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August 7, 2018

Aging Cells Rejuvenated When Hydrogen Sulfide Gives Splicing Factors a Lift

Cellular senescence in human cells. [Eva Latorre]

  • For aging cells, the Fountain of Youth gushes with hydrogen sulfide, which isn’t exactly convenient. Yes, in the laboratory, hydrogen sulfide has been shown to reverse some of the manifestations of cellular senescence, a state in which cells cease to divide but linger on, secreting inflammatory factors and driving age-related maladies. The hydrogen sulfide, however, is usually delivered by hydrogen sulfide donors in nonphysiological conditions. Could hydrogen sulfide’s benefits—which include, potentially, treatments against cancer, dementia, and diabetes—be obtained without relying on nonphysiological levels of hydrogen sulfide donors?

    To help answer this question, scientists based at the University of Exeter decided to explore the cellular events between the administration of hydrogen sulfide and the reversal of cellular phenotypes characteristic of senescence and aging. Essentially, these scientists started looking for a shortcut. And they may have found one.

    The University of Exeter team, led by Lorna W. Harries, Ph.D., associate professor, molecular genetics, assessed the effects of the slow release hydrogen sulfide donor Na-GYY4137, as well as the effects of three novel mitochondria-targeted hydrogen sulfide donors AP39, AP123, and RT01. The team evaluated how hydrogen sulfide affected splicing factor expression, cell proliferation, apoptosis, DNA replication, DNA damage, telomere length, and senescence-related secretory complex (SASP) expression in senescent primary human endothelial cells.

    "Nearly half of the aged cells we tested showed signs of rejuvenating into young cell models," says Dr. Harries, who attributed the “rescue of senescence phenotypes” to the upregulation of splicing factors, proteins that can cause genes to stop expressing one protein, and start expressing another.

    Detailed findings appeared July 19 in the journal Aging, in an article titled, “Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2.” According to this article, hydrogen sulfide had no effect on telomere length, apoptotic index, and the extent of DNA damage. Although some changes were noted in the composition of SASP, the real differences that were seen concerned splicing factor expression.

    “Na-GYY4137 produced a general 1.9–3.2-fold upregulation of splicing factor expression, whereas the mitochondria-targeted donors produced a specific 2.5- and 3.1-fold upregulation of SRSF2 and HNRNPD splicing factors only,” the article’s authors wrote. “Knockdown of SRSF2 or HNRNPD genes in treated cells rendered the cells non-responsive to hydrogen sulfide, and increased levels of senescence by up to 25% in untreated cells.”

    These findings data indicate that specific splicing factors may be implicated in endothelial cell senescence, and that these factors can be targeted by exogenous hydrogen sulfide. These factors, then, have potential as moderators of splicing factor expression and senescence phenotypes.

    "We used to think age-related diseases like cancer, dementia, and diabetes each had a unique cause, but they actually track back to one or two common mechanisms,” notes Dr. Harries. “This research focuses on one of these mechanisms, and the findings with our compounds have potentially opened up the way for new therapeutic approaches in the future. This may well be the basis for a new generation of antidegenerative drugs."

    "Our compounds provide mitochondria in cells with an alternative fuel to help them function properly," adds Matt Whiteman, Ph.D., professor, experimental therapeutics, at the University of Exeter and a coauthor of the current study. "Many disease states can essentially be viewed as accelerated aging, and keeping mitochondria healthy helps either prevent or, in many cases using animal models, reverse this.

    “These observations,” the article concluded, “suggest that modulation of intracellular and mitochondrial hydrogen sulfide through the use of donor molecules or other agents which produce or are derived from hydrogen sulfide such as perthiols and persulfides may have therapeutic potential in the future for extension of health span and treatment of age-related diseases.”

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