Today we are dealing with a new topic about anti-aging.
We would like to turn the concept around, because aging is good, but if we do it with health and vitality, then much better.

Our topic today is fisetin and cellular aging.
In the following lines you will be able to see how this substance, so present in our daily lives, would have impressive functions to reverse the aging of our cells, so that they remain active and functional for longer.
Here we start.

Aging

We have already talked a lot about the subject of aging and its different theories, but today we will focus on fisetin as a molecule representing an active ingredient.
Almost six decades ago, the phenomenon of the finite proliferation capacity of human fibroblasts was discovered (Hayflick, 1965), initiating a period of extensive studies on the mechanisms of cell growth arrest, particularly in relation to the causes of the aging process.

According to recent findings, cellular senescence, which is essentially permanent, appears to play distinct roles in normal physiology and in various pathologies.
Senescent cell phenotypes, which normally secrete pro-inflammatory proteins and target apoptosis, can undergo certain modes of pharmacologically induced intervention that lead to the reversal of cellular fate.

If we remember the theory, aging is a highly malleable process that can be modulated in different ways, such as with calorie restriction, intermittent fasting, exercise, and a plant-based diet rich in phytochemicals.
The use of bioactive compounds to eliminate senescent cells has recently emerged as a promising approach to slow aging and reduce the severity of chronic diseases.

What is fisetin?

Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a flavonol that has been identified as a secondary metabolite of many plants, found in their green parts, fruits, as well as bark and wood.
This substance shares distinct antioxidant properties with a host of other plant polyphenols.
In addition, it exhibits a specific biological activity of considerable interest in terms of the protection of functional macromolecules against oxidative stress.
On the other hand, it shows potential as an anti-inflammatory, chemopreventive, chemotherapeutic and recently also senotherapeutic agent.
DOI: 10.1017/jns.2016.41

Diet-derived antioxidants are increasingly being investigated for their health-promoting effects, including their role in cancer chemoprevention.
In general, plant-based antioxidants have received a lot of attention, as they can be consumed for longer periods of time with very little or almost no adverse effects.
Flavonoids are a widely distributed class of plant pigments, which are regularly consumed in the human diet due to their abundance.

Fisetin is currently being studied as one of the plant components of the diet and its role as an important epigenetic modulator of health status.
This substance is present in natural food products, distributed as follows: strawberries (Fragaria sp. 160 μg/g), apples (Malus sp. 26.9 μg/g), persimmons (Diospyros sp. 10.6 μg/g), lotus roots (Nelumbo sp. 5.8 μg/g), onions (Allium sp. 4.8 μg/g), grapes (Vitis sp. 3.9 μg/g), kiwis (Actinidia sp. 2.0 μg/g), peaches (Prunus sp. 0.6 μg/g), cucumbers (Cucumis sp. 0.1 μg/g) and tomatoes (Solanum sp. 0.1 μg/g). The average daily human intake is estimated to be around 0.4 mg. https://doi.org/10.1016/j.lfs.2017.12.005

The reason for this interest arises from relatively recent observations that fisetin is not only particularly effective as an antioxidant agent, but also shows remarkable selectivity in influencing multiple biological processes considered crucial for biological homeostasis.

In addition to antibiotic activity, fisetin shares distinct antioxidant activity with many other polyphenolic compounds, which was confirmed by several in vitro and in vivo models.
In addition, antioxidant effects, and in particular the induction of glutathione synthesis, are considered important when it comes to neuroprotection. https://doi.org/10.1089/ars.2012.4901

Other activities along these lines include improving long-term memory, antidepressant effects, inhibition of ischemic reperfusion injury, and improvement of behavioral deficits after stroke.

How does it work?

The chemistry of simple phenolics is quite complicated, and involves the reactivity of free radicals, ionoradicals, and organic ionic structures resulting from proton transfer.
Polyphenolic structures extended by the inclusion of a catechol ring are particularly susceptible to specific aromatic electron delocalization that may involve, as a result of contact with hydrogen acceptors, neighborhood quinone and diketone structures. https://doi.org/10.1080/10408390701856223

It has recently been shown that this natural compound could modulate different pleiotropic pathways (phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and p38, mitogen-activated protein kinases (MAPK)-dependent kappalight factor-activated B-cell chain enhancer (NF-κB)) that exerts a large number of biological effects including anti-inflammatory effects, hypolipidemic, hypoglycemic, antioxidant, neuroprotective, antiangiogenic and antitumor. https://doi.org/10.1016/j.ejphar.2021.174492

Neurological diseases

It is becoming increasingly clear that neurological diseases are multifactorial and involve alterations in multiple cellular systems.
Thus, while each disease has its own mechanisms and pathologies of initiation, certain common pathways appear to be involved in most, if not all, diseases of this type.
Therefore, modulating a single factor is unlikely to be effective in preventing the development of the disease or slowing its progression. A better approach is to identify small molecules (<900 Daltons) that have multiple biological activities relevant to the maintenance of brain function.

Not only does fisetin have direct antioxidant activity, but it can also increase intracellular levels of glutathione, the main intracellular antioxidant.
It can also activate key neurotrophic factor signaling pathways, has anti-inflammatory activity, and inhibits lipoxygenase activity, thereby reducing the production of pro-inflammatory eicosanoids and their byproducts. https://doi.org/10.2741/S425

In the study that we will present below, we attempted to evaluate the potential role of fisetin as a caloric restriction mimetic for neuroprotection in models of natural and accelerated aging induced by D-galactose in rats.
To this end, young aged rats were supplemented for six weeks with 15 mg/kg body weight of fisetin for the study with D-gal 500 mg/kg body weight subcutaneously and also naturally aged rats.
A reverse transcription polymerase chain reaction (RT-PCR) gene expression analysis was performed to assess the expression of autophagy, neuronal, aging, and inflammatory marker genes.
Apoptotic cell death and synaptosome membrane-bound ion transporter activities in brain tissues were also evaluated.

The data showed that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. In addition, it also improved mitochondrial membrane depolarization, apoptotic cell death, and alterations in synaptosome-bound ion transporter activities in the brains of aged rats.
RT-PCR data revealed that fisetin upregulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1, and neuronal markers (NSE and Ngb), and negatively regulated the expression of inflammatory genes (IL-1β and TNF-α genes) and Sirt-2 respectively in the aging brain. https://doi.org/10.1016/j.lfs.2017.11.004

Action on the mitochondria

The accumulation of reactive oxygen species (ROS) due to age-related functional decline in mitochondria is most pronounced in energy-intensive tissues, such as skeletal muscle, the heart, and the brain.
Age-related increase in ROS plays an essential role in myocyte apoptosis in the aging heart and the development of cardiovascular diseases, including atherosclerosis.
Emerging evidence suggests that ROS-induced oxidative damage contributes to brain aging.
The death of neuronal and glial cells is a major cause of brain aging.
Elevated ROS levels also correlate with an increase in age-related neuroinflammation, which can lead to neurodegeneration.

To determine radical scavenging activity, one study measured the percentage of 2,2-diphenyl-1-picrylhydracil (DPPH) radical inhibition with different concentrations of fisetin. There was a dose-dependent increase in the radical scavenging activity of fisetin. The percentage of DPPH radical inhibition was only 11.1 ± 0.52% for 0.001 g/l fisetin.
However, the inhibition effect increased to 76.9 ± 0.37% for 0.1 g/L fisetin and 89.0 ± 0.57% for 2 g/L fisetin.
In addition to the radical scavenging activity in vitro, the effect of fisetin on cellular ROS levels in vivo was examined, which decreased significantly in the treated animals compared to the control. https://doi.org/10.3390/ph15121528

Effects on intracellular glutathione

Not only does fisetin have direct antioxidant activity but it can also increase intracellular levels of glutathione, the main intracellular antioxidant.
The compound may also maintain mitochondrial function in the presence of oxidative stress.
In addition, it has anti-inflammatory activity against microglial cells and inhibits the activity of 5-lipoxygenase, thus reducing the production of lipid peroxides and their pro-inflammatory byproducts.

Glutathione plays a central role in maintaining cellular redox homeostasis.
A fairly significant number of studies have demonstrated age-dependent decreases in total glutathione. The age-related declines seen in many studies could be due to increased consumption, decreased production, or a combination of both. Higher consumption would be consistent with an increase in ROS production with age.
However, recent studies suggest that decreased production also plays an important role in the decline of brain GSH with age.

How does fisetin maintain glutathione levels?
In general, intracellular levels are regulated by a complex series of mechanisms including substrate availability and transport, synthesis and regeneration rates, glutathione utilization, and outflow to extracellular compartments.
Because glutamate and glycine are found in relatively high intracellular concentrations, cysteine limits glutathione synthesis in many cell types, including nerve cells.
In the extracellular environment, cysteine is readily oxidized to form cystine, so for most cell types, cystine transport mechanisms are essential to provide them with the cysteine needed for glutathione synthesis. https://doi.org/10.1007/s12263-009-0142-5

ACTIVATE REVIVE CELL PHONE

Active Revive Cellular, in addition to containing sufficient amounts of fisetin, synergistically adds other compounds that we cite below.

• · Green tea is rich in polyphenols, among which catechins stand out.
  Of these, the most abundant is epigallocatechingallate (EGCG), with high antioxidant power.

• · Quercetin is a flavonoid found in a wide variety of foods: apples, onions, berries, broccoli, spinach.
  It has properties with an anti-aging effect at the cellular level by improving its function, improving mitochondrial function and reducing inflammation and oxidative stress.

• · Curcumin is a polyphenol from the curcuminoid family found in the rhizomes of turmeric.
  Some of curcumin’s anti-aging properties include inhibition of certain pro-inflammatory signaling pathways and cytokines: TNF-α, IL-1b, IL-6, IL-8, and monocyte chemotactic protein 1 [MPC-1], transcription signal transducer activator (STAT), receptor (PPAR-γ), activating transcription factor 3 (ATF3), homologous protein C/EBP (CHOP), and the inducible inflammatory enzymes cilclooxygenase-(COX-)2 and metalloproteinases.
  It decreases oxidative stress by increasing the activity of superoxide dismutase (SOD) and decreasing the levels of malondialdehyde (MDA) and lipofuscin.
  It modulates the main signaling pathways that influence longevity such as IIS, mTOR, PKA, and FOXO.
  In addition, it hashormetic effects, through the stabilization of Nrf2 and improvement of the expression of HO-1.

• · Reishi is a medicinal mushroom used for centuries by traditional Chinese and Japanese medicine.
  Studies in human cells grown with this mushroom have shown that it can increase longevity by inducing autophagy and resistance to stress.
  It has antioxidant and anti-inflammatory effects and also reduces inflammation and improves cognitive function.

• · And as always, we have also added the excellent functions of resveratrol, vitamin C, Coenzyme Q10, pyrroloquinoline (PQQ), berberine and astaxanthin as essential collaborators of this preparation.

Conclusion

The pathophysiological determinants that lead to aging and related diseases are still unknown.
A lack of understanding of the many mechanisms underlying the onset of aging and related pathologies represents an obstacle to the development of targeted therapeutic strategies.

Recent evidence suggests, however, that the accumulation of senescent cells with aging may contribute to the onset of chronic and age-related diseases and conditions.
Its detrimental effects appear to be determined by metabolic changes and increased generation of reactive oxygen species.

In this case, fisetin has been shown to have a wide range of functions that would delay and even prevent the deleterious effects of aging.

Scientific evidence, which demonstrates the efficacy of senescent cell elimination in the positive modulation of inflammatory diseases, has aroused interest in the development of therapeutic strategies for the elimination of senescent cells, indicated as “senotherapy” in the absence of genetic modifications.

In this sense, fisetin has been shown to act as a sine therapeutic agent capable of extending shelf life, reducing levels of reactive oxygen species, and improving antioxidant cellular responses.