In the field of anti-aging, the flavonoid fisetin is emerging as a potent longevity compound. Fisetin affects the aging process in experimental animals through multiple pathways, including senolytics (removing senescent cells)m SIRT1 activation, calorie restriction mimic and homeostasis.
Senolytics- the rejuvenation of the cellular environment, by eliminating senescent cells. Aging is characterized by the accumulation of senescent cells. These are cells which are irreversibly unable to grow and function and are resistant to normal cellular clearance. Senescent cells not only interfere with normal tissue functioning, but may also be toxic to neighboring cells. Fisetin, has been shown to be a potent senolytic, with the ability to eliminate senescent cells. (1)
- Scenescent Cells Accelerate Aging. Scenescent cells promote inflammation, stem cell dysfunction, chronic disease, and cellular aging.(2)
- Improve Healthy Lifespan. The elimination of specific age accelerating senescent cell populations is a potential strategy in improving health and longevity.(3)
- Fisetin - was the most potent and selective senolytic among flavonoids tested. Most importantly. fisetin administered to late-life laboratory animals, restored all markers of tissue homeostasis, and amazingly extended median and maximum lifespans.(4)
REDOX HOMEOSTASIS / IONIC HOMEOSTASIS
- Fisetin Improves Redox Homeostasis. Plasma membranes are affected by increased levels of oxidation and reduced antioxidants in cellular membranes. Fisetin signifcantly increases antioxidants in membranes and activates the redox protection system. (5)
- Fisetin Improves Ionic Homeostasis. Aging affects the plasma membrane of cells, and the membrane transporters. Impairment of the membranes transport function is related to age progression and disease. Specifically, membrane transporters are responsible for ionic homeostasis between intracellular and extracellular environments. Fisetin reverses these aging declines.(6)
SIRTUIN ACTIVATION (SIRT1)
Fisetin is an SIRT1 activator. Sirtuin activation plays a significant role in longevity. Among the anti-aging benefits include inhibition of cellular senescense, reduced telomere reductions, and enhanced DNA repair. Sirtuins interact with the major longevity pathways, among which is FOXO.(7)
PLURIPOTENT STEM CELLS (Induction)
- Stem cells are the regenerative cells of the body, and represent a primary mechanism for longevity. Fisetin has the unique capablity of converting adult cells (somatic)into pluripotent stem cells. A process known as induced pluripotent stem cells (iPSC). Pluripotent stem cells revert to any specialized cells for tissue repair, organ repair, and other anti-aging regeneration.(8) Fisetn as a sirtuin activator, enhances the generation of cellular reprogramming.
- Nrf2 is a powerful antioxidant pathway with strong correlation to longevity.(9)
- Fisetin is a potent activator of Nrf2 and is responsible for the cellular antioxidant activity of fisten.(10)
PROTEOSTASIS - ABNORMAL PROTEIN ACCUMULATION / AUTOPHAGY
- Proteostasis is the homeostasis of protein generation, folding and degradation of proteins. The dysregulation of this process results in aging and disease. Alzheimers Disease (AD) is example of the accumulation of toxic proteins in the brain.
- Fisetn supports reduction in abnormal accumulation and alterations of amyloid and tau in the brain. Fisetin has both antiamyloidogenic and fibril-destabilization activity,(11)
- Alzheimers Disease is characterized by amyoid beta and phosphoryated tau fibrils. FIsetin, through increased Nrf2 activation, enhanced the autophagic removal of phosphorylated tau.(12)
CURCUMIN PXC (contains Fisetin)
(1) Glossmann HH, et al, Metformin and Aging: A Review. Gerontology. 2019. Sept.
(2) Kirkland JL, et al. Cellular Scenescence. A Translational Perspective. EBioMedicine, 2017
(3) van Deursen JM. The role of Scenescent Cells in Ageing. Nature 2014.
(4) Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018
(5) Singh S, et al. Fisetin, a potential calorie restriction mimetic, attenuates senescence biomarkers in rat erythrocytes. Biochem Cell Biol. 2019 Aug
(6) Singh S, et al. Fisetin, a potential calorie restriction mimetic,modulates ionic homeostasis in senescence induced and naturally aged rats. Biochem Cell Biol. 2019 Sept.
(7) Shin-Hae Lee, et al. Sirtuin signaling in cellular senescence and aging. BMB Rep. 2019 Jan
(8) Chen T, et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell. 2011.
(9) Bai, et al. Small Molecules as SIRT Modulators. Mini Rev Med Chem. 2018.
(10) Zhang H, et al. Nrf2⁻ARE Signaling Acts as Master Pathway for the Cellular Antioxidant Activity of Fisetin. Molecules. 2019 Feb.
(10) Zheng W, et al. Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice. Int Immunopharmacol. 2017 Apr
(11) Simunkova M, et al. Management of oxidative stress and other pathologies in Alzheimer's disease. Arch Toxicol. 2019 Aug
(12) Sunhyo K, et al. Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors Sci Rep. 2016.