A cell non-autonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism

Enriquez-Hesles, Elisa; Smith, Daniel L.; Maqani, Nazif; Wierman, Margaret B.; Sutcliffe, Matthew D.; Fine, Ryan D.; Kalita, Agata; Santos, Sean M.; Muehlbauer, Michael J.; Bain, James R.; Janes, Kevin A.; Hartman, John L.; Hirschey, Matthew D.; Smith, Jeffrey S.

doi:10.1101/2020.07.13.200493

Cited by 2 publications

(1 citation statement)

References 93 publications

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“…For example, serine levels have been shown to impact senescence (note the oxidative stress-induced senescence term in Fig. 4b) (42), and enzymes in the glycolytic pathway such as lactate dehydrogenase A (LDHA) have been shown to be important in immune cell activation (43). Intriguingly, the biological responses associated with these metabolites and those that are also observed in stunted children have been shown to be at least partially reversed by metabolite supplementation (38,42,44).…”

Section: Discussionmentioning

confidence: 99%

Histone H3 lysine 27 acetylation profile undergoes two global shifts in undernourished children and suggests one-carbon metabolite insufficiency

Kupkova

Haque

et al. 2021

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Background: Stunting is a condition in which a child does not reach their full growth potential due to chronic undernutrition. It arises during the first two years of a child's life and is associated with developmental deficiencies and life-long health problems. Current interventions provide some benefit, but new approaches to prevention and treatment grounded in a molecular understanding of stunting are needed. Epigenetic analyses are critical as they can provide insight into how signals from a poor environment lead to changes in cell function. Results: Here we profiled histone H3 acetylation on lysine 27 (H3K27ac) in peripheral blood mononuclear cells (PBMCs) of 18-week-old and one-year-old children living in an urban slum in Dhaka, Bangladesh. We show that 18-week-old children destined to become stunted have elevated levels of H3K27ac overall, functional analysis of which indicates activation of the immune system and stress response pathways as a primary response to a poor environment with high pathogen load. Conversely, overt stunting at 1-year-of age is associated with globally reduced H3K27ac that is indicative of metabolic rewiring and downregulation of the immune system and DNA repair pathways that are likely secondary responses to chronic exposure to a poor environment with limited nutrients. The results from one-year-old children also point toward deficiency in one-carbon metabolism, which is further supported by integrative analysis with results from histone H3 trimethylation on lysine 4 (H3K4me3). Conclusions: The epigenomes of stunted children undergo two global changes in H3K27ac within their first year of life, which are associated with probable initial hyperactive immune responses followed by reduced metabolic capacity. Limitation of one-carbon metabolites may play a key role in the development of stunting.

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Section: Discussionmentioning

confidence: 99%

Histone H3 lysine 27 acetylation profile undergoes two global shifts in undernourished children and suggests one-carbon metabolite insufficiency

Kupkova

Haque

et al. 2021

Preprint

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Enhancing lifespan of budding yeast by pharmacological lowering of amino acid pools

Hepowit

Macêdo

Young

et al. 2020

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The increasing prevalence of age-related diseases and resulting healthcare insecurity and emotional burden require novel treatment approaches. Several promising strategies seek to limit nutrients and promote healthy aging. Unfortunately, the human desire to consume food means this strategy is not practical for most people but pharmacological approaches might be a viable alternative. We previously showed that myriocin, which impairs sphingolipid synthesis, increases lifespan in Saccharomyces cerevisiae by modulating signaling pathways including the target of rapamycin complex 1 (TORC1). Since TORC1 senses cellular amino acids, we analyses amino acid pools and identified 17 that are lowered by myriocin treatment. Studying the methionine transporter, Mup1, we found that newly synthesized Mup1 traffics to the plasma membrane and is stable for several hours but is inactive in drug-treated cells. Activity can be restored by adding phytosphingosine to culture medium thereby bypassing drug inhibition, thus confirming a sphingolipid requirement for Mup1 activity. Importantly, genetic analysis of myriocin-induced longevity revealed a requirement for the Gtr1/2 (mammalian Rags) and Vps34-Pib2 amino acid sensing pathways upstream of TORC1, consistent with a mechanism of action involving decreased amino acid availability. These studies demonstrate the feasibility of pharmacologically inducing a state resembling amino acid restriction to promote healthy aging.

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A cell non-autonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism

Cited by 2 publications

References 93 publications

Histone H3 lysine 27 acetylation profile undergoes two global shifts in undernourished children and suggests one-carbon metabolite insufficiency

Histone H3 lysine 27 acetylation profile undergoes two global shifts in undernourished children and suggests one-carbon metabolite insufficiency

Enhancing lifespan of budding yeast by pharmacological lowering of amino acid pools

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