Transgenerational Adaptation of Longevity Changes in Response to Repeated Environmental Stresses

Adaptation to environmental stresses is crucial for survival. Our work has shown that phenotypes, such as longevity, induced by stress can be passed on across generations through transgenerational epigenetic inheritance. Transgenerational epigenetic inheritance allows organisms to respond to irregular conditions, alert their naïve descendants that stresses could still be present, and for distant descendants to eventually return to a basal state after several generations without the stress. However, it is still unclear whether organisms adapt on a transgenerational scale after repeated successive generational exposures to the same environmental stress or to successive generational exposures to different stresses. These questions have become increasingly relevant for humans. We exist in an environment where environmental toxins are routinely used in agriculture or manufacturing. When one of these toxins is identified as being harmful, a new toxin is often used to accomplish the same task, and subsequent generations are exposed to this second toxin. Are these successive generational environmental stresses additive in their transgenerational toxic effects? Surprisingly little is understood about how repeated exposures to stress across generations influences complex organismal traits. The goal of this project is to understand how repeated exposures to environmental stresses over successive generations elicits a transgenerational epigenetic adaptation which alters organismal longevity. We previously showed that hypoxia extends C. elegans lifespan in the exposed generation, causes intergenerational reduction in lipids, and a transgenerational reduction in fertility in descendants reared under normoxic conditions [1]. We have found that C. elegans adapt on a generational timescale to repeated generational hypoxia exposure. After two successive generations are exposed to hypoxia, hypoxia-exposed worms are no longer long-lived. After four successive generations are exposed to hypoxia, hypoxia-treated worms no longer lay fewer progeny than normoxic worms. RNA sequencing data across four generations repeatedly exposed to hypoxia identified genes whose expression changes underlie the adaptation of the altered longevity and fertility phenotypes. A directed genetic screen of transgenerational adaptation mediators found that deletion of two argonaute proteins accelerated transgenerational adaptation to repeated generational hypoxia. Conversely, deficiency in the H3K27 trimethyltransferase complex (MES-2 and MES-3) prevented worms from adapting. These preliminary findings have characterized the first instance of transgenerational adaptation to adverse environmental conditions over successive generations and identified molecular pathways important for transgenerational adaptation. However, whether different types of stresses can induce transgenerational adaptation to influence longevity, and how small RNAs and histone methylation can regulate this transgenerational adaptation is still unknown. This work aims to characterize mechanisms of the new phenomena of transgenerational epigenetic adaptation and begin to decipher how these epigenetic cues allow organisms to adapt to repeated stresses across generations. Project Number: 1R01AG092958-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Eric Greer | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $556,121 | Activity Code: R01 | Study Section: Cellular Mechanisms in Aging and Development Study Section[CMAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11297522