Another Example of a Marginal Senolytic Drug Candidate

Today, let us consider what happens when a new area of medical development arises, attracts a great deal of research funding, and then one or more companies raise even larger amounts of venture funding to take the first therapies to the clinic. This is the case for senolytics, the development of therapies - mostly pharmaceuticals - that can selectively destroy senescent cells. Good evidence for these cells to be a root cause of aging has existed for decades, but it wasn't until 2011 that research and scientific funding institutions were presented with animal study data that they couldn't continue to ignore. The years since have been a steady avalanche of ever more funding, evidence to link senescent cells to specific age-related conditions, and demonstrations of reversal of aspects of aging in mice through clearance of senescent cells.

What happens is that people take notice. Any group able to write a credible grant proposal in the aging research community has probably by now written several on the topic of cellular senescence. Grant writing follows the state of funding, and all academic organizations tend to steer themselves towards the better funded areas of their field. Equally, anyone in a position to start a pharmaceutical company or spin off a new program in their existing company is certainly giving strong consideration to senolytic research given the $300 million or so that Unity Biotechnology has raised to date. The upshot of all this is that a great deal of discovery work is taking place, both inside and outside the scientific community; people are sifting drug databases and the compounds of the natural world in search of gold. Of course, the median result is much less valuable.

In any sort of drug discovery research, the outcome of the average well-informed project is usually many dead ends and a marginal lead or two if luck is with the researchers. Good results are rare. This means that the present few effective senolytics will soon be vastly outnumbered by marginal and alleged senolytics, the latter being those for which the research community struggles to replicate results. That in and of itself usually indicates that the effect size is small, or that reported positive effects are due to experimental error. Going forward, as the public at large gains a greater awareness of senescent cells and senolytics, supplement makers will seize upon any plant extracts claimed to have (likely tiny) effects on senescent cells, and start marketing to the gullible. The first thing you should look at for any newly claimed senolytic is the size of the effect. Most can be safely ignored on this basis alone, as is the case in the cell culture study noted here.

Blocking negative effects of senescence in human skin fibroblasts with a plant extract

Cellular senescence is involved in the development of age-related diseases and the loss of tissue functionality with age. Senescent cells accumulate in vivo and their selective elimination increases the healthspan of mice. While transiently present senescent cells have beneficial functions in wound healing, their chronic persistence and accumulation with age negatively affects the surrounding tissue by the senescence-associated secretory phenotype (SASP). This consists of pro-inflammatory cytokines and chemokines, extracellular matrix (ECM) remodelling proteases and growth factors and results in a vicious cycle of progressive functional loss in tissues and organs.

Negative effects of cellular senescence can be counteracted by: (i) delaying the loss of cell type specific functionality mediated by senescence-associated de- or trans-differentiation, (ii) interfering with the negative effects of SASP or by (iii) selectively eliminating senescent cells. Indeed, several clinically approved drugs including glucocorticoids, metformin, rapamycin, and JAK inhibitors attenuate the SASP. In addition, senolytic substances have been identified including quercetin, dasatinib, navitoclax, piperlongumine, fisetin, A1331852, A1155463 and FOXO4 inhibiting peptides.

Solidago virgaurea, also known as goldenrod, is traditionally used as an anti-inflammatory herbal medicine. A recent study identified 3,4,5-tri-O-caffeoylquinic acid as the constituent with the highest reduction of tumour necrosis factor-alpha and interleuin (IL)-1β concentrations. However, the effect of extracts from S. virgaurea on cellular senescence and fibroblast subpopulations have not been studied so far. Here we report an alcoholic extract of Solidago alpestris (1201) with the ability to block negative effects of senescence in human skin fibroblasts including the SASP in vitro. We screened seven different plant extracts. 1201 showed the clearest effects in terms of changing cell morphology and of reducing SA-β-galactosidase activity and was therefore selected for further studies.

The extract 1201 exhibited weak senolytic activity and delayed the acquisition of a senescent phenotype. When administered to stress-induced premature senescent fibroblasts, this extract changed their global mRNA expression profile and particularly reduced the expression of various SASP components, thereby ameliorating the negative influence on nearby cells. The caffeoylquinic acids with their anti-inflammatory property are likely to be candidates for the SASP-attenuating property of 1201, whereas the three derivatives of quercetin, one of the three naturally occurring senolytics reported so far, could be the driving force behind the slow selective elimination of senescent cells. Thus, the investigated plant extract represents a promising possibility to block age-related loss of tissue functionality.

Comments

When is Oisin going to get to share in the avalanche of funding?

Posted by: Jim at April 26th, 2018 3:45 PM

@Jim, as Gary says in my interview Oisin is prefer to be independent company than get the avalanche of funding and probaly lack of their independence because investors will say what and when do to take their revenue as soon as possible. Oisin is very carefuly choose whom ask money from.

Posted by: Ariel at April 26th, 2018 6:01 PM

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