ABSTRACT
The Caenorhabditis elegans von Hippel-Lindau tumor suppressor homolog VHL-1 is a cullin E3 ubiquitin ligase that negatively regulates the hypoxic response by promoting ubiquitination and degradation of the hypoxic response transcription factor HIF-1. Here, we report that loss of VHL-1 significantly increased life span and enhanced resistance to polyglutamine and beta-amyloid toxicity. Deletion of HIF-1 was epistatic to VHL-1, indicating that HIF-1 acts downstream of VHL-1 to modulate aging and proteotoxicity. VHL-1 and HIF-1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. These findings define VHL-1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.
Subject(s)
Aging/physiology , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/physiology , Cullin Proteins/metabolism , Oxygen/physiology , Proteasome Endopeptidase Complex/metabolism , Transcription Factors/metabolism , Amyloid beta-Peptides/toxicity , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/genetics , Caloric Restriction , Cullin Proteins/genetics , Female , Fertility , Gene Expression Regulation , Homeostasis , Insulin/metabolism , Longevity/physiology , Male , Models, Animal , Peptides/toxicity , RNA Interference , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Signal Transduction , Transcription Factors/genetics , UbiquitinationABSTRACT
In Asia, contact between persons and nonhuman primates is widespread in multiple occupational and nonoccupational contexts. Simian foamy viruses (SFVs) are retroviruses that are prevalent in all species of nonhuman primates. To determine SFV prevalence in humans, we tested 305 persons who lived or worked around nonhuman primates in several South and Southeast Asian countries; 8 (2.6%) were confirmed SFV positive by Western blot and, for some, by PCR. The interspecies interactions that likely resulted in virus transmission were diverse; 5 macaque taxa were implicated as a potential source of infection. Phylogenetic analysis showed that SFV from 3 infected persons was similar to that from the nonhuman primate populations with which the infected persons reported contact. Thus, SFV infections are likely to be prevalent among persons who live or work near nonhuman primates in Asia.
Subject(s)
Retroviridae Infections/transmission , Simian foamy virus , Zoonoses/transmission , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Ape Diseases/transmission , Ape Diseases/virology , Asia/epidemiology , DNA, Viral/genetics , Female , Humans , Male , Middle Aged , Occupational Exposure , Phylogeny , Retroviridae Infections/epidemiologyABSTRACT
Dietary restriction increases lifespan and slows the onset of age-associated disease in organisms from yeast to mammals. In humans, several age-related diseases are associated with aberrant protein folding or aggregation, including neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. We report here that dietary restriction dramatically suppresses age-associated paralysis in three nematode models of proteotoxicity. Similar to its longevity-enhancing properties, dietary restriction protects against proteotoxicity by a mechanism distinct from reduced insulin/IGF-1-like signaling. Instead, the heat shock transcription factor, hsf-1, is required for enhanced thermotolerance, suppression of proteotoxicity, and lifespan extension by dietary restriction. These findings demonstrate that dietary restriction confers a general protective effect against proteotoxicity and promotes longevity by a mechanism involving hsf-1.
Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , Caloric Restriction , Longevity/physiology , Transcription Factors/metabolism , Animals , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/drug effects , Food Deprivation/physiology , Longevity/drug effects , Peptides/pharmacology , Transcription Factors/drug effectsABSTRACT
Foamy viruses (FV) are retroviruses that naturally infect many hosts, including most nonhuman primates (NHPs). Zoonotic infection by primate FV has been documented in people in Asia who reported contact with free-ranging macaques. FV transmission in Asia is a concern, given abundant human-NHP contact, particularly at monkey temples and in urban settings. We have developed three assays capable of detecting the presence of FV in Asian NHP species that are commensal with humans: enzyme-linked immunosorbent assay (ELISA), Western blot assays using recombinant viral Gag protein, and an indicator cell line that can detect macaque FV. The recombinant ELISA correlates very well with the presence of FV sequences detected by PCR. We have used these assays to demonstrate both that FV is highly prevalent among free-ranging NHPs and that seroconversion occurs at a young age in these animals. These assays should also prove useful for large-scale analysis of the prevalence of FV infections in human populations in Asia that are commensal with free-ranging NHPs.