Living longer and stronger seems possible with Resveratrol

With an increasingly ageing population,¹ the hunt to discover new ways in which to reduce the aging process and improve cellular function to prevent chronic age-related disease is in full swing. At the centre of this search are strategies and therapeutics to support mitochondrial health, as dysfunctional mitochondria are linked to many aspects of ageing including neurodegenerative, metabolic,  and cardiovascular diseases, as well as cancer.² Of these therapeutics, resveratrol has been found to activate key epigenetic targets that are involved in cellular ageing, promote mitochondrial biogenesis and protect mitochondria,³ in addition to its well-known antioxidant and anti-inflammatory mechanisms. As such, resveratrol stands out as a star phytochemical to promote healthy aging.

Mitochondria

While mitochondria are generally thought of as the energy-producing organelles, they also play a significant role in cellular signalling and metabolic function within the body. Mitochondrial and cellular homeostasis requires tight regulation and coordination between the generation of new, and removal of old, damaged mitochondria (mitochondrial biogenesis and mitophagy, respectively). Altered mitochondrial dynamics where mitochondrial biogenesis and mitophagy are inhibited, leads to the accumulation of damaged and/or dysfunctional mitochondria. This results in further mitochondrial dysfunction and a build-up of damaged mitochondria, leading to the subsequent deterioration of cellular function that occurs with age.⁴

Mitochondrial dysfunction is recognised as one of the key hallmarks of the aging process,⁵ with three main theories linking the mitochondria and ageing. Firstly, the mitochondrial free radical theory of aging (MFRTA), suggests that mitochondria become damaged due to increased production of reactive oxygen species (ROS).⁶ When ROS levels are higher than the cell’s ability to maintain redox status, ROS become deleterious. However, at low levels, ROS are considered to exert a hormetic effect and have been shown to prolong lifespan.⁶ Secondly, as mitochondria harbour their own DNA (mtDNA), errors and/or deletions in mtDNA replication have been shown to lead to mitochondrial mutations, which increase with age.⁷ Thirdly, a loss of mitochondrial integrity impacts the ability of cells to respond to different stressors and consequently impacts signalling with the nucleus, regulation of gene transcription and interaction with other organelles.⁸ This results in reduced mitochondria biogenesis due to mitochondria dysfunction, leading to disease and ageing.²

Much ado about resveratrol

Mounting evidence continues to support resveratrol, the polyphenol found naturally in grapes, red wine and the herb Raynoutria japonica (Giant Knotweed), as a unique anti-ageing molecule. This is due to the multiple molecular target’s resveratrol interacts with, explaining the versatile pharmacological effects of this compound,⁹ which beneficially effects mitochondrial function and cellular signalling. 

One such target is nitric oxide (NO), which protects against mitochondria-mediated cell death and promotes mitochondrial biogenesis.¹⁰ Further, mitochondrial activity can be modulated by NO and has been shown to increase the concentration of mitochondrial proteins and mtDNA,¹¹ dysfunction of which, has been associated with disease and ageing.¹² Resveratrol is known to stimulate NO production via several mechanisms including the upregulation of endothelial NO synthase (eNOS) expression, stimulation of eNOS enzymatic activity and reversal of eNOS uncoupling.⁹  Due to its antioxidant action, resveratrol also prevents inactivation of NO by superoxide, enhancing its bioavailability.⁹ In one study, resveratrol was shown to improve NO production in 22 healthy volunteers given 300 mL/day of red wine (total polyphenolic concentration 1.8 g/L).¹³ 

Resveratrol has also been shown to stimulate mitochondrial biogenesis via the activation of silent mating type information regulation 2 homolog 1 (SIRT1), a B3 dependant deacetylase and key regulator of aging.¹⁴ SIRT1 stimulates mitochondrial biogenesis via the deacetylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α).¹⁵ Upon deacetylation, PGC-1α increases its activity as a coactivator several other transcription factors including nuclear respiratory factor 1 (Nrf1) and Nrf2, and mitochondrial transcription factor a (mtTFA), a key regulator of mtDNA transcription and replication.¹⁶ Further SIRT1-catalysed deacetylation modulates the activity of downstream proteins, influencing many biological processes that are critical in metabolic dysfunction, cardiovascular disease, inflammation, and age-related disease.¹⁷ For example, in randomised double-blind, placebo-controlled cross over study involving 11 obese men, 150 mg/day of resveratrol was shown to increase SIRT1 and PGC-1α.¹⁸

Another important molecular target of resveratrol is the transcription factor Nrf2, which is involved in several biological functions and is considered a master regulatory of the antioxidant response.¹⁹ Nrf2 increases mitochondrial membrane potential, increasing the availability of substrates for respiration and ATP production.²⁰ It also regulates levels of glutathione, which contributes to the mitochondrial redox balance and protects them from oxidative damage.²¹ Further, when cells are exposed to oxidative stress, Nrf2 translocates into the nucleus, activating the antioxidant response element (ARE) and subsequent transcription of antioxidant enzymes.²² Resveratrol has been shown to modulate Nrf2 signalling via the blockage of Keap1 by changing Nrf2 mediators, its expression and its nuclear translocation.²² 

Resveratrol: the promising anti-ageing polyphenol

With an impressive (and growing) list of molecular interactions, resveratrol is quickly becoming a trusted anti-ageing molecule. This is attributed to its beneficial effects on the mitochondria, as dysfunction of these organelles is implicated in ageing and the development of age-related conditions such as cardiovascular, metabolic and neurodegenerative diseases. Resveratrol acts on several important molecular targets, namely NO, SIRT1 and Nrf2, which regulate mitochondrial biogenesis, function and redox balance. These actions, compounded by well-known antioxidant and anti-inflammatory properties position resveratrol as a promising anti-ageing therapeutic, regulating mechanisms associated with mitochondrial dysfunction and cellular ageing, promoting longevity and reducing risk factors associated age and age-relate diseases.

The information contained within is intended to be used as an educational tool and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for your own health professional's advice.

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