Protein degradation is an essential longevity assurance pathway. Maintaining high levels of autophagy can delay age-related decline in liver function. Obstacles to protein degradation tend to shorten the lifespan: blocking autophagy causes hypersensitivity to stress, and inhibiting the ubiquitin/proteasome pathway damages the mitochondria; both of these treatments kill neurons.
Conversely, longevity enhancement tends to enhance disposal of cellular garbage: In a worm model of Alzheimer’s disease, long-lived daf-2 mutants exhibit slower protein aggregation and decreased proteotoxicity, probably as a result of higher rates of protein degradation.
Despite the overall importance of protein degradation in delaying aging, the destruction of individual proteins is not always a good thing. During a screen of worm E3 ubiquitin ligases, Mehta et al. discovered that blocking the degradation of the HIF-1 protein dramatically increases lifespan and blocked the toxicity of pathogenic, aggregation-prone proteins.
Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans
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 amyloid beta 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/IGF-1-like signaling. These findings define VHL-1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.
The initial finding was that knockdowns of the E3 ligase VHL-1 were long-lived. VHL-1 is known to degrade HIF-1, the transcription factor involved in the hypoxic response. To rule out the possibility that another substrate of VHL-1 was important in the longevity enhancement, the authors used fairly straightforward genetic analysis: Mutating EGL-9, another gene required for HIF-1 degradation, also confers the lifespan extension, but neither vhl-1 not egl- mutants could live long in the absence of HIF-1.
The VHL-1/EGL-9/HIF-1 pathway is distinct from other means of lifespan extension: both daf-2 mutants and calorie restricted animals could extend the lifespan of hif-1 mutants, and conversely vhl-1 mutations could further extend the lifespan of daf-2 animals. This distinction may exist only at the level of the more upstream signaling events, however: DAF-16, the longevity assurance transcription factor that is disinhibited by daf-2 mutation, shares many target genes with HIF-1, so it is possible that the longevity enhancements rely on the same stable of stress-resistance and repair genes.
Will boosting HIF-1 levels also influence lifespan in mammals? Probably not, at least not in any simple way: the proteins involved are highly conserved — but VHL-1 is a tumor suppressor in humans, so targeting it with a drug is almost definitely a bad idea. Since suppression of the hypoxic response (especially angiogenesis) is likely to be important to the mechanism of tumor suppression by VHL-1, the same goes for HIF-1. It wouldn’t be incredibly surprising if this particular mechanism of lifespan regulation weren’t conserved between worms and mammals: worms don’t like oxygen as much as we do, so even if the machinery is conserved, the physiological consequences of activating that machinery might not be.
Still, as the authors point out, there might be some value in exploring manipulations of the hypoxic response in post-mitotic tissue – like brain — where the risk of tumorigenesis would presumably be smaller.
Mehta, R., Steinkraus, K., Sutphin, G., Ramos, F., Shamieh, L., Huh, A., Davis, C., Chandler-Brown, D., & Kaeberlein, M. (2009). Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans Science DOI: 10.1126/science.1173507
Autophagy is also used to dispose of intracellular pathogens. Some pathogens will attack autophagy machinery leading to the reduction of autophagy in the cell.
Junk is not the only thing that accumulates as the cell is now a breeding ground for pathogens.
This trying tweak to metabolism stuff really makes my head spin.
Lets look at the pathogens f**king up metabolism and spreading inflammation.
We need to know more about the heathy human microbiome.
Can you (or anyone) provide a reference to a study demonstrating that pathogens attack the autophagic machinery?
Next step: Is there any evidence that these pathogens are present (possibly at sub-acute levels) in human cells, either during the aging process or in aged individuals?
Detectability shouldn’t be an issue; modern PCR technology allows detection of a single copy of a genome.
We want to compare the microbiomes of aged tissue and of individual cells with youthful tissue and cells.
Do you think there may already be a study or does one need to be done?
I’m starting to think of autophagy as the intracellular immune system.
As a non-technical data point, the following personal experience may be relevent:
Limited hypoxia exposure is a method athletes use to improve red blood cell count, and so improve performance. As a cyclist, I have been sleeping for about 6 hours per night, five days a week, at 15.5% O2 (21% – sea level) in a hypoxic tent (for ~ 1 month). I have noticed that my fasting glucose is averaging 73 mg/dL after hypoxia vs 82 when sleeping without the device. I understand that reduced glucose levels are associated with reduced inflammation (diabeties, heart disease…) So perhaps this is a side benefit to the improved strength on the bike I am witnessing.
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