An antisteatosis response regulated by oleic acid through lipid droplet-mediated ERAD enhancement.

Although excessive lipid accumulation is a hallmark of obesity-related pathologies, some lipids are beneficial. Oleic acid (OA), the most abundant monounsaturated fatty acid (FA), promotes health and longevity. Here, we show that OA benefits Caenorhabditis elegans by activating the endoplasmic reticulum (ER)-resident transcription factor SKN-1A (Nrf1/NFE2L1) in a lipid homeostasis response. SKN-1A/Nrf1 is cleared from the ER by the ER-associated degradation (ERAD) machinery and stabilized when proteasome activity is low and canonically maintains proteasome homeostasis. Unexpectedly, OA increases nuclear SKN-1A levels independently of proteasome activity, through lipid droplet-dependent enhancement of ERAD. In turn, SKN-1A reduces steatosis by reshaping the lipid metabolism transcriptome and mediates longevity from OA provided through endogenous accumulation, reduced H3K4 trimethylation, or dietary supplementation. Our findings reveal an unexpected mechanism of FA signal transduction, as well as a lipid homeostasis pathway that provides strategies for opposing steatosis and aging, and may mediate some benefits of the OA-rich Mediterranean diet.

Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity.

Chronic inflammation predisposes to aging-associated disease, but it is unknown whether immunity regulation might be important for extending healthy lifespan. Here we show that in C. elegans, dietary restriction (DR) extends lifespan by modulating a conserved innate immunity pathway that is regulated by p38 signaling and the transcription factor ATF-7. Longevity from DR depends upon p38-ATF-7 immunity being intact but downregulated to a basal level. p38-ATF-7 immunity accelerates aging when hyperactive, influences lifespan independently of pathogen exposure, and is activated by nutrients independently of mTORC1, a major DR mediator. Longevity from reduced insulin/IGF-1 signaling (rIIS) also involves p38-ATF-7 downregulation, with signals from DAF-16/FOXO reducing food intake. We conclude that p38-ATF-7 is an immunometabolic pathway that senses bacterial and nutrient signals, that immunity modulation is critical for DR, and that DAF-16/FOXO couples appetite to growth regulation. These conserved mechanisms may influence aging in more complex organisms.

Limited Alzheimer-type neurodegeneration in experimental obesity and type 2 diabetes mellitus.

Alzheimer's disease (AD) is associated with brain insulin resistance and insulin deficiency, whereas Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance. This study assesses the degree to which T2DM causes AD-type neurodegeneration. In a C57BL/6 mouse model of obesity and T2DM, we characterized the histopathology, gene expression, and insulin and insulin-like growth factor (IGF)-receptor binding in temporal lobe. High fat diet (HFD) feeding for 16 weeks doubled mean body weight, caused T2DM, and marginally reduced mean brain weight. These effects were associated with significantly increased levels of tau, IGF-I receptor, insulin receptor substrate-1 (IRS-1), IRS-4, ubiquitin, glial fibrillary acidic protein, and 4-hydroxynonenol, and decreased expression of beta-actin. HFD feeding also caused brain insulin resistance manifested by reduced BMAX for insulin receptor binding, and modestly increased brain insulin gene expression. However, HFD-fed mouse brains did not exhibit AD histopathology, increases in amyloid-beta or phospho-tau, or impairments in IGF signaling or acetylcholine homeostasis. Obesity and T2DM cause brain atrophy with insulin resistance, oxidative stress, and cytoskeleton degradation, but the absence of many features that typify AD suggests that obesity and T2DM may contribute to, but are not sufficient to cause AD.

Dietary restriction involves NAD⁺ -dependent mechanisms and a shift toward oxidative metabolism.

Interventions that slow aging and prevent chronic disease may come from an understanding of how dietary restriction (DR) increases lifespan. Mechanisms proposed to mediate DR longevity include reduced mTOR signaling, activation of the NAD⁺ -dependent deacylases known as sirtuins, and increases in NAD⁺ that derive from higher levels of respiration. Here, we explored these hypotheses in Caenorhabditis elegans using a new liquid feeding protocol. DR lifespan extension depended upon a group of regulators that are involved in stress responses and mTOR signaling, and have been implicated in DR by some other regimens [DAF-16 (FOXO), SKN-1 (Nrf1/2/3), PHA-4 (FOXA), AAK-2 (AMPK)]. Complete DR lifespan extension required the sirtuin SIR-2.1 (SIRT1), the involvement of which in DR has been debated. The nicotinamidase PNC-1, a key NAD⁺ salvage pathway component, was largely required for DR to increase lifespan but not two healthspan indicators: movement and stress resistance. Independently of pnc-1, DR increased the proportion of respiration that is coupled to ATP production but, surprisingly, reduced overall oxygen consumption. We conclude that stress response and NAD⁺ -dependent mechanisms are each critical for DR lifespan extension, although some healthspan benefits do not require NAD⁺ salvage. Under DR conditions, NAD⁺ -dependent processes may be supported by a DR-induced shift toward oxidative metabolism rather than an increase in total respiration.

mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity.

The nematode worm Caenorhabditis elegans provides a powerful system for elucidating how genetic, metabolic, nutritional, and environmental factors influence aging. The mechanistic target of rapamycin (mTOR) kinase is important in growth, disease, and aging and is present in the mTORC1 and mTORC2 complexes. In diverse eukaryotes, lifespan can be increased by inhibition of mTORC1, which transduces anabolic signals to stimulate protein synthesis and inhibit autophagy. Less is understood about mTORC2, which affects C. elegans lifespan in a complex manner that is influenced by the bacterial food source. mTORC2 regulates C. elegans growth, reproduction, and lipid metabolism by activating the SGK-1 kinase, but current data on SGK-1 and lifespan seem to be conflicting. Here, by analyzing the mTORC2 component Rictor (RICT-1), we show that mTORC2 modulates longevity by activating SGK-1 in two pathways that affect lifespan oppositely. RICT-1/mTORC2 limits longevity by directing SGK-1 to inhibit the stress-response transcription factor SKN-1/Nrf in the intestine. Signals produced by the bacterial food source determine how this pathway affects SKN-1 and lifespan. In addition, RICT-1/mTORC2 functions in neurons in an SGK-1-mediated pathway that increases lifespan at lower temperatures. RICT-1/mTORC2 and SGK-1 therefore oppose or accelerate aging depending upon the context in which they are active. Our findings reconcile data on SGK-1 and aging, show that the bacterial microenvironment influences SKN-1/Nrf, mTORC2 functions, and aging, and identify two longevity-related mTORC2 functions that involve SGK-regulated responses to environmental cues.