There will be Many Marginal Senolytic Drug Candidates

Senolytic compounds are those that can destroy senescent cells with minimal harm to other cells. Since a slow accumulation of senescent cells is one of the causes of aging, effective senolytics will be a form of rejuvenation therapy - and a high-class one at that, since senolytics have the potential to be both cheap and needed only once every few years at most. Now that research aimed at discovery of senolytic drug candidates is underway in earnest, we should expect that one of the outcomes will be a large number of compounds that are in fact not so great at this job: small effects, not discriminating enough in effects on senescent versus normal cells, or otherwise unsuitable. A good sign that the effect size in humans will likely be small is that the compound is already in widespread use, as is the case for most extracts from well-studied plants. I think this one is likely to be an example of the type, along with flavenoids such as fisetin and quercetin.

Intrinsic skin aging is a complex biological phenomenon mainly caused by intracellular stressors. Among various factors that accelerate intrinsic aging, the major causes are cellular senescence and mitochondrial dysfunction. When proliferating cells are exposed to various types of stressors, they may undergo growth arrest, termed as cellular senescence. Senescent cells exhibit various phenomena, such as cell-cycle arrest, gene expression changes, and secretion of inflammatory cytokines. Reactive oxygen species (ROS) mainly accelerate cellular senescence and also play a role in determining the lifespan of mammalian cells. Although senescent cells are relatively rare in young organisms, their number increases with aging. Senescent cells secrete numerous factors that have harmful effects on cells.

Kaempferia parviflora Wall. ex Baker, commonly called black ginger, has been used as a dietary supplement and traditional medicine in tropical countries. K. parviflora is reported to have antioxidative, anti-inflammatory, antiviral, and anticancer activities. However, its effect on intrinsic skin aging has not been verified. We investigated the inhibitory effect of K. parviflora on intrinsic skin aging process by evaluating its effect on cellular senescence and mitochondrial dysfunction using H2O2-exposed human dermal fibroblasts. In addition, its effect on skin aging phenotypes was evaluated using hairless mice.

Based on our results, KPE was found to attenuate cellular senescence in H2O2-treated fibroblasts and hairless mice by suppressing SA-β-gal activity and the expression of cell-cycle inhibitors. The restrained expression of cell-cycle inhibitors upon KPE treatment activates the E2F group, which is responsible for cell proliferation. In addition, KPE prevents cellular senescence by regulating the PI3K/AKT signaling pathway. In conclusion, KPE delays intrinsic skin aging process by inhibiting cellular senescence and mitochondrial dysfunction. KPE does not only attenuate cellular senescence through inhibition of the p53/p21, p16/pRb, and PI3K/AKT signaling pathways but also improve mitochondrial biogenesis through PGC-1α stimulation. Consequently, KPE prevents wrinkle formation, skin atrophy, and loss of elasticity by increasing collagen and elastic fibers in hairless mice.



What a lucky break that senolytics will likely bring both health and aesthetic benefits.

If there was a sure fire way to bring interest to the field, vanity is a good path to take.

We just need to find the really good ones. Probably some molecule discovered in the 60's, its been sitting as some buried patent in some university for the last 50 years. Hooray for high throughput screening!

Posted by: Mark Borbely at August 29th, 2017 9:32 AM

While I agree with the general point of this post, note that the authors aren't even claiming a senolytic effect - just that it inhibits conversion of non-senescent to senescent cells in vitro in response to oxidative stress, which is (a) what you'd expect of an antioxidant, and (b) probably irrelevant in vivo.

Posted by: Michael at August 29th, 2017 6:24 PM

Yet another Flavenoid (5,7 dimethoxyflavone) similar to Quercetin and fisetin. The skin results are rather extraordinary if they are to be believed, I am suspicious of the veracity of research done at Yonsei University. The mouse dose is very high, 200mg/kg/day for many weeks, not really practical as a regular supplement for humans. If it is actually working as a senolytic, one would think a periodic monthly dosing would be sufficient. I think I will buy some and add it to my Quercetin, Fisetin, Long Pepper rotation.

Posted by: JohnD at August 30th, 2017 2:11 PM
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