium influences glycerol production and other aspects of osmotic stress response.

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Select kynurenine pathway interventions extend lifespan in invertebrate models and are of interest in treating age-associated diseases. Kynurenine pathway activity is responsive to inflammatory signaling, and we are evaluating the potential for these interventions to increase pathogen resistance and curtail age-associated immune decline in Caenorhabditis elegans and mammals. The kynurenine pathway facilitates the catabolism of tryptophan to nicotinamide adenine dinucleotide (NAD). Our lab has found that supplementing the kynurenine metabolite 3-hydroxyanthranilic acid (3HAA) or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends lifespan in C. elegans. 3HAA has demonstrated pro/anti-inflammatory properties in mammals, suggesting a potential role in immune function. C. elegans have a primitive immune system that lacks an adaptive element, but it recapitulates aspects of innate immune signaling and pathogen response. I hypothesize kynurenine pathway interventions that impact C. elegans’ lifespan similarly improve pathogen resistance and immunity. Interventions within the kynurenine pathway are capable of differentially impacting pathogenesis and lifespan of C. elegans challenged with Psuedomonas aeruginosa. C. elegans subjected to select lifespan-extending kynurenine pathway interventions fared better when challenged with P. aeruginosa at older ages. Additionally, fluorescent infection tracking has displayed decreased infection rates in worms with elevated 3HAA. Our data suggests pro-immune activity is facilitated by 3HAA acting downstream of the dbl-1 pathway in addition to directly inhibiting bacterial growth. Our goal is to discover the mechanism(s) through which the kynurenine pathway interacts with immune function in animals and identify potential targets for clinical therapy in aging populations.

Cells are constantly subjected to a variety of intrinsic and extrinsic stresses—oxidative, protein misfolding, osmotic—and respond by activating a range of molecular pathways to mitigate and repair damage—oxidative stress response, unfolded protein response, osmotic stress response. While individual stress response pathways have been described in detail, and some interventions improve resistance to multiple forms of stress (e.g. dietary restriction, insulin signaling inhibition), surprisingly little is known about how these responses differ when cells are challenged with multiple types of stress simultaneously. The molecular architecture underlying multi-stress response has broad implications for aging and age-associated disease. One characteristic of aging is a progressive increase in multiple categories of cellular stress accompanied by a decline in cellular stress response capability. Human diseases rarely involve a single form of stress—Alzheimer’s disease is characterized by neuroinflammation, oxidative stress, and misfolded proteins, while cancer exhibits oxidative stress, DNA damage, and localized hypoxia. Determining how cells respond differently to one form of stress in the presence of another is critical to building an accurate model of the aging cellular environment. We are using Caenorhabditis elegans to systematically evaluate the molecular network that cells employ when challenged by multiple simultaneous stressors and how different stress combinations impact organismal survival and health. Here we present our initial characterization of C. elegans response to multiple categories of cellular stress (oxidative, osmotic, ER, Golgi, heavy metal), which stressors elicit non-additive interactions when combined, and how these combinations impact survival, health, and established stress response pathways.