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Supplementation with cis-MUFA (oleic acid) but not trans-MUFA (elaidic acid) increases lipid droplet number and extends lifespan a, Chemical structure of the cis-MUFA oleic acid and the trans-MUFA elaidic acid. b,c, Number of intestinal lipid droplets, assessed by fluorescence, in dhs-3p::dhs-3::GFP worms following supplementation with sterically different dietary MUFAs. b, Zoomed-in images of the intestine. Scale bar, 5 µm. c, Number of lipid droplets in n = 31, 29 and 28 worms following control, dietary oleic acid and dietary elaidic acid supplementation, respectively. Data are the mean ± s.d. Each dot represents the number of puncta in a 26 × 26 µm² area in the intestine of an individual worm. P values were determined using a two-tailed Mann–Whitney test. d, Cis-MUFA (oleic acid), but not trans-MUFA (elaidic acid), extends lifespan; n ≥ 128 worms for each condition. Percentages of the median lifespan extension and P values (log-rank Mantel–Cox test) are indicated; NS, not significant. c,d, Data are representative of three (d) or four (c) independent experiments. Source data are provided. Source data
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Dietary mono-unsaturated fatty acids (MUFAs) are linked to longevity in several species. But the mechanisms by which MUFAs extend lifespan remain unclear. Here we show that an organelle network involving lipid droplets and peroxisomes is critical for MUFA-induced longevity in Caenorhabditis elegans. MUFAs upregulate the number of lipid droplets in...
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Citations
... Conversely, dietary fatty acids such as mono-unsaturated fatty acids (MUFA) are linked to longevity by upregulating both peroxisomal and lipid droplet number. Notably, PRX-5 inhibition abolishes MUFA-induced longevity in C.elegans 83 . In summary, our muscle-specific peroxisomal deficient mouse model underscores the importance of preserving peroxisomal function and their interplay with mitochondria to maintain muscle force, integrity, and innervation during the aging process. ...
Whole-body energy expenditure, as well as glucose and lipid metabolism, are regulated by skeletal muscles, which account for 40-50% of human body mass. Peroxisomes are dynamic organelles that play a crucial role in lipid metabolism and clearance of reactive oxygen species, however their role in muscles remains poorly understood.
To clarify this issue, we generated a muscle-specific transgenic mouse line with peroxisome import deficiency resulting from deletion of peroxisomal biogenesis factor 5 (Pex5). Pex5 inhibition disrupted the tethering between peroxisomes and mitochondria, impaired lipid metabolism and reduced muscle force and exercise performance. Moreover, mitochondrial content and function were also altered, accelerating age-related structural defects, neuromuscular junction degeneration, and muscle atrophy. Altogether, our findings show the importance of preserving peroxisomal function and their contact sites with mitochondria to maintain muscle health during aging.
... We found a significant reduction in the number of LDs and significant increase in the size of the LDs (Fig4C-D), supporting the observed lipid depletion phenotype ( Fig 4A,B) and impacts in LDs. To bolster these results, we took an orthogonal approach and crossed our open gate mutant into the ABR339 strain which contains endogenous lpin-1 fused to GFP, a homolog of LIPIN1, which is important for the ER membrane LD biogenesis, bud formation [68][69][70][71] and works effectively as a LD marker as proven by the co-staining in LD with Nile red (FigS4A). In agreement with the BODIPY, we found significant decrease in the number of LDs and significant increase in size (Fig4E-F). ...
... To complement our understanding of LDs remodeling in the open gate mutants, we looked into the sub-organelles, peroxisomes, which are tightly linked to LDs 68,72 . Peroxisomes not only play a pivotal role in the catabolism of long-chain and very-long-chain fatty acids, but also participate in the dynamics and composition of LDs through their involvement in the metabolism of specific lipid species that can be associated with LDs 68,72,73 . Additionally, peroxisomes are directly involved in the biosynthesis of plasmalogens, critical phospholipids for the structure and function of cellular membranes 72,74 . ...
... Additionally, peroxisomes are directly involved in the biosynthesis of plasmalogens, critical phospholipids for the structure and function of cellular membranes 72,74 . For this, we crossed the open gate mutant into the WBM1177 strain which contains a GFP fused to a peroxisome localization sequence (SKL) eft-3p::GFP-SKL 68 . Surprisingly, we observed notable changes in the morphology of the peroxisomes, characterized by significant increases in both size and number (Fig4G-H). ...
Proteasome dysfunction is implicated in the pathogenesis of neurodegenerative diseases and age-related proteinopathies. Using a C. elegans model, we demonstrate that 20S proteasome hyperactivation, facilitated by 20S gate-opening, accelerates the targeting of intrinsically disordered proteins. This leads to increased protein synthesis, extensive rewiring of the proteome and transcriptome, enhanced oxidative stress defense, accelerated lipid metabolism, and peroxisome proliferation. It also promotes ER-associated degradation (ERAD) of aggregation-prone proteins, such as alpha-1 antitrypsin (ATZ) and various lipoproteins. Notably, our results reveal that 20S proteasome hyperactivation suggests a novel role in ERAD with broad implications for proteostasis-related disorders, simultaneously affecting lipid homeostasis and peroxisome proliferation. Furthermore, the enhanced cellular capacity to mitigate proteostasis challenges, alongside unanticipated acceleration of lipid metabolism is expected to contribute to the longevity phenotype of this mutant. Remarkably, the mechanism of longevity induced by 20S gate opening appears unique, independent of known longevity and stress-resistance pathways. These results support the therapeutic potential of 20S proteasome activation in mitigating proteostasis-related disorders broadly and provide new insights into the complex interplay between proteasome activity, cellular health, and aging.
... Acetyl-CoA directly engages in dynamic histone acetylation. Changes in lipid levels trigger responses from lipid-sensing nuclear receptors, exemplified by peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR), which wield direct or indirect gene expression control through DNA binding or epigenetic modifier recruitment [22,23]. These intricate lipid metabolism nuances collectively converge, skillfully choreographing profound epigenetic modifications through a network of intricate interplays [24]. ...
Cancer cells, which divide indefinitely and without control, are frequently exposed to various stress factors but manage to adapt and survive. The mechanisms by which cancer cells maintain cellular homeostasis and exploit stress conditions are not yet clear. Here, we elucidate the roles of diverse cellular metabolism and its regulatory mechanisms, highlighting the essential role of metabolism in cellular composition and signal transduction. Cells respond to various stresses, including DNA damage, energy stress, and oxidative stress, thereby causing metabolic alteration. We provide profound insight into the adaptive mechanisms employed by cancer cells to ensure their survival among internal and external stressors through a comprehensive analysis of the correlation between metabolic alterations and cellular stress. Furthermore, this research establishes a robust framework for the development of innovative therapeutic strategies that specifically target the cellular adaptations of cancer cells.
... Notably, by using epistasis experiments and inhibitor studies, we found that this HSF-1-mediated combination of increased MUFA synthesis and utilization plays a critical role in combating proteotoxicity. These results add to an expanding list of studies that demonstrated the beneficial effects of increasing the ratio of MUFAs over PUFAs 42 and supplementing growth media with oleic acid 16,30,42 or reported on the direct link between increased β-oxidation and lifespan extension 37,38,43,44 . It is intriguing to note that both measures, increasing MUFA/PUFA ratios and enhancing β-oxidation, have been associated with decreasing the levels of ROS and mitigating oxidative damage 42,43 . ...
... These results add to an expanding list of studies that demonstrated the beneficial effects of increasing the ratio of MUFAs over PUFAs 42 and supplementing growth media with oleic acid 16,30,42 or reported on the direct link between increased β-oxidation and lifespan extension 37,38,43,44 . It is intriguing to note that both measures, increasing MUFA/PUFA ratios and enhancing β-oxidation, have been associated with decreasing the levels of ROS and mitigating oxidative damage 42,43 . Given, however, that all three events-H3K4me3 depletion, HSF-1 upregulation and increased MUFA production-need to happen during C. elegans development, further investigations are clearly needed to determine when in life and how increases in mitochondrial β-oxidation promote stress resistance and longevity. ...
Transient events during development can exert long-lasting effects on organismal lifespan. Here we demonstrate that exposure of Caenorhabditis elegans to reactive oxygen species during development protects against amyloid-induced proteotoxicity later in life. We show that this protection is initiated by the inactivation of the redox-sensitive H3K4me3-depositing COMPASS complex and conferred by a substantial increase in the heat-shock-independent activity of heat shock factor 1 (HSF-1), a longevity factor known to act predominantly during C. elegans development. We show that depletion of HSF-1 leads to marked rearrangements of the organismal lipid landscape and a significant decrease in mitochondrial β-oxidation and that both lipid and metabolic changes contribute to the protective effects of HSF-1 against amyloid toxicity. Together, these findings link developmental changes in the histone landscape, HSF-1 activity and lipid metabolism to protection against age-associated amyloid toxicities later in life.
... Naturally, these explanations are not mutually exclusive and other mechanisms may also be involved. For example, disparities in longevity both within and between species could be attributed to factors such as cell division dynamics and growth [29], the composition of cell membranes [30], DNA damage and repair [31], and the erosion of telomeres and telomerase activity [32]. These mechanisms likely interact with one another. ...
Relationships of growth, metabolism, reproduction, and body size to the biological process of aging and longevity have been studied for decades and various unifying “theories of aging” have been proposed to account for the observed associations. In general, fast development, early sexual maturation leading to early reproductive effort, as well as production of many offspring, have been linked to shorter lifespans. The relationship of adult body size to longevity includes a remarkable contrast between the positive correlation in comparisons between different species and the negative correlation seen in comparisons of individuals within the same species. We now propose that longevity and presumably also the rate of aging are related to the “pace-of-life.” A slow pace-of-life including slow growth, late sexual maturation, and a small number of offspring, predicts slow aging and long life. The fast pace of life (rapid growth, early sexual maturation, and major reproductive effort) is associated with faster aging and shorter life, presumably due to underlying trade-offs. The proposed relationships between the pace-of-life and longevity apply to both inter- and intra-species comparisons as well as to dietary, genetic, and pharmacological interventions that extend life and to evidence for early life programming of the trajectory of aging. Although available evidence suggests the causality of at least some of these associations, much further work will be needed to verify this interpretation and to identify mechanisms that are responsible.
... Data distribution was assumed to be normal, but this was not formally tested. No statistical method was used to predetermine the sample size, but our sample sizes are similar to those reported in previous publications 19,70,71 . No data were excluded from the analyses. ...
Loss of function during aging is accompanied by transcriptional drift, altering gene expression and contributing to a variety of age-related diseases. CREB-regulated transcriptional coactivators (CRTCs) have emerged as key regulators of gene expression that might be targeted to promote longevity. Here we define the role of the Caenorhabditis elegans CRTC-1 in the epigenetic regulation of longevity. Endogenous CRTC-1 binds chromatin factors, including components of the COMPASS complex, which trimethylates lysine 4 on histone H3 (H3K4me3). CRISPR editing of endogenous CRTC-1 reveals that the CREB-binding domain in neurons is specifically required for H3K4me3-dependent longevity. However, this effect is independent of CREB but instead acts via the transcription factor AP-1. Strikingly, CRTC-1 also mediates global histone acetylation levels, and this acetylation is essential for H3K4me3-dependent longevity. Indeed, overexpression of an acetyltransferase enzyme is sufficient to promote longevity in wild-type worms. CRTCs, therefore, link energetics to longevity by critically fine-tuning histone acetylation and methylation to promote healthy aging.
... (Pgc1α)转录，从而抑制线粒体功能和产热 [ [124,125] ，动物模型研究也证实 IF 饮食方式能够延长啮齿类动 物及果蝇的健康寿命 [126,127] ， 而脂肪组织可能部分介导了 IF 饮食方式的代谢益处 [128,129] 。除此之外，限制蛋白质饮食也可改善代谢健康，延长寿命。限制蛋白质 摄入而不限制脂肪或碳水化合物的摄入可延长果蝇寿命 [130] 。在小鼠中，限制蛋 白质饮食可减轻小鼠体重，缓解肥胖、糖代谢紊乱以及脂肪组织功能障碍，改善 衰老相关的机体功能减退，延长寿命 [131,132] 。饮食干预可能通过调控动物体内储 脂器官中脂滴数量影响寿命，在秀丽隐杆线虫中，饮食补充单不饱和脂肪酸通过 增加其肠道中的脂滴数量促进长寿，而在哺乳动物中，尽管一些非脂质储存细胞 中的脂滴数量与其功能呈负相关， 但是否能够利用饮食干预调控脂肪细胞中脂滴 数量从而调控衰老进程仍值得探索 [133,134] 。有趣的是，衰老和饮食干预都会导致 肠道菌群组成及代谢发生变化 [135] ，而肠道菌群可通过产生代谢物或分泌 miRNA 等方式调控脂肪组织及机体脂质代谢 [136,137] ...
... assimilation of total N in peanut pod (Table 3). Notably, the accumulation of oleic acid, an important monounsaturated fatty acid, could also contribute to driving human lifespan extension due to its strong ability to scavenge reactive oxygen species (Folick et al., 2015;Mutlu et al., 2021;Papsdorf et al., 2023). Consistent with the seed quality data, the functional profiling of microbial communities revealed that pathways associated with lipid metabolism such as "Fatty acid biosynthesis" was enriched in IC compared with MP ( Fig. 7E & S6). ...
... This is consistent with other reports in skeletal muscle showing compensatory increases in peroxisomal FAO in response to impaired mitochondrial FAO [76]. Further, an increase in peroxisome and LD number can be driven by MUFA supplementation, which in turn elevates the phospholipid MUFA:PUFA ratio and reduces the capacity for lipid oxidation [77]. On the contrary, impaired peroxisomal b-oxidation promotes the accumulation of PUFA-CoAs and represses large LD formation [78]. ...
Background and Aims
Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the impact by which liver-specific CPT1a deletion impacts hepatic lipid metabolism.
Approach and Results
Six-to-eight-week old male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (HFD; 60% kcal fat) for 15 weeks. Mice were necropsied after a 16 hour fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase (ALT) levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in both whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis ( Plin2 , Cidec , G0S2 ) and in polyunsaturated fatty acid (PUFA) metabolism ( Elovl5, Fads1, Elovl2 ), while only female LKO mice increased genes involved in inflammation ( Ly6d, Mmp12, Cxcl2 ). Kinase profiling showed decreased protein kinase A (PKA) activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice.
Conclusions
Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.
Graphical Summary
... The researchers proposed a model in which MondoA/Mlx colocalization with LD inhibits its transcriptional activity limiting glucose-dependent transcription. More recently, work by Brunet and colleagues suggest that MUFA intercalation into LD and peroxisomes promote longevity, though downstream transcription factors are little explored (Papsdorf et al., 2023 ). Mitochondria and LD physically interact with one another to regulate metabolism (Boutant et al., 2017 ). ...
The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in Caenorhabditis elegans. These transcription factors coordinate nutrient sensing with carbohydrate and lipid metabolism across the evolutionary spectrum. While most studies have focused on the downstream outputs, little is known about the upstream inputs that regulate these transcription factors in a live organism. Here, we found that knockdown of various glucose metabolic enzymes decreases MML-1 localization in the nucleus and identified two hexokinase isozymes, hxk-1 and hxk-2, as the most vigorous regulators of MML-1 function. Upon hexokinase knockdown, MML-1 redistributes to mitochondria and lipid droplets (LD) and concomitantly, transcriptional targets are downregulated and germline longevity is abolished. Further, we found that hxk-1 regulates MML-1 through mitochondrial β-oxidation, while hxk-2 regulates MML-1 through modulating the pentose phosphate pathway (PPP) and its coordinated association with lipid droplets. Similarly, inhibition of the PPP rescues mammalian MondoA nuclear translocation and transcriptional function upon starvation. These studies reveal how metabolic signals and organellar communication regulate a key convergent metabolic transcription factor to promote longevity.
