A Nutrition-Longevity Tradeoff Enforced by Innate Immunity

Wani, Khursheed Ahmad; Goswamy, Debanjan; Irazoqui, Javier E.

doi:10.1016/j.molcel.2019.05.012

Cited by 3 publications

(4 citation statements)

References 11 publications

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“…The innate immune response genes are constitutively activated by pgph-2 o/e, further supporting the CR-mimetic role of the glycerol shunt in promoting healthy aging. In accordance, recent advances highlight the role of CR in activating the innate immune response and the association between innate immunity and healthy longevity across taxa 20,[39][40][41][42]74 . HLH-30/TFEB and DAF-16/FOXO have been demonstrated to act as combinatorial transcription factors to promote resistance to stress and extend lifespan 30 .…”

Section: Discussionmentioning

confidence: 89%

“…3c and Supplementary Data 3). Noticeably, innate immune response terms such as 'defense to bacterium' or 'defense to external stimuli' are also enriched, supporting a role for pgph-2 in the promotion of healthy aging [39][40][41][42] and the possible involvement of hlh-30 in this response (Fig. 3c).…”

Section: Rna-seq Analysis Reveals Catabolic and Longevity Signatures ...mentioning

confidence: 81%

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Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans

Possik,

Klein,

Sanjab

et al. 2023

Nat Commun

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Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here, we show that the overexpression of the C. elegans G3PP homolog, PGPH-2, decreases fat levels and mimics, in part, the beneficial effects of calorie restriction, particularly in glucotoxicity conditions, without reducing food intake. PGPH-2 overexpression depletes glycogen stores activating AMP-activate protein kinase, which leads to the HLH-30 nuclear translocation and activation of autophagy, promoting healthy aging. Transcriptomics reveal an HLH-30-dependent longevity and catabolic gene expression signature with PGPH-2 overexpression. Thus, G3PP overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and may be an attractive target for age-related metabolic disorders linked to excess nutrients.

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Section: Discussionmentioning

confidence: 89%

Section: Rna-seq Analysis Reveals Catabolic and Longevity Signatures ...mentioning

confidence: 81%

Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans

Possik,

Klein,

Sanjab

et al. 2023

Nat Commun

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“…A tightly controlled immune activation is critical because its dysregulation has a major impact on a number of vital biological functions (Bird, 2019;Ganeshan et al, 2019;Jung et al, 2019;Kuchroo et al, 2012;Libert et al, 2006). In addition, the significant metabolic challenge posed by immune activation, immunopathology, and immune homeostasis necessitates an allocation of nutrients and energy that may lead to shortened longevity (Ayres, 2020;Bä ckhed et al, 2019;Franceschi et al, 2018;Kaiser et al, 2020;Riera and Dillin, 2015;Solana et al, 2006;Tracey, 2002;Wani et al, 2019;Wu et al, 2019). Hence, the imbalance caused by immune activation results in a tradeoff between immunity and longevity that is evolutionarily conserved throughout the animal kingdom.…”

Section: Introductionmentioning

confidence: 99%

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

Otarigho

Aballay

2021

Cell Reports

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A body of evidence indicates that metazoan immune and aging pathways are largely interconnected, but the mechanisms involved in their homeostatic control remain unclear. In this study, we find that the PITX (pairedlike homeodomain) transcription factor UNC-30 controls the tradeoff between immunity and longevity from the nervous system in Caenorhabditis elegans. PITX/UNC-30 functional loss enhances immunity in a GATA/ELT-2-and p38 MAPK/PMK-1-dependent manner and reduced longevity by activating MXD/MDL-1 and the C2H2-type zinc finger transcription factor PQM-1. The immune inhibitory and longevity stimulatory functions of PITX/UNC-30 require the sensory neuron ASG and a signaling pathway controlled by NPR-1, which is a G protein-coupled receptor related to mammalian neuropeptide Y receptors. Our findings uncover a suppressive role of GABAergic signaling in the neural control of a biological tradeoff where energy is allocated toward immunity at the expense of longevity.

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“…A tightly controlled immune activation is critical as its dysregulation has a major impact on a number of vital biological functions (Bird, 2019; Ganeshan et al, 2019; Jung et al, 2019; Kuchroo et al, 2012; Libert et al, 2006). In addition, the significant metabolic challenge posed by immune activation, immunopathology, and immune homeostasis necessitates an allocation of nutrients and energy that may lead to shortened longevity (Ayres, 2020; Backhed et al, 2019; Franceschi et al, 2018; Kaiser et al, 2020; Riera and Dillin, 2015; Solana et al, 2006; Tracey, 2002; Wani et al, 2019; Wu et al, 2019). Hence, the imbalance caused by immune activation results in a tradeoff between immunity and longevity that is evolutionarily conserved throughout the animal kingdom.…”

Section: Introductionmentioning

confidence: 99%

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

Otarigho

Aballay

2021

Preprint

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A body of evidence indicates that metazoan immune and aging pathways are largely interconnected, but the mechanisms involved in their homeostatic control remain unclear. In this study, we found that the PITX (paired like homeodomain) transcription factor UNC-30 controls the tradeoff between immunity and longevity from the nervous system in Caenorhabditis elegans. PITX/UNC-30 functional loss enhanced immunity in a GATA/ELT-2- and p38 MAPK/PMK-1-dependent manner and reduced longevity by activating the MXD/MDL-1 and PQM-1 pathways. The immune inhibitory and longevity stimulatory functions of PITX/UNC-30 required the sensory neuron ASG and a neurotransmitter signaling pathway controlled by NPR-1, which is a G protein-coupled receptor related to mammalian neuropeptide Y receptors. Our findings uncovered a suppressive role of GABAergic signaling in the neural control of a biological tradeoff where energy is allocated towards immunity at the expense of longevity.

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A Nutrition-Longevity Tradeoff Enforced by Innate Immunity

Cited by 3 publications

References 11 publications

Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans

Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

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