Serotonin deficiency from constitutive SKN-1 activation drives pathogen apathy.

When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defense capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals new insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival. KEY POINTS: Identify an apathy-like behavioral response for pathogens resulting from the constitutive activation of the cytoprotective transcription factor SKN-1.Uncover the obligate role for serotonin synthesis in both neuronal and non-neuronal cells for the apathy-like state and ability of serotonin treatment to restore normal behaviors.Characterize the timing and tissue specificity of SKN-1 nuclear localization in neurons and intestinal cells in response to pathogen exposure.Define the unique and context-specific transcriptional signatures of animals with constitutive SKN-1 activation when exposed to pathogenic environments.Reveal necessity for both neuronal and non-neuronal serotonin signaling in host survival from pathogen infection.

Metabolic Rewiring of Mycobacterium tuberculosis upon Drug Treatment and Antibiotics Resistance.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge, further compounded by the issue of antimicrobial resistance (AMR). AMR is a result of several system-level molecular rearrangements enabling bacteria to evolve with better survival capacities: metabolic rewiring is one of them. In this review, we present a detailed analysis of the metabolic rewiring of Mtb in response to anti-TB drugs and elucidate the dynamic mechanisms of bacterial metabolism contributing to drug efficacy and resistance. We have discussed the current state of AMR, its role in the prevalence of the disease, and the limitations of current anti-TB drug regimens. Further, the concept of metabolic rewiring is defined, underscoring its relevance in understanding drug resistance and the biotransformation of drugs by Mtb. The review proceeds to discuss the metabolic adaptations of Mtb to drug treatment, and the pleiotropic effects of anti-TB drugs on Mtb metabolism. Next, the association between metabolic changes and antimycobacterial resistance, including intrinsic and acquired drug resistance, is discussed. The review concludes by summarizing the challenges of anti-TB treatment from a metabolic viewpoint, justifying the need for this discussion in the context of novel drug discovery, repositioning, and repurposing to control AMR in TB.

Diet-gene interactions ensure optimal life span and health.

An organism encounters an extensive range of dietary choices in its niche. The macronutrient and micronutrient quotients of these diets instruct downstream molecular events, eventually orchestrating complex physiological responses that determine their life-history traits. In response to diverse nutritional inputs, organisms deploy multiple adaptive mechanisms to maintain optimal life span and health. However, we know little about these processes. Although we have come to appreciate the complex relationship between diet and genes in modulating life span in response to diverse nutritional inputs, it can be difficult to identify these interactions in the laboratory, as an organism maintains a normal life span on a wide range of diet. But in rare cases, a mutant laboratory animal, with the mutation attributable to a single gene, may display altered physiological traits on only one diet but not on others. These 'diet-gene pairs' contribute immensely to our understanding of how diet quality influences physiological traits like longevity and health.

Taurine deficiency as a driver of aging.

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.

Adaptive capacity to dietary Vitamin B12 levels is maintained by a gene-diet interaction that ensures optimal life span.

Diet regulates complex life-history traits such as longevity. For optimal lifespan, organisms employ intricate adaptive mechanisms whose molecular underpinnings are less known. We show that Caenorhabditis elegans FLR-4 kinase prevents lifespan differentials on the bacterial diet having higher Vitamin B12 levels. The flr-4 mutants are more responsive to the higher B12 levels of Escherichia coli HT115 diet, and consequently, have enhanced flux through the one-carbon cycle. Mechanistically, a higher level of B12 transcriptionally downregulates the phosphoethanolamine methyltransferase pmt-2 gene, which modulates phosphatidylcholine (PC) levels. Pmt-2 downregulation activates cytoprotective gene expression through the p38-MAPK pathway, leading to increased lifespan only in the mutant. Evidently, preventing bacterial B12 uptake or inhibiting one-carbon metabolism reverses all the above phenotypes. Conversely, supplementation of B12 to E. coli OP50 or genetically reducing PC levels in the OP50-fed mutant extends lifespan. Together, we reveal how worms maintain adaptive capacity to diets having varying micronutrient content to ensure a normal lifespan.