A Systems Approach to Reverse Engineer Lifespan Extension by Dietary Restriction
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE77111 | GEO | 2016/01/22
SECONDARY ACCESSION(S): PRJNA309446
REPOSITORIES: GEO
Similar Datasets
Project description:Dietary restriction (DR) is the most powerful natural means to extend lifespan. Although several genes can mediate responses to alternate DR regimens, no single genetic intervention has recapitulated the full effects of DR, and no unified system is known for different DR regimens. Here we obtain temporally resolved transcriptomes during calorie restriction and intermittent fasting in Caenorhabditis elegans and find that early and late responses involve metabolism and cell cycle/DNA damage, respectively. We uncover three network modules of DR regulators by their target specificity. By genetic manipulations of nodes representing discrete modules, we induce transcriptomes that progressively resemble DR as multiple nodes are perturbed. Targeting all three nodes simultaneously results in extremely long-lived animals that are refractory to DR. These results and dynamic simulations demonstrate that extensive feedback controls among regulators may be leveraged to drive the regulatory circuitry to a younger steady state, recapitulating the full effect of DR.
| S-EPMC5110149 | biostudies-literature
Project description:A Systems Approach to Reverse Engineer Lifespan Extension by Dietary Restriction
| PRJNA309446 | ENA
Project description:A rather peculiar but very potent means of achieving longevity is through axenic dietary restriction (ADR), where animals feed on (semi-)defined culture medium in absence of any other lifeform. The little knowledge we already have on ADR is mainly derived from studies using the model organism Caenorhabditis elegans, where ADR more than doubles organismal lifespan. What is underlying this extreme longevity so far remains enigmatic, as ADR seems distinct from other forms of DR and bypasses well-known longevity factors. We here focus first on CUP-4, a protein present in the coelomocytes, which are endocytic cells with a presumed immune function. Our results show that loss of cup-4 or of the coelomocytes affects ADR-mediated longevity to a similar extent. As the coelomocytes have been suggested to have an immune function, we then investigated different central players of innate immune signalling, but could prove no causal links with axenic lifespan extension. We propose that future research focuses further on the role of the coelomocytes in endocytosis and recycling in the context of longevity.
| S-EPMC10298762 | biostudies-literature
Project description:Dietary restriction extends healthy lifespan in diverse organisms and reduces fecundity. It is widely assumed to induce adaptive reallocation of nutrients from reproduction to somatic maintenance, aiding survival of food shortages in nature. If this were the case, long life under dietary restriction and high fecundity under full feeding would be mutually exclusive, through competition for the same limiting nutrients. Here we report a test of this idea in which we identified the nutrients producing the responses of lifespan and fecundity to dietary restriction in Drosophila. Adding essential amino acids to the dietary restriction condition increased fecundity and decreased lifespan, similar to the effects of full feeding, with other nutrients having little or no effect. However, methionine alone was necessary and sufficient to increase fecundity as much as did full feeding, but without reducing lifespan. Reallocation of nutrients therefore does not explain the responses to dietary restriction. Lifespan was decreased by the addition of amino acids, with an interaction between methionine and other essential amino acids having a key role. Hence, an imbalance in dietary amino acids away from the ratio optimal for reproduction shortens lifespan during full feeding and limits fecundity during dietary restriction. Reduced activity of the insulin/insulin-like growth factor signalling pathway extends lifespan in diverse organisms, and we find that it also protects against the shortening of lifespan with full feeding. In other organisms, including mammals, it may be possible to obtain the benefits to lifespan of dietary restriction without incurring a reduction in fecundity, through a suitable balance of nutrients in the diet.
| S-EPMC2798000 | biostudies-literature
Project description:Dietary restriction (DR) increases lifespan in many organisms, but its underlying mechanisms are not fully understood. Mitochondria play a central role in metabolic regulation and are known to undergo changes in structure and function in response to DR. Mitochondrial membrane potential (Δψm) is the driving force for ATP production and mitochondrial outputs that integrate many cellular signals. One such signal regulated by Δψm is nutrient-status sensing. Here, we tested the hypothesis that DR promotes longevity through preserved Δψm during adulthood. Using the nematode Caenorhabditis elegans, we find that Δψm declines with age relatively early in the lifespan, and this decline is attenuated by DR. Pharmacologic depletion of Δψm blocked the longevity and health benefits of DR. Genetic perturbation of Δψm and mitochondrial ATP availability similarly prevented lifespan extension from DR. Taken together, this study provides further evidence that appropriate regulation of Δψm is a critical factor for health and longevity in response to DR.
| S-EPMC10400507 | biostudies-literature
Project description:In many organisms, dietary restriction (DR) leads to lifespan extension through the activation of cell protection and pro-longevity gene expression programs. In the nematode C. elegans, the DAF-16 transcription factor is a key aging regulator that governs the Insulin/IGF-1 signaling pathway and undergoes translocation from the cytoplasm to the nucleus of cells when animals are exposed to food limitation. However, how large is the influence of DR on DAF-16 activity, and its subsequent impact on lifespan has not been quantitatively determined. In this work, we assess the endogenous activity of DAF-16 under various DR regimes by coupling CRISPR/Cas9-enabled fluorescent tagging of DAF-16 with quantitative image analysis and machine learning. Our results indicate that DR regimes induce strong endogenous DAF-16 activity, although DAF-16 is less responsive in aged individuals. DAF-16 activity is in turn a robust predictor of mean lifespan in C. elegans, accounting for 78% of its variability under DR. Analysis of tissue-specific expression aided by a machine learning tissue classifier reveals that, under DR, the largest contribution to DAF-16 nuclear intensity originates from the intestine and neurons. DR also drives DAF-16 activity in unexpected locations such as the germline and intestinal nucleoli.
| S-EPMC9941123 | biostudies-literature
Project description:Dietary restriction (DR) extends lifespan in various species and also slows the onset of age-related diseases. Previous studies from flies and yeast have demonstrated that the target of rapamycin (TOR) pathway is essential for longevity phenotypes resulting from DR. TOR is a conserved protein kinase that regulates growth and metabolism in response to nutrients and growth factors. While some of the downstream targets of TOR have been implicated in regulating lifespan, it is still unclear whether additional targets of this pathway also modulate lifespan. It has been shown that the hypoxia inducible factor-1 (HIF-1) is one of the targets of the TOR pathway in mammalian cells. HIF-1 is a transcription factor complex that plays key roles in oxygen homeostasis, tumor formation, glucose metabolism, cell survival, and inflammatory response. Here, we describe a novel role for HIF-1 in modulating lifespan extension by DR in Caenorhabditis elegans. We find that HIF-1 deficiency results in extended lifespan, which overlaps with that by inhibition of the RSKS-1/S6 kinase, a key component of the TOR pathway. Using a modified DR method based on variation of bacterial food concentrations on solid agar plates, we find that HIF-1 modulates longevity in a nutrient-dependent manner. The hif-1 loss-of-function mutant extends lifespan under rich nutrient conditions but fails to show lifespan extension under DR. Conversely, a mutation in egl-9, which increases HIF-1 activity, diminishes the lifespan extension under DR. This deficiency is rescued by tissue-specific expression of egl-9 in specific neurons and muscles. Increased lifespan by hif-1 or DR is dependent on the endoplasmic reticulum (ER) stress regulator inositol-requiring protein-1 (IRE-1) and is associated with lower levels of ER stress. Therefore, our results demonstrate a tissue-specific role for HIF-1 in the lifespan extension by DR involving the IRE-1 ER stress pathway.
| S-EPMC2676694 | biostudies-literature
Project description:Rhodiola rosea has been extensively used to improve physical and mental performance and to protect against stress. We, and others, have reported that R. rosea can extend lifespan in flies, worms, and yeast. However, its molecular mechanism is currently unknown. Here, we tested whether R. rosea might act through a pathway related to dietary restriction (DR) that can extend lifespan in a range of model organisms. While the mechanism of DR itself is also unknown, three molecular pathways have been associated with it: the silent information regulator 2 (SIR2) proteins, insulin and insulin-like growth factor signaling (IIS), and the target of rapamycin (TOR). In flies, DR is implemented through a reduction in dietary yeast content. We found that R. rosea extract extended lifespan in both sexes independent of the yeast content in the diet. We also found that the extract extended lifespan when the SIR2, IIS, or TOR pathways were genetically perturbed. Upon examination of water and fat content, we found that R. rosea decreased water content and elevated fat content in both sexes, but did not sensitize flies to desiccation or protect them against starvation. There were some sex-specific differences in response to R. rosea. In female flies, the expression levels of glycolytic genes and dSir2 were down-regulated, and NADH levels were decreased. In males however, R. rosea provided no protection against heat stress and had no effect on the major heat shock protein HSP70 and actually down-regulated the mitochondrial HSP22. Our findings largely rule out an elevated general resistance to stress and DR-related pathways as mechanistic candidates. The latter conclusion is especially relevant given the limited potential for DR to improve human health and lifespan, and presents R. rosea as a potential viable candidate to treat aging and age-related diseases in humans.
| S-EPMC3660385 | biostudies-literature
Project description:Dietary restriction (DR) is widely regarded as a viable intervention to extend lifespan and healthspan in diverse organisms. The precise molecular regulatory mechanisms are largely unknown. Epigenetic modifications are not stable upon DR and also keep changing with age. Here, we employed whole genome bisulfite sequencing to determine the DNA methylation changes upon DR in adult Drosophila. Our results indicate that although a low level of DNA methylation exists in the adult Drosophila genome, there is no significant difference in DNA methylation levels upon DR when compared to unrestricted flies. This suggests that other epigenetic components such as histone modifications might be altered by DR.
| S-EPMC6865161 | biostudies-literature
Project description:Dietary restriction (DR) increases lifespan in a broad variety of organisms and improves health in humans. However, long-term transgenerational consequences of dietary interventions are poorly understood. Here, we investigated the effect of DR by temporary fasting (TF) on mortality risk, age-specific reproduction and fitness across three generations of descendants in Caenorhabditis elegans. We show that while TF robustly reduces mortality risk and improves late-life reproduction of the individuals subject to TF (P0), it has a wide range of both positive and negative effects on their descendants (F1-F3). Remarkably, great-grandparental exposure to TF in early life reduces fitness and increases mortality risk of F3 descendants to such an extent that TF no longer promotes a lifespan extension. These findings reveal that transgenerational trade-offs accompany the instant benefits of DR, underscoring the need to consider fitness of future generations in pursuit of healthy ageing.
| S-EPMC8113902 | biostudies-literature