Aging involves different cellular mechanisms and metabolic pathways. Each element can be optimized or modulated: caloric intake, exposure to toxic chemicals/stress, sleep, genetics/epigenetics, physical activity, and nutrients provided by food.
Polyphenols are elements in our diet that are present in plants. They have more than one phenol group per molecule. They are divided into groups that include phenolic acids, flavonoids, stilbenes, pterostilbenes, lignans, and tannins. Science is proving that some of these are relevant in the regulation of cellular senescence, in aging and in longevity.
Dr. Celia Gonzalo Gleyzes – Neolife Medical Team
To clarify a few concepts:
Sirtuins are a family of NAD-dependent protein deacetylase that play a critical role in a large number of biological processes, like the regulation of the cell’s energy state, cellular differentiation, and aging. Sirtuin 1 (Sirt 1), was initially identified in yeast as an important protein in aging. Sirtuin 6 plays a more relevant role in more complex organisms, like humans.
The link between Sirtuin 6 and Alzheimer’s disease is currently being investigated.
It is thought to play a part in telomere maintenance, DNA repair, genome integrity, energy metabolism, and inflammation. There’s a deficit of Sirtuin 6 in patients with Alzheimer’s disease, which makes it a future therapeutic target (1) (2).
Hormesis is a term used by toxicologists to refer to a biphasic dose response to an environmental agent that is characterized by a beneficial stimulation/effect with low doses and an inhibitory/toxic effect with high doses.
This is seen as an adaptive response of the cells and the organisms to a moderate (usually intermittent) level of stress. Examples include ischemic preconditioning, exercise, caloric restriction, and exposure to low doses of specific phytochemicals.
Hormetic responses involve enzymes like kinases and deacetylases, and transcription factors like Nrf-2 and NF-B. As a result, the cells increase their production of cytoprotective and restorative proteins including growth factors, antioxidant enzymes, and chaperones.
The famous saying “What doesn’t kill you makes you stronger” rings true in this case, as intermittent or pulsed exposure may produce opposite effects when compared to continuous exposure. Initial exposure may lead to an adaptive stress response with long-lasting protection against subsequent exposures. Stress in early life may increase resilience in later life, and a lack of stress may lead to vulnerability (3) (4).
Senescence refers to a stable cessation of cell division in cells subjected to a wide variety of types of stress. Cellular senescence plays an important role in various physiological and pathological situations, like development, regeneration, aging, or cancer.
The elimination of senescent cells with abnormal functioning (with the help of senolytics) would lead to an improvement in the state of the adjacent healthy cells, even perhaps allowing the regeneration of certain tissues.
Polyphenols with modulating effect on senescence, aging, and longevity
This is the 3,5,4′-trihydroxystilbene, polyphenol class: stilbenes. It is a polyphenolic phytoalexin (antimicrobial present in some plants) present in the grape Vitis vinífera), studied for its in vitro and in vivo properties (antioxidant, anti-inflammatory, anticancer).
Resveratrol promotes longevity in simple organisms like the Saccaromyces cerevisiae yeast, the C.elegans worm, the Drosophila melanogaster fly, and the Nothobranchius guentheri fish. Some studies indicate that the molecule would be less effective in larger species.
It can apparently lead to a 60% increase in life expectancy in some animal models, but the results vary depending on dosage, sex, genetics, and diet composition.
More research is needed in mammals at the moment, but the results are promising in experimental models of pathologies like amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease.
The antiaging effect of resveratrol comes from the activation capacity of Sirt1. Its effect is compared to that of caloric restriction (CR).
On the other hand, resveratrol prevents the oxidative stress (OS) induced by aging. Under conditions of OS, Sirt1 plays an important role, reducing levels of ROS (reactive oxygen species, which contribute to oxidative stress), and improving mitochondrial function.
Another anti-aging mechanism of resveratrol involves the plasma membrane redox system (PMRS) that is able to neutralize free radicals and protect cells from oxidative stress.
Proinflammatory cytokines (IL-8 and TNF-alpha) are reduced by resveratrol and anti-inflammatory ones (such as IL-10) are overexpressed.
In conclusion, resveratrol has been seen to induce responses in numerous biological models at hormetic doses.
The 3,5,7,3´,4´-pentahydroxyflavone, polyphenol class: flavonoids, subclass: flavonols, can increase the longevity of yeasts and C.elegans by 60 and 15% respectively.
Foods like red onion, broccoli, apples, and grapes contain large amounts of quercetin.
A combination of quercetin and dasatinib proved to be effective in removing preadipocytes and senescent endothelial cells. In an in vivo model of aged mice, this combination improved the ventricular ejection fraction, which would mean an improvement of the cardiovascular system in the elderly. Other experiments in mice showed improved physical conditions and increased longevity.
In humans, a pilot study was conducted involving 14 patients with idiopathic pulmonary fibrosis (a disease that leads to accelerated aging of the alveolar epithelium). The intermittent administration of the cocktail three days a week for more than three weeks improved the patients’ physical condition.
Quercetin alone improves senescence markers in renal tubule cells and renal fibrosis in obese dyslipidemic mice with a diet rich in fats.
Polyphenol class: other polyphenols, subclass: curcuminoids. It is a dye that comes from turmeric (from its root).
A 10% decrease in the senescent cells of the intervertebral discs (from donors) was observed, as well as the proliferation of healthy cells with a dose of 5 mcM of curcumin. Additionally, the production of inflammatory cytokines was reduced.
EF24, an analog of curcumin, designed to improve the bioavailability of curcumin, manages to induce the apoptosis (destruction) of senescent cells.
Numerous studies suggest that curcumin improves brain function in aging animals. It is also reported that this molecule would protect the cerebral cortex and hippocampus from aluminum toxicity.
The fact that curcumin may also induce senescence may be of interest in cancer research and liver fibrosis.
The catechins contained in green tea, similarly referred to as 3.5, 7, 3′, 4′-pentahydroxyflavone; polyphenol class: flavonoids; subclass: flavonols, administered to rats in water (0.02% dilution) are linked to an improvement in brain functions. The protective effect is evident in the reduction of beta-amyloid plaques.
EGCG, a flavonoid in this category, showed that under conditions of heat and oxidative stress, the treatment with this molecule improved longevity in C.elegans by 13.1% and 172.9% respectively. The effect was linked to the increased expression of proteins associated with stress resistance and genes associated with aging (5).
Polyphenols and their beneficial effects
We have found that certain polyphenols may have beneficial effects in terms of longevity and some therapeutic effects on some diseases. Further research will lead us to a future application in humans. We have yet to find the right dosages, so our current recommendation is to ensure you have a varied and balanced diet.
(1) Papel de las sirtuinas en el envejecimiento de cèlulas madre adultas [The roles of sirtuins in the aging of adult stem cells]. García García, María. URL: https://digibuo.uniovi.es/dspace/handle/10651/17918
(2) Emerging Roles of Sirtuin 6 in Alzheimer’s Disease. Mohamad Nasir NF1,2,3, Zainuddin A2,4, Shamsuddin S5,6. URL: https://www.ncbi.nlm.nih.gov/pubmed/29260452
(3) Hormesis defined. Author links open overlay panelMark P.Mattson. URL: https://www.sciencedirect.com/science/article/pii/S1568163707000712?via%3Dihub
(4) Hormesis in Health and Chronic Diseases. Li X1, Yang T2, Sun Z3. https://www.ncbi.nlm.nih.gov/pubmed/31521464.
(5) Mechanisms of aging and potential role of selected polyphenols in extending healthspan. Russo GL1, Spagnuolo C2, Russo M2, Tedesco I2, Moccia S2, CervelleraC2. URL: https://www.sciencedirect.com/science/article/abs/pii/S0006295219304186?via%3Dihub