The genetics of ageing Kenyon, Cynthia J
Nature (London),
03/2010, Letnik:
464, Številka:
7288
Journal Article
Recenzirano
The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more. Assuming that the ancestor we share with nematodes aged rapidly, this means that over ...evolutionary time mutations have increased lifespan more than 2,000-fold. Which genes can extend lifespan? Can we augment their activities and live even longer? After centuries of wistful poetry and wild imagination, we are now getting answers, often unexpected ones, to these fundamental questions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutations in genes affecting endocrine signaling, stress responses, metabolism, and telomeres can all increase the life spans of model organisms. These mutations have revealed evolutionarily ...conserved pathways for aging, some of which appear to extend life span in response to sensory cues, caloric restriction, or stress. Many mutations affecting longevity pathways delay age-related disease, and the molecular analysis of these pathways is leading to a mechanistic understanding of how these two processes—aging and disease susceptibility—are linked.
Although individuals age and die with time, an animal species can continue indefinitely, because of its immortal germ-cell lineage. How the germline avoids transmitting damage from one generation to ...the next remains a fundamental question in biology. Here we identify a lysosomal switch that enhances germline proteostasis before fertilization. We find that Caenorhabditis elegans oocytes whose maturation is arrested by the absence of sperm exhibit hallmarks of proteostasis collapse, including protein aggregation. Remarkably, sperm-secreted hormones re-establish oocyte proteostasis once fertilization becomes imminent. Key to this restoration is activation of the vacuolar H
-ATPase (V-ATPase), a proton pump that acidifies lysosomes. Sperm stimulate V-ATPase activity in oocytes by signalling the degradation of GLD-1, a translational repressor that blocks V-ATPase synthesis. Activated lysosomes, in turn, promote a metabolic shift that mobilizes protein aggregates for degradation, and reset proteostasis by enveloping and clearing the aggregates. Lysosome acidification also occurs during Xenopus oocyte maturation; thus, a lysosomal switch that enhances oocyte proteostasis in anticipation of fertilization may be conserved in other species.
The goal of aging research is to extend healthy, active life. For decades, C. elegans daf-2 insulin/insulin-like growth factor 1 (IGF-1) receptor mutants have served as a model for extended lifespan ...and youthfulness. However, a recent report suggested that their longevity is associated with an undesirable phenotype: a disproportionately long period of decrepitude at the end of life. In the human population, such an outcome would be a burden to society, bringing into question the relevance of daf-2 mutants as a model for life extension. However, here we report that, following an extended period of movement, daf-2 mutants survive longer in a decrepit state because of a beneficial trait: they are resistant to colonization of the digestive tract by dietary bacteria, a condition that leads to premature death in the wild-type and prevents their manifestation of decrepitude. If bacterial colonization is prevented, then daf-2 mutants lead both chronologically and proportionately healthier lives relative to the wild-type.
Display omitted
•Long-lived daf-2 mutants remain active longer but then experience extended decrepitude•daf-2 mutants are resistant to death caused by dietary bacteria•Eliminating food-induced mortality in the wild-type extends end-of-life decrepitude•Reduced late-life mortality explains the extended state of decrepitude in daf-2 mutants
Podshivalova et al. show that long-lived C. elegans insulin/IGF-1 receptor mutants remain active longer but then resist bacterially induced mortality, allowing them to survive into a state of end-of-life decrepitude. Thus, changes that slow aging and also prevent an age-associated catastrophe can extend both the youthful and infirm periods of life.
In
C. elegans, removing the germ cells extends life span by triggering the nuclear localization and activation of the DAF-16/FOXO transcription factor in the intestine. In this study, we identify and ...analyze genes required for germline removal to extend life span. We find that the reproductive system communicates with the intestine through lipophilic-hormone signaling and that a gene called
kri-1 is likely to act in the intestine to promote DAF-16 nuclear localization in response to this signal. This lipophilic-signaling pathway and
kri-1 are not required for DAF-16's nuclear localization and life-span extension in animals with decreased insulin/IGF-1 signaling. Thus, this pathway specifically enables the integration of cues from the reproductive system with central DAF-16-activation pathways to influence the aging of the animal.
In long-lived C. elegans insulin/IGF-1 pathway mutants, the life-extending FOXO transcription factor DAF-16 is present throughout the animal, but we find that its activity in a single tissue can ...delay the aging of other tissues and extend the animal’s life span. To better understand the topography of DAF-16 action among the tissues, we analyzed a collection of DAF-16-regulated genes. DAF-16 regulated most of these genes in a cell-autonomous fashion, often using tissue-specific GATA factors to direct their expression to specific tissues. DAF-16 could also act cell nonautonomously to influence gene expression. DAF-16 affected gene expression in other cells, at least in part, via the lipid-gene regulator MDT-15. DAF-16, and probably MDT-15, could act cell nonautonomously in the endoderm to ameliorate the paralysis caused by expressing Alzheimer’s Aβ protein in muscles. These findings suggest that MDT-15-dependent intercellular signals, possibly lipid signals, can help to coordinate tissue physiology, enhance proteostasis, and extend life in response to DAF-16/FOXO activity.
Display omitted
► DAF-16 regulates genes both cell autonomously and cell nonautonomously ► DAF-16 can act at in the endoderm to delay muscle aging ► DAF-16 can act at a distance to protect animals from amyloid paralysis ► Cell-non-autonomous gene regulation by DAF-16 involves the lipid-gene regulator MDT-15
Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on life span itself. We found that adding a small amount of glucose to ...the medium (2%) shortened the life span of
C. elegans by inhibiting the activities of life span-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the downregulation of an aquaporin glycerol channel,
aqp-1. We show that changes in glycerol metabolism are likely to underlie the life span-shortening effect of glucose and that
aqp-1 may act cell nonautonomously as a feedback regulator in the insulin/IGF-1-signaling pathway. Insulin downregulates similar glycerol channels in mammals, suggesting that this glucose-responsive pathway might be conserved evolutionarily. Together, these findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms.
Many ectotherms, including
C. elegans, have shorter life spans at high temperature than at low temperature. High temperature is generally thought to increase the “rate of living” simply by increasing ...chemical reaction rates. In this study, we questioned this view and asked whether the temperature dependence of life span is subject to active regulation.
We show that thermosensory neurons play a regulatory role in the temperature dependence of life span. Surprisingly, inhibiting the function of thermosensory neurons by mutation or laser ablation causes animals to have even shorter life spans at warm temperature. Thermosensory mutations shorten life span by decreasing expression of
daf-9, a gene required for the synthesis of ligands that inhibit the DAF-12, a nuclear hormone receptor. The short life span of thermosensory mutants at warm temperature is completely suppressed by a
daf-12(-) mutation.
Our data suggest that thermosensory neurons affect life span at warm temperature by changing the activity of a steroid-signaling pathway that affects longevity. We propose that this thermosensory system allows
C. elegans to reduce the effect that warm temperature would otherwise have on processes that affect aging, something that warm-blooded animals do by controlling temperature itself.
Inhibiting insulin/IGF-1 signalling extends lifespan and delays age-related disease in species throughout the animal kingdom. This life-extension pathway, the first to be defined, was discovered ...through genetic studies in the small roundworm Caenorhabditis elegans. This discovery is described here.
Aberrant protein aggregation is a hallmark of many age-related diseases, yet little is known about whether proteins aggregate with age in a non-disease setting. Using a systematic proteomics ...approach, we identified several hundred proteins that become more insoluble with age in the multicellular organism Caenorhabditis elegans. These proteins are predicted to be significantly enriched in beta-sheets, which promote disease protein aggregation. Strikingly, these insoluble proteins are highly over-represented in aggregates found in human neurodegeneration. We examined several of these proteins in vivo and confirmed their propensity to aggregate with age. Different proteins aggregated in different tissues and cellular compartments. Protein insolubility and aggregation were significantly delayed or even halted by reduced insulin/IGF-1-signaling, which also slows aging. We found a significant overlap between proteins that become insoluble and proteins that influence lifespan and/or polyglutamine-repeat aggregation. Moreover, overexpressing one aggregating protein enhanced polyglutamine-repeat pathology. Together our findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
