New Research: Fisetin as a potential supplement to extend health and lifespan

Study: Fisetin is a senotherapeutic that extends health and lifespan

Publication status and journal: Open Access in EBioMedicine published by The Lancet.

Motivation behind study: Some drugs have senolytic activities, clearing out senescent cells but they also have considerable toxicity. Earlier, quercetin a flavonoid, used as a cheap supplement, shown some senotherapeutic promise as well. The current study screened a panel of other flavonoids whose senolytic, senotherapeutic activity might be lead to an improvement upon quercetin.

Aging process studied and modulated: Cellular senescence is one of the 9 hallmark processes of biological aging where proliferating or terminally differentiated non-dividing cells enter a state of cell cycle arrest, resistance to apoptosis and usually develop a cellular phenotype secreting molecules making a hostile tissue microenvironment, See our earlier post entitled Cellular senescence: zombie cells and matrix metalloproteinases

Supplement screened: Fisetin is a naturally occurring flavonoid polyphenol, present in low concentrations in many fruits and vegetables eg. apples, grapes, onions, cucumbers and higher concentrations in strawberries. It is available as an oral dietary supplement. As the article says: ‘ Importantly, no adverse effects of fisetin have been reported, even when given at high doses’ citing this earlier study, called Fisetin Acts on Multiple Pathways to Reduce the Impact of Age and Disease on CNS Function.

Experiments done: In vitro, on cultured cells using mouse and human fibroblasts and in vivo, on animal tissues: progeroid syndrome and aged wild type mice. Human adipose tissue explants were used.

Selected results: 

‘In primary murine embryonic fibroblasts induced to senescence through oxidative stress and in human fibroblasts induced to senescence with the genotoxin etoposide, fisetin was most effective at reducing senescent markers.’

Chronic fisetin treatment reduced senescent markers in all studied tissues in progeroid mice showing accelerated aging: fat, spleen, liver, kidney.

Also in progeroid mice, fisetin also reduced oxidative stress in liver by measuring a lipid peroxidation product and increased intracellular glutathione hinting at antioxidant activity.

In naturally aged mice fisetin significantly  reduced the fraction of senescent cells in white adipose tissue.

In terms of lifespan extension:
To determine if fisetin-mediated clearance of senescent cells impacts the health or lifespan of mice, WT f1 C57BL/6:FVB mice were fed a diet containing 500 ppm fisetin beginning at 85 wks of age, roughly equivalent to age 75 years in humans. This resulted in an extension of median as well as maximal lifespan.
Strangely the paper does not express median lifespan extension in an explicitly quantified manner using percentages. There’s only 2 figures, Figure 5/A and Figure 5/B, a survival curve and a figure showing median lifespan in a box plot like manner, only including the actual individual data (mice) points. According to Fig 5/B median lifespan increased from 27 months to 30 months.

Bottom line: Best to cite the last paragraph of the paper:

Given that fisetin is a natural product found in common foods and available as an oral dietary supplement and has no reported adverse side effects, our pre-clinical data suggest that fisetin should be imminently translatable and could have a significant benefit to the health of elderly patients. Based on these mouse studies, clinical trials to evaluate the short-term benefits of intermittent fisetin treatment on certain aspects of aging such as frailty are currently underway.