Pomegranate - An Ancient Fruit with Infinite Wisdom

Pomegranate has multiple modes of action influencing various bodily systems; hence the reason pomegranate, in particular the standardised extract offers a plethora of health benefits; recognising the potential of this remarkable fruit led to the creation of Skin+Beyond.

The following blog will showcase the therapeutic modes of action and benefits pomegranate extract (PE) has to offer. Backed up by over 3,000 studies on PubMed. PE exhibits many attributes including antioxidant, anti-inflammatory, prebiotic, mitophagy (regeneration of cellular parts), autophagy, skin protection, hormone and gene regulation.

NB Patented, pomegranate extract (PE) is different to the fruit since it contains the key compounds linked to health in standardized amounts, mainly from the inedible peel.

PE contains potent antioxidants, namely punicalagins that are not only unique to pomegranate, but possess powerful bioactive free radical scavenging properties, with Pomella® standardised to 30% punicalagins. (1)

PE upregulates Nrf2 activity, an important mediator of antioxidant signalling during inflammation by boosting antioxidant enzymes e.g. superoxide dismutase. (2)

Inflammation is the key driver of all ageing processes and not just skin, mediated at every stage of disease progression by nuclear factor kappa beta (NF-κB), the master inflammatory pathway.

Punicalagins found in PE not only demonstrate potent anti-oxidant activity, but anti- inflammatory by suppressing the master inflammatory pathway, NF-κB that is implicated in every chronic disease including skin ageing, cancers, heart disease, stroke, autoimmune diseases e.g. rheumatoid arthritis, diabetes, Parkinson’s and Alzheimer’s to name a few. (3)

Pomegranate extract or PE exerts potent prebiotic properties that not only boosts gut health, but all areas of health.

PE polyphenols are converted into Urolithin-A by gut microbes. (4) This novel anti-ageing postbiotic improves mitophagy, the regeneration of the mitochondria or energy plants of the cells. (5) See under “Mitophagy” below.

PE polyphenols, especially punicalagins that are unique to pomegranate have put Urolithin- A in the higher echelons of health compounds with wide ranging benefits including skin, gut, joints, muscle, heart, brain, exercise performance and longevity to name a few.

Further PE via prebiotic action boosts akkermansia muciniphila, a novel probiotic strain that protects the gut barrier from inflammatory damage and exerts weightloss, anti-obesity and anti-diabetic properties as well as protecting the digestive tract from inflammatory/immune disorders e.g. IBD, Crohn’s. (6)

Mitochondrial dysfunction is the root to most if not all conditions of ageing. (7)

Due to age and/or poor lifestyle factors, the mitochondria (energy plants of the cells) are not replaced or regenerated via mitophagy, causing a reduced output of cellular energy (ATP) and more free radicals. Combined they lead to ageing of different bodily systems e.g. skin, joints, heart, brain, muscle, immune etc.

Mitophagy represents a new paradigm in anti-ageing, courtesy of Urolithin-A and transcription factor EB, that is metabolized (in the gut) and upregulated respectively via pomegranate polyphenols. By optimising mitophagy, you are essentially giving your engine (mitochondria) a tune up that runs the car (body) better with less exhaust emissions (free radicals in cells).

Similar to mitophagy, but this clearing and recycling process involves other parts of the cells that have become senescent or aged, including toxic and damaged aggregated proteins that are the hallmarks of neurodegeneration.

Autophagy plays an important role when it comes to ageing and longevity. As a person ages, autophagy decreases, which can lead to a build-up of cellular junk parts that hamper normal cellular functioning, and cause inflammation and mitochondrial damage.

Transcription factor EB (TFEB) regulates autophagy. (8) See directly below.

Pomegranate extract or PE also shows a separate mechanism of improving or rebooting mitophagy by activating the gene regulator, Transcription Factor EB (TFEB) independent of the gut postbiotic, Urolithin-A. Singapore researchers made this remarkable finding in 2019. (9)

TFEB has widespread implications for health including neuroprotection, anti-cancer and anti-inflammatory attributes. (10)

In fact improved expression of TFEB via pomegranate balances the immune response so effectively that it has been linked to the prevention of sepsis, a significant finding since sepsis has been implicated in 20% of global deaths. (11)

TFEB has been referred to as the master regulator of mitophagy (12) and autophagy. (13)

PE protects dermal fibroblasts (collagen and elastin producing cells) from UV damage similar to MitoQ, a £60 per month super antioxidant. This potent antioxidant and anti- inflammatory activity gives PE the ability to boost collagen and elastin synthesis. (14)

NB Dermal fibroblasts provide the machinery for dermal hyaluronic acid or HA synthesis and should be the key priority in targeting skin hydration. Importantly HA from creams and ingestible formats is cleared quickly and degraded from the dermis. (15)

Glycation is a process caused by free radicals from stimuli such as UV light and sugars reacting with proteins and fats to form advanced glycation end products (AGEs); these AGEs damage keratin, collagen and elastin in connective tissues e.g. skin, joints, vascular system (heart, brain), resulting in premature ageing. In fact glycation is a major issue for diabetics. (16)

Pomegranate especially in the patented Pomella® extract form, is a natural AGE product inhibitor and anti-inflammatory agent, showing great potential as an anti-glycative agent, thus slowing the progression this damaging process. (17)

Pomegranate offers so many mechanisms of action on skin health that it genuinely offers “All in one skin solution” that is 100% natural including the following:

PE and specifically Pomella® exerts potent, synergistic effects on protecting keratinocytes from free radical induced oxidative damage. (18)

PE protects the collagen and elastin producing cells, the dermal fibroblasts from DNA damage caused by free radicals, specifically the DNA of mitochondria that generate cellular energy, the lifeforce of all bodily systems including skin.

Skin ageing researchers in the UK, made a remarkable finding when PE compared well to MitoQ, a patented super antioxidant when protecting against UV induced damage. Further PE has many other therapeutic properties other than antioxidant. (19)

NB This was an inferior pomegranate product, and PE has many more attributes than just antioxidant.

Further antioxidant action of PE bioactives prevent glycation that damages keratinocytes and alters ceramide (fats) production in the epidermis, and damages the collagen and elastin structures in the dermis and the extracellular matrix. (20)

The key polyphenol unique to PE, punicalagins exerts potent anti-inflammatory attributes on via the inhibition of NF-κB, TFEB upregulation and courtesy of its gut metabolite, Urolithin-A Inflammation drives more free radicals and oxidative stress, leading to damage to epidermis and dermis layers of skin. (21)

PE also boosts skin barrier integrity via the prebiotic action in the gut that influences the skin via the gut-skin axis. It does this by making Urolithin-A that exerts gut barrier protection, which is anti-inflammatory, in turn protecting the skin via the gut-skin axis. (22)

Further PE boosts the novel probiotic, akkermansia muciniphila that also exerts gut barrier protection, that is anti-inflammatory in turn protecting the skin via the gut-skin axis. (23)

PE improves mitophagy via the gut metabolite Urolithin-A and upregulation of the gene expressor, transcription factor EB (TFEB). Both keratinocytes (keratin) and dermal fibroblasts (collagen and elastin) benefit from regenerating their mitochondria or energy plants via the mitophagy process that declines with age and/or poor lifestyle. (24)

If senescent cells and aggregated proteins are not cleared in the ECM due to a breakdown in autophagy, mitochondrial damage will result, thus effecting collagen synthesis and hyaluronic acid synthesis.

Autophagy plays a key role in the health of keratinocytes and dermal fibroblasts, thus optimising keratin, collagen and elastin production. (25)

Fortunately pomegranate extract or PE via the upregulation of transcription factor EB (TFEB) stimulates autophagy. (26)

Pomegranate extract or PE boosts collagen synthesis by protecting the dermal fibroblasts from oxidative damage and improving mitophagy. This amazing finding has only come to light recently and it represents a paradigm shift in bodily ageing. This study showed in relation to skin urolithin A increased type 1 collagen expression and reduced MMP-1 expression. (27)

NB MMP-1 is largely responsible for collagen and elastin degradation along with glycation.

PE prevents and slows glycation, a process caused by environmental stimuli e.g. UV rays and where sugar in the form of circulating glucose reacts with proteins, in turn forming advanced glycation end products or AGEs that damage the collagen matrix in skin as well as other areas such as joints; PE inhibits glycation significantly. (28)

PE and its polyphenols have been shown to prevent methylglyoxal (MGO) induced DNA damage of keratin producing cells (keratinocytes), and boost collagen and hyaluronic acid production in the extracellular matrix. (29)

NB Damage to keratin via AGE products also affects the structure and production of ceramides. Although PE does not directly boost ceramide production, it indirectly does and the niacinamide in Skin+Beyond boosts ceramide synthesis by 34%. (30)

This in turn helps to retain moisture and skin barrier integrity, thus maintaining firmness and protecting skin from environmental insults that cause inflammation and associated damage.

Please note there may be references to other extracts, but they have the same amounts of the key bioactive compounds e.g. 30% punicalagins.

• PE boosts water content by +51% in the stratum corneum, and +40% increase in skin hydration overall since PE boosts the production of hyaluronic acid that has impressive water retention properties (31)
• Pomegranate boosts hyaluronic acid (HA) in the extracellular matrix by 50%, and prevents cross Cross linkages prevent removal of damaged collagen (32)

NB The extracellular matrix or ECM that makes up over 70% of the skin, is the key player in repairing and regenerating the skin. (33)

• PE reduces wrinkle volume or depth by -26% and skin roughness by -31% (34)
• PE boosts blood microcirculation by reducing blood vessel permeability; this increases nutrient, water and oxygen delivery to the skin layers, in turn improving radiance (35)
• PE reduces the appearance of dark spots or hyperpigmentation and inhibits tyrosinase to decrease melanogenesis, reducing both melanocytes and melanosomes (36)
• PE can be helpful for severe cases of acne, especially when it’s inflammatory driven evidenced by papules and pustules. By reducing inflammation in the gut via S+B prebiotic action, you will alleviate all inflammatory linked skin conditions (37)
• PE protects against free radicals and oxidative stress caused by environmental stressors e.g. UV sunlight, pollution and toxins (38)
• PE improves skin tone and reduces dark spots and blemishes (39)
• Pomegranate extract also has been proven to boost hair health; the researchers found better hair strength, increased hair density and thickness, and an improved speed of hair growth in the participants (40)

Pomegranate extract or PE promotes hormone health since it contains the highest amount of oestrogen in the plant kingdom; hence the reason it is a boon for postmenopausal women; further PE boosts healthy estrogen in younger women, and prevents xenoestrogens (toxic metabolites) from chemicals and other products e.g. plastics

Pomegranate extract or PE offers postmenopausal protection from osteoporosis, heart disease, moods and hormone cancers e.g. breast; these benefits extend to all women. (41)

Longevity is very dependent on the amount of muscle you have! Sarcopenia is a muscle wasting condition that accelerates over 40, and is central to chronic decline and early

mortality. Believe it or not muscle wastage is linked to cognitive decline and even dementia. (42)

Pomegranate extract or PE makes Urolithin-A in the gut, which boosts mitophagy that prevents and reverses sarcopenia (loss of muscle mass); muscle mass and strength are the ultimate determinants in preventing chronic decline and improving longevity. (43)

Further Urolithin-A actually boosts NAD+ levels and upregulates the sirtuin-1 gene in skeletal muscle. NAD+ is a crucial co-factor in cellular energy production or ATP in the mitochondria.(44)

NB The sirtuin-1 gene is central to longevity, and NAD+ is often referred to as “The biggest discovery in regenerative medicine” or “The secret of life and anti-ageing”. Importantly niacinamide, another ingredient in Skin+Beyond is an effective precursor for making NAD+. No need for expensive NR and NMN precursors.

Pomegranate is often referred to as “The heart fruit” due to its positive effect on multiple factors that lead to heart disease and stroke. effective multiple mechanisms of action, including the reduction of arterial plaque by 36% in one year and that includes the carotid arteries supplying the brain with blood, in turn preventing and reducing the risk of stroke as well as heart attack. (45)

There is no such thing as bad cholesterol; oxidized cholesterol (oxLDL), a key factor in heart disease, is when LDL becomes oxidised or damaged due to inflammation from poor lifestyle. A further study showed a 59% reduction in oxidised cholesterol (oxLDL), a more accurate predictor of arteriosclerosis and associated heart attacks compared to LDL cholesterol. Further the study showed: (46)

• 130% increase in antioxidant capacity
• 21% reduction in systolic blood pressure
• 39% improvement in arterial plaque in one year

Due to various stimuli e.g. toxins, infections, gut inflammation (gut-brain axis), neurons come under assault via oxidative stress, inflammation and free radicals. Resultant neuroinflammation results from overstimulated microglia, the immune cells of the brain and key protectors of neurons. (47)

Pomegranate extract or PE has been demonstrated in a recent study to control (balance) microglia activation and dampen neuroinflammation, in turn protecting brain cells from further damage in an Alzheimer’s model. (48)

Further autophagy helps clear these toxic, aggregated proteins. When autophagy is dysfunctional in microglia, phagocytosis (clearing damaged cells and toxic proteins) breaks down and neuroinflammation ensues, leading to neurodegeneration.

Autophagy is boosted by the upregulation of Transcription Factor EB or TFEB (49), which in turn is upregulated by pomegranate extract or PE polyphenols as identified by researchers from Singapore in 2019. (50)

Another key factor in the initiation and progression of neurodegeneration is mitochondrial dysfunction. Caused by environmental stimuli induced oxidative stress and inflammation, and the breakdown in mitophagy system that removes and regenerates the damaged mitochondria, the energy plants of the cells. (51)

Pomegranate upregulates or boosts mitophagy via the production of the gut metabolite Urolithin-A and the upregulation of the gene expresser, TFEB. Further the pomegranate metabolite, Urolithin-A exerts antioxidant and anti-inflammatory attributes, and crosses the blood-brain barrier to protect neurons and their mitochondria (energy plants), in turn preventing the chronic microglia response (overreaction) that causes neuroinflammation, protein aggregate formation, and potential neuronal damage and loss. (52,53)

Glycation plays a role in the formation of amyloid protein aggregates, the hallmark of Alzheimer’s, and further amyloid proteins found in Alzheimer’s patients show evidence of glycation. This is significant when you consider that pomegranate prevents and retards glycation (see under “Anti-glycative”) and prevents the formation of amyloid plaques or deposits via microglial inhibition and autophagy as discussed here.

Interestingly the researchers in this study concluded that oxidative stress causes both

glycation and amyloid protein formation, and therefore effective treatment strategies could include antioxidants, and in particular polyphenols that are well studied for proven for their antioxidant and anti-inflammatory attributes. (54)

It’s often overlooked that the gut and brain are dependent on each other for optimum health via the gut-brain axis making the gut microbiome a key player not only in preventing neurodegenerative and mental health conditions; hence the reason the gut is often referred to as “The second brain”. (55)

When the good to bad microbes in the gut become imbalanced known as gut dysbiosis, the immune system reacts with an inflammatory response that migrates to the brain via the vagus nerve and in the case of gut barrier damage via the bloodstream.

If gut dysbiosis and associated gut inflammation is left unchecked, the intestinal barrier can be breached, often referred to as leaky gut syndrome, in turn allowing microbes, undigested food particles and toxins into the bloodstream. This prompts a chronic immune response and inevitable autoimmunity that causes a plethora of disease states e.g. irritable bowel disease Crohn’s, type I diabetes, rheumatoid arthritis, Lupus, MS, MND, Alzheimer’s.

The prebiotic activity of PE has three mechanisms of action:

• The gut metabolite, Urolithin-A protects the gut from inflammation and damage, which in turn prevents neurological and psychiatric problems via the gut-brain axis or leaky gut (56)
• PE boosts the numbers of akkermansia muciniphila, a novel probiotic that protects the gut barrier, in turn preventing damage and resultant inflammation and gut barrier permeability that causes brain inflammation (57)
• Boosting of probiotic numbers including Lactobacillus and Bifidobacteria family strains keeps a healthy balance of good to bad microbes (58)

Pomegranate improves immunity via multiple mechanisms of action. Mitophagy (via Urolithin-A and TFEB) or the regeneration of mitochondria to prevent uncontrolled immune responses such as chronic inflammatory chemical release and excess immune cell activation. The key is a balanced response to threats. (59)

Gut health equals immune health since 70% of immune cells are made in the gut. The potent prebiotic activity of PE promotes gut health. (60) See above under “Brain”.

Further PE upregulates TFEB that in turn improves immune health, so much so it has been shown to prevent sepsis, a pervasive condition due to imbalanced immune response, that can be deadly. (61)

Prebiotic action of pomegranate polyphenols as outlined above under “Brain” protect both the gut and beyond the gut into the digestive tract; worthy of special note is the novel gut microbe akkermansia muciniphila (AKKM) boosted by pomegranate polyphenols. (62)

AKKM consumes mucin in the gut wall, in turn releasing short chain fatty acids (SCFAs) that protects the digestive tract including the colon from inflammatory disorders (IBD, ulcerative colitis, Crohn’s) and cancers including colon. (63)

Pomegranate improves metabolic health by exhibiting cardiovascular (See under “Cardiovascular”), anti-obesity and anti-diabetic properties. It does so via a range of modes of action e.g. anti-oxidant, anti-inflammatory, prebiotic. However rising star in metabolic health is the exciting probiotic, akkermansia muciniphila that is boosted by pomegranate polyphenols and exerts its metabolic enhancing attributes through its actions in the gut and digestive tract. (64), (65)

Pomegranate extract or PE exerts multiple modes of action on preventing and improving joint and bone disorders.

Pomegranate extract or PE exerts potent antioxidant and anti-inflammatory properties that protect the fibroblasts (collagen and elastin producing cells) in joints and bone from free radical induced oxidative damage. (66)

PE boosts collagen synthesis and inhibits collagen and elastin degrading enzymes (MMPs), in turn boosting and protecting the health of joints and bone. Further PE exhibits ant- glycative properties, in turn protecting connective tissue from this other degrading process affecting connective tissues. (67, 68)

PE upregulates the gene encoder, transcription factor EB or TFEB that improves mitophagy (similar to Urolithin-A) and autophagy, in turn protecting joints and bones from degenerative disorders including osteoarthritis, rheumatoid arthritis and osteoporosis. (69)

Further pomegranate contains the highest amount of oestrogen in the plant World; post- menopausal women are low in oestrogen, which is also linked to joint and bone conditions. (70,71)

As well as the joint and bone promoting properties of PE (See under “Joints”); PE has potent sports performance and recovery attributes. (72)

The pomegranate gut metabolite Urolithin-A promotes NAD+ and Sirt-1 gene expression, both linked to increased muscle mass and increased lifespan. (73)

Further Urolithin-A prevents and reverses sarcopenia (loss of muscle mass); muscle mass and strength are the ultimate determinants in longevity. Hence the reason Urolithin-A also increased the lifespan of c. elegans worms. (74)

Pomegranate extract or PE demonstrates potent anti-cancer activity in many cancers including breast, colon, prostate, skin and lung. (75)

Written by Clark Russell, Founder of Skin + Beyond, a unique, hybrid prebiotic drink with patented Pomegranate Extract for skin and much, much more.