The Sheekey Science Show – Senolytics

This new senescence biomarker may help evaluate senolytic efficacy.

Senescent cells, also known as “zombie cells”, accumulate with age. There are many different ways in which a cell can become senescent, however, they share similar features including cell cycle arrest and the secretion of a variety of factors, referred to as the senescence associated secretory phenotype (SASP).

The Sheekey Science Show - Senolytics

Many of these factors are proinflammatory, and whilst thought to be useful for “senescence surveillance” whereby immune cells are recruited to remove senescent cells, if the cells are not cleared this can result in chronic inflammation which could have deleterious pro-aging effects. Due to our current understanding it has been hypothesised that clearance of senescent cells, using senolytics, could have therapeutic potential for alleviating symptoms of age-related diseases.
The Sheekey Science Show - Senolytics

Many senolytics, such as fisetin and dasatinib & quercetin are in early-stage clinical trials. Detecting senescent cells and evaluating the efficacy of these senolytics is currently challenging without using quite invasive procedures, yet this is invaluable for getting senolytics tested in trials. Therefore, it is exciting to see in a recent paper from the Buck Institute that they have identified a lipid, dihomo-15d-PGJ2 that accumulates in senescent cells but is only released (& detectable by plasma and urine samples) on senolysis.

The Sheekey Science Show - Senolytics

Therefore, dihomo-15d-PGJ2 may be a new senescence biomarker to help evaluate senolytic efficacy. Moreover, they show in this study that the accumulation of dihomo-15d-PGJ2 is not just a bystander of senescence, but actually plays a key role in promoting senescence development; in part this is due to the ability of dihomo-15d-PGJ2 to activate the protein Ras, a G-protein that has many downstream targets including my favourite protein p53. p53 can then activate the enzymes that generate dihomo-15d-PGJ2 and so you end up with a positive feedback loop reinforcing dihomo-15d-PGJ2 accumulation and senescence.

Therefore, this study shows the importance of lipids, particularly a type of oxylipin, prostaglandins, in the development of senescence.

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