Early-adulthood spike in protein translation drives aging via juvenile hormone/germline signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE239506 | GEO | 2023/08/01
REPOSITORIES: GEO
Similar Datasets
Project description:Protein translation (PT) declines with age in invertebrates, rodents, and humans. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing an early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age related functional decline via juvenile hormone-lipid transfer protein axis and germline signaling. Our findings suggest that PT is adaptively suppressed after early-adulthood, alleviating later-life proteostatic burden, slowing down age-related functional decline, and improving lifespan. Our work provides a theoretical framework for understanding how lifetime PT dynamics shape future aging trajectories.
2023-10-24 | PXD044118 | Pride
Project description:Aging and the age-associated decline of the proteome is determined in part through neuronal control of evolutionarily conserved transcriptional effectors, which safeguard homeostasis under fluctuating metabolic and stress conditions by regulating an expansive proteostatic network. We have discovered the Caenorhabditis elegans homeodomain-interacting protein kinase (HPK-1) acts as a key transcriptional effector to preserve neuronal integrity, function, and proteostasis during aging. Loss of hpk-1 results in drastic dysregulation in expression of neuronal genes, including premature upregulation of genes associated with neuronal aging. During normal aging hpk-1 expression increases throughout the nervous system and in more cell-clusters than any other kinase. Within the aging nervous system, hpk-1 is co-expressed with key longevity transcription factors, including daf-16 (FOXO), hlh-30 (TFEB), skn-1 (Nrf2), and hif-1, which suggests hpk-1 expression mitigates natural age-associated physiological decline. Consistently, pan-neuronal overexpression of hpk-1 extends longevity, preserves proteostasis both within and outside of the nervous system, and improves stress resistance. Neuronal HPK-1 improves proteostasis through kinase activity. HPK-1 functions cell non-autonomously within serotonergic and GABAergic neurons to improve proteostasis in distal tissues by specifically regulating divergent components of the proteostatic network. Increased serotonergic HPK-1 enhances the heat shock response and survival to acute stress. In contrast, GABAergic HPK-1 induces basal autophagy and extends longevity. Our work establishes hpk-1 as a key neuronal transcriptional regulator that is critical for the preservation of neuronal function during aging and insight as to how the nervous system partitions acute and chronic adaptive response pathways to delay aging by maintaining organismal homeostasis.
2023-07-28 | GSE220744 | GEO
Project description:Abstract: Protein homeostasis (proteostasis) is critical for cell function, and its decline is proposed as a hallmark of aging. Somatic stem cells (SCs) have a unique ability to maintain their proteostatic capacity, yet mechanisms to achieve this remain incompletely understood. Here, we describe and characterize a ‘proteostatic checkpoint’ in Drosophila intestinal SCs (ISCs). Following a breakdown of proteostasis, ISCs coordinate cell cycle arrest with protein aggregate clearance by Atg8-mediated activation of the Nrf2-like transcription factor cap-n-collar C (CncC), which induces the cell cycle inhibitor Dacapo and proteolytic genes. The capacity to engage this checkpoint is lost in ISCs from aging flies, and we show that it can be restored by treating flies with an Nrf2 activator, or by over-expression of CncC or Atg8a. This limits age-related intestinal barrier dysfunction and can result in lifespan extension. Our findings identify a new mechanism by which somatic SCs preserve proteostasis, and highlight potential intervention strategies to maintain regenerative homeostasis. Purpose of Study: To explore the transcriptional program downstream of CncC in Drosophila ISCs in more detail, we performed RNAseq analysis on FACS-purified wild-type or CncC-deficient escargot-positive cells (ISCs/EBs) in which the proteostatic checkpoint was engaged through the expression of HttQ138 or through the knockdown of rpn3. Results: While knockdown of rpn3 resulted in a more pronounced and broader transcriptional response than the expression of HttQ138, 93 of the 200 genes that were induced by HttQ138 expression (using a cut-off of 3-fold induction and a minimum expression of 10 FPKM) were also induced by knockdown of rpn3, illustrating a broad overlap of transcriptional changes elicited by the two conditions. Induction of 167 of those 200 genes was dependent on CncC. GO analysis of either the 93 genes induced in both stress conditions, or of the 167 CncC-dependent genes revealed a significant enrichment of genes encoding proteins involved in proteolysis and protein metabolism.
2019-02-05 | GSE125385 | GEO
Project description:Environmental factors such as temperature can modulate animal’s lifespan. However, the underlying mechanisms remain largely undefined. Through proteomic analysis of C. elegans at different time points (young adult, middle age, and old age) and under two temperature conditions (20°C and 25°C), we found that temperature affects C. elegans lifespan largely by modulating the proteostasis. Surprisingly, although animals live shorter at the higher temperature, we found that worms cultured at 25°C for one day at early adulthood promotes the protein homeostasis by decreasing the synthesis and increasing the degradation, suggesting the beneficial effects. Consistent with the finding, animals shifting from 20°C to 25°C for 24 hours between the larval L4 to adult Day 3 stages indeed live longer and are more resistant to stresses. Furthermore, we found that the one-day thermal induced lifespan extension is mediated by the FOXO transcriptional factor DAF-16. These results reveal an unexpected and complicated mechanism underlying the temperature effects on aging, which could potentially aid to develop strategies for treating aging related diseases.
2023-03-11 | PXD024916 | Pride
Project description:Our early life environment has a profound influence on developing organs and tissues that impacts metabolic function, and determines health and disease susceptibility across the life-course. We show an adverse early-life exposure that causes metabolic dysfunction in adulthood reprograms active and repressive histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature at specific genes and chromatin states. This epigenomic reprogramming persists long after the initial exposure, but remarkably, can remain transcriptionally- and metabolically-silent until later-life exposure to a Western-style (high fat-fructose-cholesterol) diet. These findings reveal the importance of epigenome:environment interactions across the life-course, which early in life accelerate epigenomic aging and reprogram the epigenome, and later in adulthood, can unlock metabolically restriced epigenetic reprogramming to drive metabolic dysfunction.
2020-03-11 | GSE130434 | GEO
Project description:Our early life environment has a profound influence on developing organs and tissues that impacts metabolic function, and determines health and disease susceptibility across the life-course. We show an adverse early-life exposure that causes metabolic dysfunction in adulthood reprograms active and repressive histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature at specific genes and chromatin states. This epigenomic reprogramming persists long after the initial exposure, but remarkably, can remain transcriptionally- and metabolically-silent until later-life exposure to a Western-style (high fat-fructose-cholesterol) diet. These findings reveal the importance of epigenome:environment interactions across the life-course, which early in life accelerate epigenomic aging and reprogram the epigenome, and later in adulthood, can unlock metabolically restriced epigenetic reprogramming to drive metabolic dysfunction.
2020-03-11 | GSE130409 | GEO
Project description:Aging is associated with a progressive loss of tissue and metabolic homeostasis. Changes in the cellular management of the proteome, as well as changes in cellular metabolism have been implicated in this decline, yet our understanding of causal relationships between these changes remains incomplete. Genetic studies have shown that single-gene perturbations are sufficient to significantly impact the aging process, delaying all associated cellular deficiencies, and thus increasing lifespan. Here, we explore metabolic and proteostatic changes associated with lifespan extension by one such perturbation. Focusing on the Drosophila brain, we comprehensively characterize protein turnover rates and assess metabolic flux to identify changes in protein and metabolic homeostasis in long-lived animals. Using organism-wide 15N labeling, we observe that the turnover rates of ~2000 proteins in the fly head decline with age, and that this decline is prevented in animals with lifespan-extending elevation of Jun-N-terminal Kinase (JNK) activity. Combining transcriptomic, metabolomic, and metabolic flux analysis, we find that JNK activation in the brain results in decreased steady-state Glucose-6-phosphate levels coupled to elevated carbon flux into the pentose phosphate pathway due to the transcriptional induction of Glucose-6-phosphate Dehydrogenase. This metabolic change promotes proteostasis in the aging brain, likely via increased NADPH against oxidative stress response. Through a comprehensive characterization of the cellular and biochemical changes elicited by a lifespan extending mutation, our study thus identifies a JNK-induced metabolic switch that increases lifespan by promoting neuronal proteostasis.
| MSV000080118 | MassIVE
Project description:Cardiac fibrosis is a pathophysiologic hallmark of the aging heart. In the uninjured heart, cardiac fibroblasts exist in the quiescent state, but little is known about how proliferation rates and fibroblast transcriptional programs change throughout the lifespan of the organism from the immediate postnatal period to adult life and old age. Using EdU pulse labeling, we demonstrate that more than 50% of cardiac fibroblasts are actively proliferating in the first day of post-natal life. However, within 4 weeks of birth in the juvenile animal, only 10% of cardiac fibroblasts are proliferating. By early adulthood, the fraction of proliferating cardiac fibroblasts further decreases to approximately 2%, where it so remains throughout the rest of the organism’s life span. Examination of absolute cardiac fibroblast numbers demonstrated concordance with age related changes in fibroblast proliferation with no significant differences in absolute cardiac fibroblast numbers between animals 14 weeks and 1.5 years of age. We demonstrate that the maximal changes in cardiac fibroblast transcriptional programs and in particular collagen expression occur within the first weeks of life from the immediate postnatal to the juvenile period. We show that even though the aging heart exhibits an increase in the total amount of accumulated collagen, transcription of various collagens and ECM genes both in the heart and cardiac fibroblast is maximal in the newly born and juvenile animal and decreases with organismal aging. Examination of DNA methylation changes both in the heart and in cardiac fibroblasts did not demonstrate significant changes in differentially methylated regions between young and old mice. Our observations demonstrate that cardiac fibroblasts attain a stable proliferation rate and transcriptional program early in the life span of the organism and suggest a model of cardiac aging where phenotypic changes in the aging heart are not directly attributable to changes in proliferation rate or altered collagen expression in cardiac fibroblasts.
2020-10-26 | GSE160074 | GEO
Project description:Although DNA methylation data yields highly accurate age predictors, little is known about the dynamics of this quintessential epigenomic biomarker during lifespan. To narrow the gap, we investigate the methylation trajectories of male mouse colon at five different time points of aging. Our study indicates the existence of sudden hypermethylation events at specific stages of life. Precisely, we identify two epigenomic switches during early-to-midlife (3-9 months) and mid-to-late-life (15-24 months) transitions, separating the rodents' life into three stages. These nonlinear methylation dynamics predominantly affect genes associated with the nervous system and enrich in bivalently marked chromatin regions. Based on groups of nonlinearly modified loci, we construct a clock-like classifier STageR (STage of aging estimatoR) that accurately predicts murine epigenetic stage. We demonstrate the universality of our clock in an independent mouse cohort and with publicly available datasets.
2024-01-15 | GSE248002 | GEO
Project description:The balance between protein synthesis and protein breakdown is known as protein homeostasis (proteostasis) and loss of proteostasis is one of the Hallmarks of Aging. The latter is maybe best illustrated by the fact that many age-related diseases like Parkinson’s and Alzheimer’s are characterized by the appearance of protein aggregates. However, very few studies actually measure protein half-life, and hence the observed lowered protein translation rates in many longevity models do not necessarily mean that the combined rate of synthesis and degradation (i.e. proteostasis) is lost or changed. To get a better insight in the actual changes in proteostasis of each protein in the proteome we have developed a quantitative mass-spectrometry based method that allows for the estimation of the half-life of each individual protein in the proteome and that is suitable for use in C. elegans. We have used this method to determine protein half-lives in developing C. elegans models of longevity and age-related disease and found that proteostasis, as measured by proteome-wide protein half-life is indeed dramatically changed in these models. However, the observed changes are in some cases unexpected and suggest that the combined rate of protein synthesis and breakdown does not necessarily correlate with eventual lifespan or healthspan. Furthermore, we show that the proteostasis network has a remarkable plasticity; in the tested models large changes in protein half-life are observed in the entire proteome rather than in a subset of proteins, thereby largely balancing the relative rate at which various biological processes proceed. Lastly, our data indicate that proteostasis is regulated at the level of the whole organism rather than at the single cell level. The here described method and observations are a start to further unravel how proteostasis and healthy aging are intertwined.
2016-07-29 | PXD004561 | Pride