Lifespan-extending Effect Research Articles

Dietary restriction impacts health and lifespan of genetically diverse mice.

Caloric restriction extends healthy lifespan in multiple species1. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored2-8. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity9. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice. We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling-an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life. Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.

Hypoxia-reoxygenation Extends the Lifespan of Caenorhabditis elegans via SKN-1- and DAF-16A-Dependent Stress Hormesis.

To study the role of hypoxia-reoxygenation and anoxia-starvation on the lifespan of C. elegans and elucidate the mechanism at molecular levels. Increasing evidence indicates that reactive oxygen species (ROS) act as signaling molecules that promote health. Hormesis occurs when a moderate stress level induces a beneficial adaptive response, protecting organisms against subsequent exposure to severe stress. Caenorhabditis elegans is a widely used model organism to study aging and displays a broad hormetic ability to couple with stress. To date, only few methods are available to induce stress hormesis in C. elegans. The objectives of this study were to explore the effects of hypoxia-reoxygenation and anoxia-starvation on the lifespan of C. elegans, exploring the involvement of ROS and oxidative stress-related pathways, and examining the hormetic property of H/R. The C. elegans were cultured in hypoxic conditions (1% O2) with OP50 bacteria for 24 h followed by reoxygenation (20% O2) (H/R) or in anoxic conditions (0% O2; 100% N2) without OP50 bacteria for 24 h followed by reoxygenation (20% O2) and food supplementation (A/S). Survivals were plotted and estimated for probability with Kaplan-Meier analysis. The H/R extended the lifespan of C. elegans, and H/R-pretreated worms showed improved resistance toward A/S compared to naïve worms. The C. elegans SKN-1 and DAF-16 are important oxidative stress response factors homologous to mammalian Nrf2 and FOXO3, respectively. Mutations in SKN-1 and DAF-16 blocked H/R-induced life extension. Next, H/R treatment in C. elegans activated both SKN-1 and DAF-16, as indicated by the upregulation of putative target genes of SKN-1 (gcs-1 and gss-1) and DAF-16 (sod-3). Moreover, pre-treatment with antioxidants (N-acetylcysteine, chlorogenic acid, and sulforaphane) reduced ROS levels and diminished the lifespan extension effect of H/R, indicating their dependency on ROS. These results provide evidence that H/R is beneficial for lifespan and stress resistance by activating the adaptive cellular response pathway (SKN-1 and DAF-16A) toward oxidative stress.

Sea cucumber (Acaudina leucoprocta) peptides exhibit anti-aging effect in Drosophila melanogaster via regulation of microbiota dysbiosis and metabolic disorder

As the population ages, the pursuit of extended lifespan and improved healthspan has gained significance. This study assessed the anti-aging properties of sea cucumber peptides derived from Acaudina leucoprocta (SCP) through microbiome and metabolome analyses in Drosophila melanogaster. Supplementation with 0.2%, 0.4%, 0.6%, and 0.8% of SCP significantly boosted the survival rate and extended the mean and median lifespans in both male and female flies. Among them, 0.6% SCP treatment extended the mean and median lifespans of male flies by 21.01% and 25.48 %, which showed the most prominent lifespan-prolonging effect. Moreover, SCP enhanced the healthspan of male flies by improving their climbing ability, intestinal barrier function, and memory performance. Additionally, SCP boosted the survival rate of flies subjected to oxidative, starvation, and heat stress, with no significant effect observed under cold stress conditions. The lifespan-extension effect of SCP remained unaffected by dietary restriction, but was partially inhibited when provided with antibiotic-supplemented food. SCP modulated microbiota with increased the abundance of Lactobacillus, Rhodococcus, and Propioniciclava and decreased Acetobacter, Achromobacter, Pedobacter, and norank_f_Saprospiraceae, which closely related with lifespan-extension effect. Furthermore, SCP induced a metabolic profile in 30-day-old flies more akin to that of 3-day-old flies, impacted 13 significantly regulated metabolites associated with amino acid, nucleotide, and carbohydrate metabolisms. These findings highlight SCP intervention as a promising anti-aging strategy.

Divergent effects of entomopathogenic fungi and medicinal mushroom species on Drosophila melanogaster lifespan

We tested the effect of entomogenous fungi isolated from the Coleoptera species Ophrida xanthospilota and of the medicinal mushroom Lentinula edodes on the lifespan of Drosophila melanogaster. All the four analyzed strains of entomogenous fungi showed pathogenicity to D. melanogaster by causing 100% mortality of fruit flies within 20 culture days. The shortest lifespan was recorded in flies treated with Fusarium verticillioides (15 days). On the contrary, L. edodes showed a remarkable lifespan-extending effect on the model organism, with fruit fly individuals surviving for 55 culture days. Fungal growth was microscopically observed on the bodies of dead fruit flies treated with the four entomogenous fungal species, confirming that the tested fungi were responsible for the mortality of the model insects. Our findings showed that the four fungal species previously found on the body of Coleoptera individuals are entomopathogenic and could be exploited in agriculture applications for the biocontrol of noxious pests. The significant lifespan extending effect on Drosophila produced by the analyzed L. edodes strain could represent very important experimental evidence of the anti-aging and lifespan prolonging effects of this medicinal mushroom species.

Regulation of Aging Processes: A Perspective of Dietary Restriction Models

The moderate restriction of dietary energy intake (dietary restriction: DR) extends the lifespan and health span of various laboratory animals, suggesting that it delays the aging process inherent in many animal species. Attenuated growth hormone and insulin-like growth factor-1 (IGF-1) signaling caused by mutations also increases the lifespan of mice, even those allowed to feed freely. In nematodes, the Daf16, mammalian Forkhead box O (FoxO) transcription factor, was shown to be required for lifespan extension in response to reduced IGF-1 signaling. Because DR also decreases the plasma concentration of IGF-1 in mammals, the IGF-1-FoxO axis may play a central role in the lifespan extension effect of DR and, thus, retardation of aging. Studies using knockout mice under DR conditions revealed the importance of FoxO1 and nuclear factor erythroid-derived 2-like 2 (Nrf2) in tumor suppression, and FoxO3 in lifespan extension. Human genomic studies also identified a strong association between a FOXO3 single nucleotide polymorphism and longevity. The aging mechanism is the most important risk factor for disease and frailty in aging humans. Therefore, further research on the application of DR to humans, the development of compounds and drugs that mimic the effects of DR, and mechanisms underlying FOXO3 polymorphisms for longevity is highly relevant to extending the human health span.

Phloretic acid requires the insulin/IGF-1 pathway and autophagy to enhance stress resistance and extend the lifespan of Caenorhabditis elegans.

Objective: In humans, aging is associated with increased susceptibility to most age-related diseases. Phloretic acid (PA), a naturally occurring compound found in Ginkgo biloba and Asparagus, exhibits has potential as an anti-aging agent and possesses antioxidant, anti-inflammatory, and immunomodulatory properties. This study aimed to investigate the effects of PA on longevity and stress resistance in Caenorhabditis elegans (C.elegans) and the mechanisms that underlie its effects. Methods: First, we examined the effects of PA on lifespan and healthspan assay, stress resistance and oxidative analysis, lipofuscin levels. Second, we examined the insulin/insulin-like pathway, mitochondria, autophagy-related proteins, and gene expression to explain the possible mechanism of PA prolonging lifespan. Results: Our findings demonstrated that PA dose-dependently extended the C.elegans lifespan, with 200μMPA showing the greatest effect and increased the C.elegans lifespan by approximately 16.7%. PA enhanced motility and the pharyngeal pumping rate in senescent C.elegans while reducing the accumulation of aging pigments. Further investigations revealed that daf-16, skn-1, and hsf-1 were required for mediating the lifespan extension effect of PA in C.elegans since its impact was suppressed in mutant strains lacking these genes. This suggests that PA activates these genes, leading to the upregulation of downstream genes involved in stress response and senescence regulation pathways. Furthermore, PA did not extend the lifespan of the RNAi atg-18 and RNAi bec-1 but it attenuated SQST-1 accumulation, augmented autophagosome expression, upregulated autophagy-related gene expression, and downregulated S6K protein levels. These findings suggest that the potential life-extending effect of PA also involves the modulation of the autophagy pathway. Conclusion: These findings results highlight the promising anti-aging effects of PA and warrant further investigation into its pharmacological mechanism and medicinal development prospects.

Cacao Procyanidins-Induced Lifespan Extension in Caenorhabditis elegans in a Nervous System and CaMKII-Dependent Manner.

Procyanidins are gaining attention due to their potential health benefits. We found that cacao liquor procyanidin (CLPr) from Theobroma cacao seeds increased the lifespan of Caenorhabditis elegans, a representative model organism for aging studies. The genetic dependence of the lifespan-extending effect of CLPr was consistent with that of blueberry procyanidin, which is dependent on unc-43, osr-1, sek-1, and mev-1, but not on daf-16, sir-2.1, or skn-1. The lifespan-extending effect of CLPr was inhibited by neuron-specific RNA interference (RNAi) targeting unc-43 and pmk-1, and in worms with loss-of-function mutations in the odr-3, odr-1, or tax-4 genes, which are essential in sensory neurons, including AWC neurons. It was also inhibited in worms in which AWC neurons or AIB interneurons had been eliminated, and in worms with loss-of-function mutations in eat-4 or glr-1, which are responsible for glutamatergic synaptic transmission. These results suggest that the lifespan-extending effect of CLPr is dependent on the nervous system. In addition, it also requires unc-43 and pmk-1 expression in nonneuronal cells, as demonstrated by the experiments with RNAi in wild-type worms, the neuronal cells of which are not affected by systemic RNAi. The osr-1 gene is expressed in hypodermal and intestinal cells and regulates the response to osmotic stress along with unc-43/calcium/calmodulin-dependent protein kinase II and the p38 mitogen-activated protein kinase pathway. Consistent with this, CLPr improved osmotic stress tolerance in an unc-43- and pmk-1-dependent manner, and it was also dependent on AWC neurons. The lifespan-extending and osmotic-tolerance-improving activities were attributed to procyanidins with a tetrameric or higher-order oligomeric structure.

Magnolol extends lifespan and improves age-related neurodegeneration in Caenorhabditis elegans via increase of stress resistance

Magnolol is a naturally occurring polyphenolic compound in many edible plants, which has various biological effects including anti-aging and alleviating neurodegenerative diseases. However, the underlying mechanism on longevity is uncertain. In this study, we investigated the effect of magnolol on the lifespan of Caenorhabditis elegans and explored the mechanism. The results showed that magnolol treatment significantly extended the lifespan of nematode and alleviated senescence-related decline in the nematode model. Meanwhile, magnolol enhanced stress resistance to heat shock, hydrogen peroxide (H2O2), mercuric potassium chloride (MeHgCl) and paraquat (PQ) in nematode. In addition, magnolol reduced reactive oxygen species and malondialdehyde (MDA) levels, and increased superoxide dismutase and catalase (CAT) activities in nematodes. Magnolol also up-regulated gene expression of sod-3, hsp16.2, ctl-3, daf-16, skn-1, hsf-1, sir2.1, etc., down-regulated gene expression of daf-2, and promoted intranuclear translocation of daf-16 in nematodes. The lifespan-extending effect of magnolol were reversed in insulin/IGF signaling (IIS) pathway-related mutant lines, including daf-2, age-1, daf-16, skn-1, hsf-1 and sir-2.1, suggesting that IIS signaling is involved in the modulation of longevity by magnolol. Furthermore, magnolol improved the age-related neurodegeneration in PD and AD C. elegans models. These results indicate that magnolol may enhance lifespan and health span through IIS and sir-2.1 pathways. Thus, the current findings implicate magnolol as a potential candidate to ameliorate the symptoms of aging.

Butein Increases Resistance to Oxidative Stress and Lifespan with Positive Effects on the Risk of Age-Related Diseases in Caenorhabditis elegans.

Butein is a flavonoid found in many plants, including dahlia, butea, and coreopsis, and has both antioxidant and sirtuin-activating activities. In light of the postulated role of free radicals in aging, we examined the effects of butein on aging and on genetic or nutritional models of age-related diseases in Caenorhabditis elegans. Butein showed radical scavenging activity and increased resistance to oxidative stress in Caenorhabditis elegans. The mean lifespan of Caenorhabditis elegans was significantly increased by butein, from 22.7 days in the untreated control to 25.0 days in the butein-treated group. However, the lifespan-extending effect of butein was accompanied by reduced production of progeny as a trade-off. Moreover, the age-related decline in motility was delayed by butein supplementation. Genetic analysis showed that the lifespan-extending effect of butein required the autophagic protein BEC-1 and the transcription factor DAF-16 to regulate stress response and aging. At the genetic level, expression of the DAF-16 downstream target genes hsp-16.2 and sod-3 was induced in butein-treated worms. Butein additionally exhibited a preventive effect in models of age-related diseases. In an Alzheimer's disease model, butein treatment significantly delayed the paralysis caused by accumulation of amyloid-beta in muscle, which requires SKN-1, not DAF-16. In a high-glucose-diet model of diabetes mellitus, butein markedly improved survival, requiring both SKN-1 and DAF-16. In a Parkinson's disease model, dopaminergic neurodegeneration was completely inhibited by butein supplementation and the accumulation of α-synuclein was significantly reduced. These findings suggest the use of butein as a novel nutraceutical compound for aging and age-related diseases.

Indian Almond (Terminalia catappa Linn.) Leaf Extract Extends Lifespan by Improving Lipid Metabolism and Antioxidant Activity Dependent on AMPK Signaling Pathway in Caenorhabditis elegans under High-Glucose-Diet Conditions.

This study aimed to evaluate the antioxidant and antiaging effects of Indian almond (Terminalia catappa Linn.) leaf extract (TCE) on high-glucose (GLU)-induced obese Caenorhabditis elegans. Since TCE contains high contents of flavonoids and phenolics, strong radical scavenging activity was confirmed in vitro. The stress-resistance effect of TCE was confirmed under thermal and oxidative stress conditions at nontoxic tested concentrations (6.25, 12.5, and 25 μg/mL). GLU at 2% caused lipid and reactive oxygen species (ROS) accumulation in C. elegans, and TCE inhibited lipid and ROS accumulation under both normal and 2% GLU conditions in a concentration-dependent manner. In addition, TCE proved to be effective in prolonging the lifespan of C. elegans under normal and 2% GLU conditions. The ROS reduction effect of TCE was abolished in mutants deficient in daf-16/FOXO and skn-1/Nrf-2. In addition, the lifespan-extending effect of TCE in these two mutants disappeared. The lifespan-extending effect was abolished even in atgl-1/ATGL-deficiency mutants. The TCE effect was reduced in aak-1/AMPK-deficient mutants and completely abolished under 2% GLU conditions. Therefore, the effect of prolonging lifespan by inhibiting lipid and ROS accumulation under the high GLU conditions of TCE is considered to be the result of atgl-1, daf-16, and skn-1 being downregulated by aak-1. These results suggest that the physiological potential of TCE contributes to antiaging under metabolic disorders.

Transient inhibition of mitochondrial function by chrysin and apigenin prolong longevity via mitohormesis in C. elegans.

Mild inhibition of mitochondrial function leads to longevity. Genetic disruption of mitochondrial respiratory components either by mutation or RNAi greatly extends the lifespan in yeast, worms, and drosophila. This has given rise to the idea that pharmacologically inhibiting mitochondrial function would be a workable strategy for postponing aging. Toward this end, we used a transgenic worm strain that expresses the firefly luciferase enzyme widely to evaluate compounds by tracking real-time ATP levels. We identified chrysin and apigenin, which reduced ATP production and increased the lifespan of worms. Mechanistically, we discovered that chrysin and apigenin transiently inhibit mitochondrial respiration and induce an early ROS, and the lifespan-extending effect is dependent on transient ROS formation. We also show that AAK-2/AMPK, DAF-16/FOXO, and SKN-1/NRF-2 are required for chrysin or apigenin-mediated lifespan extension. Temporary increases in ROS levels trigger an adaptive response in a mitohormetic way, thereby increasing oxidative stress capacity and cellular metabolic adaptation, finally leading to longevity. Thus, chrysin and apigenin represent a class of compounds isolated from natural products that delay senescence and improve age-related diseases by inhibiting mitochondrial function and shed new light on the function of additional plant-derived polyphenols in enhancing health and delaying aging. Collectively, this work provides an avenue for pharmacological inhibition of mitochondrial function and the mechanism underlining their lifespan-extending properties.

Inhibition of the MEK/ERK pathway suppresses immune overactivation and mitigates TDP-43 toxicity in a Drosophila model of ALS

TDP-43 is an important DNA/RNA-binding protein that is associated with age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, its pathomechanism is not fully understood. In a transgenic RNAi screen using Drosophila as a model, we uncovered that knockdown (KD) of Dsor1 (the Drosophila MAPK kinase dMEK) suppressed TDP-43 toxicity without altering TDP-43 phosphorylation or protein levels. Further investigation revealed that the Dsor1 downstream gene rl (dERK) was abnormally upregulated in TDP-43 flies, and neuronal overexpression of dERK induced profound upregulation of antimicrobial peptides (AMPs). We also detected a robust immune overactivation in TDP-43 flies, which could be suppressed by downregulation of the MEK/ERK pathway in TDP-43 fly neurons. Furthermore, neuronal KD of abnormally increased AMPs improved the motor function of TDP-43 flies. On the other hand, neuronal KD of Dnr1, a negative regulator of the Drosophila immune deficiency (IMD) pathway, activated the innate immunity and boosted AMP expression independent of the regulation by the MEK/ERK pathway, which diminished the mitigating effect of RNAi-dMEK on TDP-43 toxicity. Finally, we showed that an FDA-approved MEK inhibitor trametinib markedly suppressed immune overactivation, alleviated motor deficits and prolonged the lifespan of TDP-43 flies, but did not exhibit a lifespan-extending effect in Alzheimer disease (AD) or spinocerebellar ataxia type 3 (SCA3) fly models. Together, our findings suggest an important role of abnormal elevation of the MEK/ERK signaling and innate immunity in TDP-43 pathogenesis and propose trametinib as a potential therapeutic agent for ALS and other TDP-43-related diseases.

Nutritional Programming of the Lifespan of Male Drosophila by Activating FOXO on Larval Low-Nutrient Diet.

Nutrition during the developmental stages has long-term effects on adult physiology, disease and lifespan, and is termed nutritional programming. However, the underlying molecular mechanisms of nutritional programming are not yet well understood. In this study, we showed that developmental diets could regulate the lifespan of adult Drosophila in a way that interacts with various adult diets during development and adulthood. Importantly, we demonstrated that a developmental low-yeast diet (0.2SY) extended both the health span and lifespan of male flies under nutrient-replete conditions in adulthood through nutritional programming. Males with a low-yeast diets during developmental stages had a better resistance to starvation and lessened decline of climbing ability with age in adulthood. Critically, we revealed that the activity of the Drosophila transcription factor FOXO (dFOXO) was upregulated in adult males under developmental low-nutrient conditions. The knockdown of dFOXO, with both ubiquitous and fat-body-specific patterns, can completely abolish the lifespan-extending effect from the larval low-yeast diet. Ultimately, we identify that the developmental diet achieved the nutritional programming of the lifespan of adult males by modulating the activity of dFOXO in Drosophila. Together, these results provide molecular evidence that the nutrition in the early life of animals could program the health of their later life and their longevity.

Targeting mTOR for Anti-Aging and Anti-Cancer Therapy

The balance between anabolism and catabolism is disrupted with aging, with the rate of anabolism being faster than that of catabolism. Therefore, mTOR, whose major function is to enhance anabolism and inhibit catabolism, has become a potential target of inhibition for anti-aging therapy. Interestingly, it was found that the downregulation of the mTOR signaling pathway had a lifespan-extending effect resembling calorie restriction. In addition, the mTOR signaling pathway promotes cell proliferation and has been regarded as a potential anti-cancer target. Rapamycin and rapalogs, such as everolimus, have proven to be effective in preventing certain tumor growth. Here, we reviewed the basic knowledge of mTOR signaling, including both mTORC1 and mTORC2. Then, for anti-aging, we cited a lot of evidence to discuss the role of targeting mTOR and its anti-aging mechanism. For cancer therapy, we also discussed the role of mTOR signaling in different types of cancers, including idiopathic pulmonary fibrosis, tumor immunity, etc. In short, we discussed the research progress and both the advantages and disadvantages of targeting mTOR in anti-aging and anti-cancer therapy. Hopefully, this review may promote more ideas to be generated for developing inhibitors of mTOR signaling to fight cancer and extend lifespan.

Reverse electron transfer is activated during aging and contributes to aging and age-related disease.

Mechanisms underlying the depletion of NAD+ and accumulation of reactive oxygen species (ROS) in aging and age-related disorders remain poorly defined. We show that reverse electron transfer (RET) at mitochondrial complex I, which causes increased ROS production and NAD+ to NADH conversion and thus lowered NAD+ /NADH ratio, is active during aging. Genetic or pharmacological inhibition of RET decreases ROS production and increases NAD+ /NADH ratio, extending the lifespan of normal flies. The lifespan-extending effect of RET inhibition is dependent on NAD+ -dependent Sirtuin, highlighting the importance of NAD+ /NADH rebalance, and on longevity-associated Foxo and autophagy pathways. RET and RET-induced ROS and NAD+ /NADH ratio changes are prominent in human induced pluripotent stem cell (iPSC) model and fly models of Alzheimer's disease (AD). Genetic or pharmacological inhibition of RET prevents the accumulation of faulty translation products resulting from inadequate ribosome-mediated quality control, rescues relevant disease phenotypes, and extends the lifespan of Drosophila and mouse AD models. Deregulated RET is therefore a conserved feature of aging, and inhibition of RET may open new therapeutic opportunities in the context of aging and age-related diseases including AD.

Bacillus subtilis TO-A extends the lifespan of Caenorhabditis elegans.

Clostridium butyricum TO-A, Enterococcus faecium T-110, and Bacillus subtilis TO-A are sold as oral probiotic preparations and reportedly exhibit many beneficial effects on the health of hosts, including humans and livestock. In this study, we compared the ability of these clinically applied probiotic bacteria with Escherichia coli OP50 in extending the lifespan of Caenorhabditis elegans. To compare the C. elegans lifespan-extending effects of the three bacteria, experiments were performed using a nematode growth medium containing a small amount of trypticase soy agar. The maximum lifespans of worms fed C. butyricum TO-A, E. faecium T-110, or B. subtilis TO-A increased by 11, 12, and 26%, respectively, compared with worms fed E. coli OP50. In addition, we conducted a metabolomic analysis of methanol extracts of B. subtilis TO-A cells, which exhibited the strongest lifespan-extending effect on C. elegans among the probiotic bacteria tested in this study. As a result, 59 candidate substances involved in extending the lifespan of C. elegans were identified in B. subtilis TO-A cells.

Hypsizygus marmoreus extract exhibited antioxidant effects to promote longevity and stress resistance in Caenorhabditis elegans.

In this study, we explored the lifespan extension effect of a popular edible mushroom, Hypsizygus marmoreus, using the model organism Caenorhabditis elegans (C. elegans). The results showed that Hypsizygus marmoreus extract (HME) could increase the lifespan of C. elegans and ameliorate the healthspan by improving motility, attenuating lipofuscin accumulation, and enhancing the ability to withstand oxidative and heat stress. Then, we found noteworthy enhancements in SOD and CAT activities and reactive oxygen species (ROS) scavenging activity in vivo. Combined with the up-regulation of the expression of antioxidant genes (skn-1, sod-1, sod-3, mev-1, and gst-4), HME may function as an antioxidant in nematodes, which may be closely related to its phenolic compounds. Furthermore, we found that HME promoted the transfer of the transcription factor SKN-1 to the nucleus but had no impact on the lifespan of skn-1 mutants, indicating that SKN-1 was essential for Hypsizygus marmoreus to exert beneficial biological effects in C. elegans. Our findings elucidated that dietary supplementation with Hypsizygus marmoreus might have beneficial anti-aging effects and contribute to exploring the lifespan extension and underlying mechanisms of Hypsizygus marmoreus in C. elegans.

The natural product rotundic acid treats both aging and obesity by inhibiting PTP1B

AbstractThe occurrence of obesity is associated with age. But their interplay remains mysterious. Here, we discovered that rotundic acid (RA), a plant-derived pentacyclic triterpene, was a powerful agent for both anti-aging and treating obesity. Considering that obese individuals decrease the appetite-suppressing and energy-expenditure-enhancing functions of leptin leading to obesity, we found RA was a leptin sensitizer, evidenced by observations that RA enhanced the leptin sensitivity to normal diet-induced obese (DIO) mice, and had minimal or no use to normal lean mice, leptin receptor-deficient (db/db) mice, and leptin-deficient (ob/ob) mice. Simultaneously, RA significantly increased energy expenditure, BAT thermogenesis, and glucose metabolism in DIO mice, as the results of enhancing leptin sensitivity. Regarding mode of action, we demonstrated that RA is a noncompetitive inhibitor of leptin negative regulators protein tyrosine phosphatase 1B (PTP1B) and T-cell PTP through interaction with their C-terminus, thus leading to weight loss through enhancing leptin sensitivity. Besides, we showed that deletion of yPTP1 in yeast completely abolished the lifespan extension effect of RA, celstrol, and withaferin A, while these compounds exhibited PTP1B inhibition activity. Furthermore, PTP1B knockdown extend lifespan in yeast and human cells, indicating PTP1B is an important factor regulating cellular aging.

Responses of bitter melon saponins to oxidative stress and aging via the IIS pathway linked with sir-2.1 and hlh-30.

Saponins from bitter melon (BMS) exert potential bioactivities and pharmacological activities, including anti-oxidation and lifespan extension. However, the exact mechanisms of BMS in response to oxidative stress remain unknown. Results demonstrated that bitter melon saponins could strengthen locomotive activities (body bend and head thrashing) accompanied by delaying the muscle fiber damage with age in Caenorhabditis elegans. In addition, BMS inhibited the ROS accumulation, improved the activities of antioxidant enzymes like SOD (by 57.90% and 94.34% for 100 μg/ml and 200 μg/ml BMS, respectively) and CAT (by 51.45% and 56.91% for 100 μg/ml and 200 μg/ml BMS, respectively), and extend the lifespan of N2 and CL2006 worms under paraquat-induced oxidative stress. Mechanism study suggested that BMS modulated the mRNA expressions of oxidation-related regulators, like the upregulation of cat-1, hsf-1, sir-2.1, and hlh-30. Furthermore, gene-deficient mutants verified that IIS (insulin/insulin-like growth factor-1 signaling) pathway linked with sir-2.1 and hlh-30 factors were involved in the BMS's lifespan-extension effects under oxidative stress. In general, this study supplemented the explanation of BMS in promoting oxidation-resistance and lifespan-extension activities, which could be served as a potential candidate for anti-aging. PRACTICAL APPLICATIONS: Our previous studies have suggested that saponins from bitter melon exhibited fat-lowering activity in C. elegans. However, little was known about the mechanism underlying the anti-oxidation effects of BMS in C. elegans. Current results indicated that the IIS pathway linked with sir-2.1 and hlh-30 transcriptional factors jointly to increase the lifespan in BMS' responses to oxidative stress. Our findings are beneficial to understand the main nutritional ingredients in bitter melon, which are ideal and expected in functional foods for aging.

Itaconate prolongs the healthy lifespan by activating UPRmt in Caenorhabditis elegans

Itaconate (ItA), a byproduct of the Krebs cycle, has recently emerged as an anti-inflammatory metabolite for inhibiting the overactive immune response. In addition to its immunomodulatory and antimicrobial effects, ItA may have other therapeutic avenues. Herein, the effect of ItA on aging was explored in order to better establish the therapeutic potential of this promising metabolite. ItA extended the lifespan and enhanced the stress resistance of Caenorhabditis elegans (C. elegans), even at the doses of 0.01 and 0.1 μM. Moreover, the lifespan extension effect of ItA was pronounced even for the aged worms (days 7 and 9 post adult stage). Furthermore, ItA was found to extend the healthy longevity of C. elegans in a mitochondria-dependent manner. ItA protected the mitochondrial integrity, increased ATP content, and decreased the reactive oxygen species (ROS) in C. elegans. Mechanistic investigations showed that ItA specifically activated the mitochondrial unfolded protein response (UPRmt) in worms and significantly increased the expression of activating transcription factor associated with stress-1 (ATFS-1) that senses mitochondrial stress and communicates with the nucleus during the UPRmt. ItA extended the lifespan of C. elegans in an ATFS-1-dependent manner. In summary, this study elucidates the molecular mechanism by which ItA extends the healthy lifespan and highlights the importance of mitochondrial integrity in the intervention of aging.