ABSTRACT
Dietary restriction extends lifespan and inhibits reproduction in many species. In Caenorhabditis elegans, inhibiting reproduction by germline removal extends lifespan. Therefore, we asked whether the effect of dietary restriction on lifespan might proceed via changes in the activity of the germline. We found that dietary restriction could increase the lifespan of animals lacking the entire reproductive system. Thus, dietary restriction can extend lifespan independently of any reproductive input. However, dietary restriction produced little or no increase in the long lifespan of animals that lack germ cells. Thus, germline removal and dietary restriction may potentially activate lifespan-extending pathways that ultimately converge on the same downstream longevity mechanisms. In well-fed animals, the somatic reproductive tissues are generally completely required for germline removal to extend lifespan. We found that this was not the case in animals subjected to dietary restriction. In addition, in these animals, loss of the germline could either further lengthen lifespan or shorten lifespan, depending on the genetic background. Thus, nutrient levels play an important role in determining how the reproductive system influences longevity.
Subject(s)
Caenorhabditis elegans/physiology , Caloric Restriction , Animals , Food , Longevity/physiology , ReproductionABSTRACT
Many conditions that shift cells from states of nutrient utilization and growth to states of cell maintenance extend lifespan. We have carried out a systematic lifespan analysis of conditions that inhibit protein synthesis. We find that reducing the levels of ribosomal proteins, ribosomal-protein S6 kinase or translation-initiation factors increases the lifespan of Caenorhabditis elegans. These perturbations, as well as inhibition of the nutrient sensor target of rapamycin (TOR), which is known to increase lifespan, all increase thermal-stress resistance. Thus inhibiting translation may extend lifespan by shifting cells to physiological states that favor maintenance and repair. Interestingly, different types of translation inhibition lead to one of two mutually exclusive outputs, one that increases lifespan and stress resistance through the transcription factor DAF-16/FOXO, and one that increases lifespan and stress resistance independently of DAF-16. Our findings link TOR, but not sir-2.1, to the longevity response induced by dietary restriction (DR) in C. elegans, and they suggest that neither TOR inhibition nor DR extends lifespan simply by reducing protein synthesis.
Subject(s)
Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Gene Expression Regulation/genetics , Longevity/genetics , Protein Biosynthesis/genetics , Saccharomyces cerevisiae Proteins/metabolism , Animals , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Caloric Restriction , Eukaryotic Initiation Factors/genetics , Eukaryotic Initiation Factors/metabolism , Forkhead Transcription Factors , Heat Stress Disorders/genetics , Heat Stress Disorders/metabolism , Protein Serine-Threonine Kinases , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Ribosomal Protein S6 Kinases/genetics , Ribosomal Protein S6 Kinases/metabolism , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism , Saccharomyces cerevisiae Proteins/genetics , Signal Transduction/physiology , Survival Rate , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
The great majority of cases of the Hutchinson-Gilford progeroid syndrome (HGPS) ("Progeria of Childhood'') are caused by a single nucleotide mutation (1824 C->T) in the LMNA gene which encodes lamin A and C, nuclear intermediate filaments that are important components of the nuclear lamina. The resultant mutant protein (Delta50 lamin A) is thought to act in a dominant fashion. We exploited RNA interference technology to suppress Delta50 lamin A expression, with the long range goal of intervening in the pathogenesis of the coronary artery atherosclerosis that typically leads to the death of HGPS patients. Short hairpin RNA (shRNA) constructs were designed to target the mutated pre-spliced or mature LMNA mRNAs, and were expressed in HGPS fibroblasts carrying the 1824 C->T mutations using lentiviruses. One of the shRNAs targeted to the mutated mRNA reduced the expression levels of Delta50 lamin A to 26% or lower. The reduced expression was associated with amelioration of abnormal nuclear morphology, improvement of proliferative potential, and reduction in the numbers of senescent cells. These findings provide a rationale for potential gene therapy.
Subject(s)
Coronary Artery Disease/genetics , Genetic Therapy , Lamin Type A/genetics , Progeria/genetics , Progeria/pathology , RNA Interference , Cell Culture Techniques , Cell Nucleus , Cell Proliferation , Cellular Senescence , Coronary Artery Disease/physiopathology , Fibroblasts , Gene Expression Profiling , Humans , Lamin Type A/physiology , Phenotype , Point MutationABSTRACT
In C. elegans, the transcription factor DAF-16 promotes longevity in response to reduced insulin/IGF-1 signaling or germline ablation. In this study, we have asked how different tissues interact to specify the lifespan of the animal. We find that several tissues act as signaling centers. In particular, DAF-16 activity in the intestine, which is also the animal's adipose tissue, completely restores the longevity of daf-16(-) germline-deficient animals, and increases the lifespans of daf-16(-) insulin/IGF-1-pathway mutants substantially. Our findings indicate that DAF-16 may control two types of downstream signals: DAF-16 activity in signaling cells upregulates DAF-16 in specific responding tissues, possibly via regulation of insulin-like peptides, and also evokes DAF-16-independent responses. We suggest that this network of tissue interactions and feedback regulation allows the tissues to equilibrate and fine-tune their expression of downstream genes, which, in turn, coordinates their rates of aging within the animal.
