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Lifespan extension by diet restriction in DNA repair deficient progeroid Ercc1Δ/- mice [mRNA]

ABSTRACT: DNA repair-deficient Ercc1Δ/- mice show premature cell death, senescence and numerous accelerated aging features limiting lifespan to 4-6 month. Simultaneously they exhibit a ‘survival response’, which suppresses growth and enhances maintenance, resembling the anti-aging response induced by dietary restriction (DR). Here we report that subjecting these progeroid, dwarf mutants to actual dietary restriction (DR) resulted in the largest lifespan increase recorded in mammals. Thirty percent DR tripled median and maximal remaining lifespan, and drastically retarded numerous aspects of accelerated aging, e.g. DR animals retained 50% more neurons and maintained full motoric function. The DR response in Ercc1Δ/- mice resembled DR in wild type animals including reduced insulin signaling. Interestingly, ad libitum Ercc1Δ/- liver expression profiles showed preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. Our findings strengthen the link between DNA damage and aging, establish Ercc1Δ/- mice as powerful model for identifying interventions to promote healthy aging, reveal untapped potential for reducing endogenous damage, provide new venues for understanding the molecular mechanism of DR, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and DR-like interventions for preventing neurodegenerative diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE77321 | GEO | 2016/09/09

SECONDARY ACCESSION(S): PRJNA310020

REPOSITORIES: GEO

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Lifespan extension by diet restriction in DNA repair deficient progeroid Ercc1Δ/- mice [miRNA]

Project description:DNA repair-deficient Ercc1Δ/- mice show premature cell death, senescence and numerous accelerated aging features limiting lifespan to 4-6 month. Simultaneously they exhibit a ‘survival response’, which suppresses growth and enhances maintenance, resembling the anti-aging response induced by dietary restriction (DR). Here we report that subjecting these progeroid, dwarf mutants to actual dietary restriction (DR) resulted in the largest lifespan increase recorded in mammals. Thirty percent DR tripled median and maximal remaining lifespan, and drastically retarded numerous aspects of accelerated aging, e.g. DR animals retained 50% more neurons and maintained full motoric function. The DR response in Ercc1Δ/- mice resembled DR in wild type animals including reduced insulin signaling. Interestingly, ad libitum Ercc1Δ/- liver expression profiles showed preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. Our findings strengthen the link between DNA damage and aging, establish Ercc1Δ/- mice as powerful model for identifying interventions to promote healthy aging, reveal untapped potential for reducing endogenous damage, provide new venues for understanding the molecular mechanism of DR, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and DR-like interventions for preventing neurodegenerative diseases.

2016-09-09 | GSE77226 | GEO

Disentangling mTOR signalling from the lifespan extending effect of dietary restriction in progeroid DNA-repair deficient mice

Project description:Dietary restriction (DR) and rapamycin, the best-known DR-mimetic, are two intervention that extend health- and lifespan across multiple species. We have recently shown that DR works extremely well in progeroid DNA repair deficient mice and dramatically extend their lifespan by ~200%. We next questioned the applicability of rapamycin in these mouse mutants. Here we show that treatments with rapamycin did significantly lower mTOR-signalling but did not improve the lifespan of DNA repair deficient Ercc1{delta}/- mice. These data are an extended version of the data in GEO Series GSE77321

2021-01-25 | GSE149029 | GEO

Expression data from dietary restricted budding yeast

Project description:Dietary restriction (also known as caloric/calorie restriction; CR) extends the lifespan of species from all three eukaryotic kingdoms. The restriction of the diet interferes directly with the aging process by triggering a tightly controlled genetic program where specific sets of genes are either upregulated downreguled. We used microarray-technology to detail the global program of gene expression underlying the anti-aging effect of dietary restriction and identified distinct classes of up- and down-regulated genes. In order to apply dietary restriction in budding yeast we cultured cells on a reduced glucose medium (0.5% vs. 2.0%), which is known as moderate DR regimen. We then compared mRNA expression of yeast cells cultured under dietary restricted (0.5% glucose) and ad libitum (2.0% glucose) conditions.

2012-06-20 | E-GEOD-38635 | biostudies-arrayexpress

Systemic lipolysis promotes healthspan in Drosophila melanogaster

Project description:Since healthspan-extending interventions such as caloric restriction or fasting robustly promote lipid catabolism, we investigated how lifespan and healthspan were affected by increased lipid catabolism via bmm (brummer, FBgn0036449), the major triglyceride hydrolase in Drosophila. Global overexpression of bmm strongly promoted lifespan extension as well as numerous markers of healthspan, including increased female fecundity, fertility maintenance, preserved locomotion activity, increased mitochondrial biogenesis and oxidative metabolism. Increased Bmm robustly upregulated the heat shock protein 70 (Hsp70) family of proteins, which equipped the flies with higher resistance to heat, cold, and ER stress via improved proteostasis. Overexpression of bmm recapitulated major physiological changes associated with dietary restriction (DR) and conveyed its effects through dSir2. Taken together, these data show that bmm overexpression has broad beneficial effects on healthspan, and implicate lipolysis as a key node underlying the beneficial effects of dietary interventions known to improve healthspan.

2022-09-27 | GSE178816 | GEO

Effect of methione restriction in the liver of WT and Lmna G609G KI mice

Project description:Dietary intervention constitutes a feasible approach for modulating metabolism and improving healthspan and lifespan. Methionine restriction (MR) delays the appearance of age-related diseases and increases longevity in normal mice. However, the effect of MR on premature aging remains to be elucidated. Here, we describe that MR extends lifespan in two different mouse models of Hutchinson-Gilford progeria syndrome (HGPS) by reversing the transcriptome alterations in inflammation and DNA-damage response genes present in this condition. Further, MR improves the lipid profile and alters the levels of bile acids, both in wild-type and in progeroid mice. Notably, treatment with the bile acid cholic acid improves healthspan and lifespan in vivo. These results suggest the existence of a metabolic pathway involved in the longevity extension achieved by MR and support the possibility of dietary interventions for treating progeria.

2018-08-27 | GSE117188 | GEO

Expression Data From Dietary Restriction, p53 Knockdown and sir2 Overexpression Mutants

Project description:Expression data from four different lifespan-extending conditions: dietary restriction in two different genetic backgrounds (canton-s and a yw, w1118 combination), sir2 overexpression and p53 knockdown (+/-). Comparison of significantly over and under-expressed genes reveals a signature for dietary restriction and lifespan extension. Abstract A major challenge in translating the positive effects of dietary restriction (DR) for the improvement of human health is the development of therapeutic mimics. One approach to finding DR mimics is based upon identification of the proximal effectors of DR life span extension. Whole genome profiling of DR in Drosophila shows a large number of changes in gene expression, making it difficult to establish which changes are involved in life span determination as opposed to other unrelated physiological changes. We used comparative whole genome expression profiling to discover genes whose change in expression is shared between DR and two molecular genetic life span extending interventions related to DR, increased dSir2 and decreased Dmp53 activity. We find twenty-one genes shared among the three related life span extending interventions. One of these genes, takeout, thought to be involved in circadian rhythms, feeding behavior and juvenile hormone binding is also increased in four other life span extending conditions: Rpd3, Indy, chico and methuselah. We demonstrate takeout is involved in longevity determination by specifically increasing adult takeout expression and extending life span. These studies demonstrate the power of comparative whole genome transcriptional profiling for identifying specific downstream elements of the DR life span extending pathway. 42 samples were used in the analysis. Sir2 overexpression flies and the yw, w1118 background DR flies had the same control. Flies were collected at ages 10 and 40 days. Tissue is whole body females.

2011-01-20 | E-GEOD-26726 | biostudies-arrayexpress

Expression Data From Dietary Restriction, p53 Knockdown and sir2 Overexpression Mutants

2011-01-20 | GSE26726 | GEO

Dietary restriction transforms the mammalian protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

Project description:Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation on relatively few identified proteins, tissue-specific sulfhydrome profiles and their associated functions are not well characterized, specifically under conditions known to modulate H2S production. We hypothesized that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific sulfhydromes. Here, we found protein persulfidation was enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking H2S producing enzyme cystathionine γ-lyase (CGL) had overall decreased tissue protein persulfidation and failed to functionally augment sulfhydromes in response to DR. Overall, we defined tissue- and CGL-dependent sulfhydromes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.

2021-01-25 | PXD022888 | Pride

Dietary restriction transforms the mammalian protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

2021-01-25 | PXD022956 | Pride

Dietary restriction transforms the mammalian protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

2021-01-25 | PXD022954 | Pride