A Class of Calorie Restriction Mimetic Targeting NRF2

NRF2, or SKN-1 in the nematode worm Caenorhabditis elegans, is one of the many coordinating stress response genes activated by calorie restriction or a range of other forms of mild cellular stress. Part of the way in which this results in improved health and extended life span in a range of species is through activating cellular protection and repair mechanisms. Researchers are interested in ways to recapture this reaction to stress via pharmaceuticals rather than diet, and so are working their way through the drug databases in search of prospects. The results here are an example of the sort of thing they are looking for: a drug already approved for use that might be adapted as a calorie restriction mimetic treatment.

Sadly this is marginal work; calorie restriction does have very positive effects on human health, but only small effects on human life span. Short-lived species have a much greater plasticity of life span in response to environmental circumstances than is the case for long-lived species such as our own. So calorie restriction is worth pursuing as something that is free, but it is not worth billions in research and development investment when there are other, potentially far more effective ways forward. Why tinker with adjusting metabolism for tiny gains when we could follow the SENS rejuvenation research road and add decades of health life with the same investment in time and funding? The real battle in aging research these days is shifting from convincing people it is worth doing at all to convincing people to adopt strategies that will produce large results: human rejuvenation, the reversal of aging, not just a modest slowing of the underlying processes.

An FDA-approved drug to treat high blood pressure, hydralazine, extended life span about 25 percent in two strains of C. elegans, one a wild type and the other bred to generate high levels of a neurotoxic protein called tau that in humans is associated with Alzheimer's disease. "This is the first report of hydralazine treatment activating the NRF2/SKN-1 signaling pathway. We found the drug extends the life span of worms as well as or better than other potential anti-aging compounds such as curcumin and metformin. The treatment also appeared to maintain their health as measured by tests of flexibility and wiggling speed."

The NRF2 pathway protects human cells from oxidative stress. The body's ability to protect itself against damaging oxygen free radicals diminishes with age. One of the hallmarks of aging and neurodegenerative diseases such as Alzheimer's and Parkinson's is oxidative stress, which is believed to result cumulatively from inflammatory and infectious illnesses throughout life. SKN-1, a C. elegans transcription factor, corresponds to NRF2 in humans. Both play a pivotal role in their respective species' responses to oxidative stress and life span.

The researchers performed in vivo (in a living creature) and in vitro (in a lab dish) studies on the worms. Compared with untreated controls, roundworms treated with the drug showed about a 25 percent increase in life span (from 15-18 days to about 20-23 days), the team reported. The results of a series of biochemical experiments indicated that the hydralazine-linked life span extension was dependent on the worms' SKN-1 pathway via a mechanism that appeared to mimic caloric restriction. "Based on these results, we suggest that hydralazine may be a good candidate for clinical trials for the treatment of age-related disorders in humans as it may also offer general health benefits to the aging population."

Link: http://www.utsouthwestern.edu/newsroom/articles/year-2017/hbp-drug.html

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