Hypoxia as a Complicated Path to the Induction of a Beneficial Stress Response

The present dominant approach to the development of therapies to treat aging is not, sadly, the SENS rejuvenation research agenda, but instead efforts to persistently activate evolved responses to cellular stress. These mechanisms normally start up in response to exercise, calorie restriction, raised temperature, and the topic here, hypoxia, among other sources of stress. The responses generally lead to some period of more aggressive cellular maintenance, particularly autophagy, responsible for identifying and recycling damaged molecules and structures within the cell.

There is comprehensive evidence to support the idea that running these mechanisms at a higher level all the time, in the absence of stress, is beneficial. It is an aspect of numerous approaches shown to modestly slow aging in various short-lived species over the past few decades. As the authors of this short commentary note, in the case of hypoxia the situation is more complex, however. A number of age-related conditions involve disarray or excessive activation of mechanisms of the hypoxia response. That must be in some way reconciled with the evidence for overactivation of the hypoxia responses to modestly slow aging life in various animal studies.

Regardless, it is the case that enhancement of stress responses doesn't come with the expectation of sizable benefits to life span in humans. We know what the results of exercise and calorie restriction look like in our species, and they don't produce anywhere near as large an effect as additional decades added to our life spans. They are means to slow aging just a little. Slightly slowing aging is only worth it if the cost of developing the necessary therapies is low. Unfortunately, it is not low. The past twenty years have seen enormous sums and the careers of many scientists poured into the effort to understand cellular metabolism sufficiently well to recreate only thin slices of the response to calorie restriction, or exercise, or other stresses. If this level of effort is to be expended, then why is it being expended on a strategy that cannot produce meaningful gains, versus something more along the lines of SENS, that can in principle result in rejuvenation and lives extended by decades or more?

Cells in metazoan species produce energy via oxidative phosphorylation, a process that requires a carbon source and oxygen (O2). O2 homeostasis is therefore of utmost importance and is maintained by intricate circulatory and respiratory systems. When the function of these is compromised, cells in the afflicted areas experience lower than optimal physiological O2 levels, a condition termed hypoxia. To cope with hypoxia, cells employ an evolutionarily conserved pathway controlled by hypoxia-inducible factors (HIFs).

Proteins encoded by hypoxia-inducible genes are functionally diverse, their primary role is to reprogram the cell towards survival under a hypoxic microenvironment and trigger specific physiological responses to help organisms adapt to conditions such as high altitude by inducing synthesis of erythropoietin, a hormone that stimulates production of red blood cells, or wound healing by activating secretion of angiogenesis-stimulating factors such as VEGF. This fine-tuned physiological response to hypoxia can, however, also be co-opted and contribute to age-related diseases.

For example: hypoxia and HIF-1 may participate in the pathogenesis of atherosclerosis; overactivation of the HIF pathway in cancer has raised significant interest in its targeting with small-molecule inhibitors; HIF-1 activates mPGES-1 gene expression in chondrocytes and contributes to the excessive catabolism underlying cartilage destruction and osteoarthritis. In the context of aging-associated diseases, more work is required to establish whether activation of HIF plays a causative role or is the consequence of some other underlying changes. In either case, there is evidence that targeting HIF-1, rather than its targets, e.g. VEGF, in at least some of these conditions may provide broader effect and eventually translate into greater therapeutic efficacy. As the number of age-associated maladies with activated HIF increases, it is rational to consider whether combining early detection with a HIF inhibitory pill could be of benefit for preventive treatment.

However, the relationship between HIF and aging is more complex. Genetic studies mainly in invertebrates have shown that HIF might control normal physiological processes that both promote and limit longevity. Life span extension imparted by stabilized HIF-1 occurs by a mechanism genetically distinct from both insulin-like signaling and dietary restriction. On the other hand, increased life span of C. elegans hif-1 deletion mutants was explained in terms of either activation of stress-regulated transcription factor DAF-16 or reactivating endoplasmic stress resistance downstream of mTOR. Further studies are warranted to understand the role of HIF-1 in longevity in mammals before merit of therapeutic modulation of its activity for age-related disease can be assessed.

Link: https://doi.org/10.18632/aging.101395


So is HIF good or bad? I guess it depends on how much?

Posted by: Nathan McKaskle at March 13th, 2018 8:42 AM
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