Saffron - Cardiovascular Benefits

Cardiovascular disease is a significant causative factor in mortality. Saffron has important anti-aging benefits including improvement of cardiovascular health. The bioactive constituents of saffron (Crocin and Crocetin) play major roles in cardiovascular fitness.

Significantly, saffron may therapeutically provide cardiovascular benefits in the following manner: (1)

• Hypertension / Blood Pressure.- Studies indicate that saffron may lower diastolic blood pressure. Much of this involved relaxation of blood vessels. Further saffron may increase nitric oxide levels, which also promote lowering of blood pressure.
• Inhibit LDL Cholesterol Oxidation -  As a potent antioxidant, saffron has been shown to inhibit LDL oxidation. Oxidized LDL is a component of atherosclerotic plaques.
• Inhibits Foam Cell Formation - Macrophage foam cell formation is a critical stage in the development of atherosclerosis. Active saffron components crocin and crocetin inhibit foam cells from developing.
• Inhibits Vascular Cell Adhesion Molecule-1 (VCAM-1) - Another important factor in atherosclerosis development. Again, VCAM-1 is suppressed by crocin and crocetin.

VASCULAR VX™  (Includes Saffron with Crocin and Crocetin)

REFERENCES:

(1) Roshanravan N, et al. The therapeutic potential of Crocus sativus Linn.: A comprehensive narrative review of clinical trials. Phytother Res. 2022 Jan

Atherosclerosis - Pterostilbene & Progression of Artery Disease

Atherosclerosis is a chronic degenerative disease condition which slowly blocks arteries, accelerate aging and is a contributing factor in most age-related deaths.The key event in the  initiation and progression of atherosclerosis is injury and inflammation to the arterial lining (endothelial cells).

• Endothelial Cell Injury Reduction 
• Atherosclerosis is intrinsically linked to damage of the endothelial cells in the artery lining. Such damage is attributed to inflammation and oxidative stress in the arterial wall. In animal models, pterostilbene mitigated the process of atherosclerosis and reduced inflammation in the blood vessels. Importantly, pterostilbene increased levels of protective Nrf2 in the endothelial cells.(1)
• Vascular Inflammation Prevention 
•  In the gut, there are bacteria that convert choline and carnitine into  trimethylamine (TMA). In turn, TMA is converted to  trimethylamine-N-oxide (TMAO).(2) Increased levels of TMAO correlate to cardiovascular disease, by increasing vascular inflammation and endothelial dysfunction.(3)
• Pterostilbene significantly reduces vascular inflammation by:
• altering the composition of gut bacteria, thereby reducing the levels of TMAO
•  decreasing inflammatory vascular markers, including TNF-alpha.(4)
• Protects Against Oxidized Low Density Lipoprotein (LDL) 
• Oxidized LDL targets the endothelium lining of the artery and causes cellular death of the endothelium. This facilitates atherosclerosis development. Pterostilbene inihibits expression of LOX-1, the cellular receptor for oxidized LDL in the endothelium. As such, pterostilbene mitigates the buildup of LDL and subsequent atherosclerosis.(5). 
• Attenuates Heart Aging (Myocardial Fibrosis)
• Oxidative stress negatively impacts heart function and accelerates aging of the heart. As a result of oxidative stress, including inflammation, the heart can become fibrotic, replacing heart tissue with non functional fibrotic tissue.  In lab studies pterostilbene has been shown to mitigate myocardial fibrosis.(6)

CURCUMIN PXC  (Pterostilbene)

REFERENCES

(1) Tang T, et al. Pterostilbene reduces endothelial cell injury in vascular arterial walls by regulating the Nrf2-mediated AMPK/STAT3 pathway in an atherosclerosis rat model. Exp Ther Med. 2020 Jan

(2) Rath S, et al. Potential TMA-Producing Bacteria Are Ubiquitously Found in Mammalia. Front Microbiol. 2020 Jan 

(3) Singh G, et al.  High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction. Int J Mol Sci 2019 Jul

(4) Koh YC, et al.  Prevention of Vascular Inflammation by Pterostilbene via Trimethylamine-N-Oxide Reduction and Mechanism of Microbiota Regulation.  Mol Nutr Food Res. 2019 Oct.

(5) Zhang L, et al.  Pterostilbene protects vascular endothelial cells against oxidized low-density lipoprotein-induced apoptosis in vitro and in vivo. Apoptosis. 2012 Jan

(6) Kang LL, et al. Pterostilbene Attenuates Fructose-Induced Myocardial Fibrosis by Inhibiting ROS-Driven Pitx2c/miR-15b Pathway. Oxid Med Cell Longev. 2019 Dec

Citrus bergamia risso (Bergamonte®) Bioactives - Promotes Longevity & Cardio Health

The unique flavonoids in citrus bergamia (Bergamonte®) have been previously shown to have potent cardioprotective properties including effective cholesterol support. Further research indicates that citrus bergamia flavonoids have additional beneficial properties which affect disease progression and longevity.(1)

• Cardiovascular Health -  Studies show that Bergamonte® decreases triglycerides, plasma blood glucose and dangerous small LDL particles (VLDL), which damage ateries and accelerate atherosclerosis. Furthermore Bergamonte® increases healthy HDL while maintaining essential levels of large LDL.
• Antioxidant & Anti-Inflammatory - These effects are systemic in nature and are believed responsible for the powerful action of Bergamonte® in supporting cardiovascular health as well as protection against degenerative diseases.
• Longevity: Activates AMPK - AMP kinase (AMPK) is involved in an important regulator of glucose and fatty acid metabolism. AMPK activation is tightly coupled with longevity, including "energy metabolism, stress resistance, and cellular proteostasis."  AMPK signaling is involved with activation of other longevity activators including FOXO and SIRT1. AMPK activation becomes inhibited with age. (2)  Bergamonte® activates AMPK.

VASCULAR STRENGTH  (Bergamonte®)

Bergamonte® is a registered trademark of HP Ingredients.

REFERENCES:

(1) HP Ingredients October 2016.

(2) Salminen A, et al. Age-related changes in AMPK activation: Role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways. Ageing Res Rev. 2016 Jul;

Remarkable Vinpocetine & Citrus Bergamot - Youthful Arteries and Suppressing Atherosclerosis

Arteries degenerate with age, via a process known as vascular remodeling, leading to atherosclerosis, stroke and other cardiovascular diseases.. Therefore, preserving youthful arteries is a very important factor in longevity. Two important supplements which have been shown to suppress degenerative changes to the arteries are vinpocetine and citrus bergamot polyphenols.

VASCULAR AGING - Involves changes to the vascular endothelium and smooth muscle which promotes increased hypertension and stiffness of the arteries. The results is an aged vascular system  which is characterized by inflammation and atherosclerosis. As such, the arteries lose their ability to expand and contract, and becomes stiff, thickened and inflamed. When the vascular system ages it becomes more susceptible to hypertension, ischemic stroke and coronary heart blockage (heart attack). Furthermore, vascular aging in the brain may lead to cognitive disorders due to diminished blood flow.

Key areas of Vascular Aging:

• NF-kB - The master transcription factor for promoting inflammation in the artery and is involved in atherosclerosis plaque progression.
• PDE1 (phosphodiesterase) - An isozyme which plays a key role in the pathological changes which occur in the vascular structure with age. Increased levels of PDE1 are associated with loss of vasodilator function, vascular smooth muscle senescence, increased blood pressure and vascular hypertrophy. (1,2)

VINPOCETINE -
Promotes youthful arteries via two mechanisms. Vinpocetine reduces the release of inflammatory cytokines from endothelial cells and vascular smooth muscle by targeting oxidative stress and inflammation of the arteries. NF-kB. Also, vinpocetine is a powerful inhibitor of PDE1.

• Suppresses Atherosclerosis - Via the inhibition of inflammation transcription factor NF-kB.(3)
• Inhibition of PDE1 - PDE1 is a key regulator in the pathological changes that occur in aging vascular functioning including changes to structure and blockage of blood flow. Aging (senescent) vascular cells are correlated with increased levels of PDE1. (4) Inhibition of PDE1 has been shown to reduce all biomarkers associated with vascular aging.

CITRUS BERGAMOT (Bergamonte®) - The polyphenols in Citrus Bergamot uniquely provide artery anti-aging benefits. Citrus Bergamot provides protection directly to the vascular endothelium, in addition to optimizing cholesterol and triglycerides and inhibiting non alcoholic liver disease.

• Vascular Endothelium Protection.  Targets arterial endothelium cells to reduce inflammation and oxidative stress. Both are associated with vascular aging.
• Inhibits Non Alcoholic Fatty Liver Disease (NAFLD). NAFLD is a common liver disease where fat accumulates in the liver, causing liver dysfunction and is correlated with increased cardiovascular disease and mortality. It is estimated that up to 25% of Americans have NAFLD. Furthermore, excess belly fat not only is predictor of increased cardiovascular risk, but normally indicates high fat in the liver and NAFLD.
• Bergamot polyphenols stimulate lipid metabolism thereby preventing toxic build-up in the liver. Removal of lipids is through enhanced autophagy. (6)
  
• Decreases Oxidized Cholesterol Receptors. LOX-1 is the receptor on the endothelium for oxidized cholesterol. Expression of LOX-1 is increased with pathological conditions including hypertenison, hyperlipidemia, and diabetes.(5, 7)
• Inhibits Phosphodiesterases (PDEs). Offers similar protections as vinpocetine in preventing age-related changes to vascular structure .(7)

 VASCULAR STRENGTH  (with Vinpocetine and Bergamot Polyphenols)

REFERENCES:

(1) Chan S, et al. PDE1 isozymes, key regulators of pathological vascular remodeling. Curr Opin Pharmacol. 2011 Dec

(2) Bautista N, et al. Phosphodiesterase 1 regulation is a key mechanism in vascular aging. Clin Sci (Lond) 2015 Dec

(3) Zhuang J, et al. Inhibitory effects of vinpocetine on the progression of atherosclerosis are mediated by Akt/NF-κB dependent mechanisms in apoE-/- mice. PLoS One. 2013 Dec.

(4) Yan, C. Cyclic nucleotide phosphodiesterase 1 and vascular aging. Clin Sci (Lond). 2015 Dec.

(5) Chen M, et al. LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther. 2002 Jul

(6) HP Ingredients. Support against NAFLD in those with Metabolic Syndrome. 2016 Apr.

(7) HP Ingredients. 2016.

Apigenin & Luteolin - Anti-Aging NAD+ Inflammatory Regulators & Brain Homeostasis

POWERFUL YELLOWS AND AGING. Apigenin and Luteolin. Many changes occur during the aging process, with the most profound being inflammation. Inflammation contradicts good health and becomes increasingly unregulated with age. Since inflammation is key in accelerating aging, it is important to modulate these effects, especially in the brain.

The gradual destruction of neurons by chronic inflammation (neuroinflammation) leads to brain deterioration and pathologies. In the arteries, inflammation facilitates the initiation and rapid onset of arteriosclerosis. It also is responsible for creating immune system dysfunction and autoimmune disease. Another affliction of the aging process is cancer, which is tightly associated with inflammation and cellular dysregulation. Apigenin and luteolin have both shown promise in supporting health aging including ensuring a healthy inflammatory response.  

Longevity NAD+.

• Apigenin increases levels of NAD+, which is a limiting factor in the ability of SIRT1 to enable numerous longevity effects. Apigenin works to increase NAD+ is via inhibition of CD38, which breaks down NAD+.(1)
• High levels of NAD+ (via SIRT1 activation)  results in inhibition of obesity in high fat diets, metabolic syndrome and  glucose intolerance.
• Degenerative brain disease associated with aging have high levels of CD38 and consequently low levels of NAD+. Therefore, apigenin may play an important role in increasing NAD+ in the brain and may mitigate brain degeneration. Biogerontology. 2014 Apr (2)

Nrf2 Activation.

• Nrf2 is a transcription factor is the trigger the cellular response to protect against damaging oxidative stress, including injury and inflammation as well as cellular homeostasis. Researchers suggest that Nrf2 may have a major impact on the health and lifespan.(3)
• Apigenin and luteolin are both Nrf2 activators.(4)

Inflammation

• Inflammatory diseases are prevalent in the aging population, as inflammation becomes a chronic condition with age. Moreover, inflammation is the  primary factor for the development of chronic ailments and skyrocketing health care costs with age.
• Chronic inflammation destroys the body (including the brain). This is not the normal immune system response, but  a chronic overstimulation, which continuously exposes the body to destructive and age accelerating inflammation. Such inflammation is normally low grade and the effects may take years to be evident.
•  Apigenin and luteolin have significant anti-inflammation properties, and may significantly reduce chronic inflammation.

Cardiovascular Artery Inflammation

• Oxidized LDL in arteries causes macrophage inflammation in the arteries which promotes arteriosclerosis. It is the survival and continued activation of the macrophages in the arteries which keep the arteries inflamed. Apigenin can induce autophagy of macrophages, thereby reducing inflammation and inhibit the progression of atherosclerosis.(5-6) 

Brain Degeneration / Neuroinflammation

• Inflammation. All Neurodegenerative diseases have chronic immune activation, in particular microglia inflammation, as a common feature. Over activation of microglia in the brain, creating a low grade chronic source of inflammation, slowly degenerates the neurons and other cognitive structures.
• Importantly, in the brain, apigenin and luteolin suppress the chronic activation of microglia - a key cause of inflammation in the brain.(7-10)
• Brain Fog. Includes symptoms "reduced cognition, inability to concentrate and multitask, as well as loss of short and long term memory." According to researchers much of this is attributed to inflammation and microglial activation in particular. Luteolin, inhibits many steps in the inflammation process in the brain, and, may be effective in in ameliorating brain fog.(9)
• Neurogenesis. Apigenin induces neurogenesis by promoting neuronal differentiation of stem cells primarily in the hippocampus (the memory center).(11)
• Apigenin reverses inflammation induced depression in lab animals. Effectively attenuated by apigenin were proinflammatory cytokines IL-1β (interleukin-1β) and TNF-α (tumor necrosis factor-α). (12)
• Protects neurovascular coupling. Apigenin maintains neurovascular coupling. This is an important relationship between the neurons and the vascular network in the brain. Maintenance of brain health depends on the ability to preserve and increase cerebral blood flow and oxygenation. Termed "white matter hypersensities" are the areas of the brain which developed micro vascular deficiencies, lack of blood flow, causing loss of neuro function. (13)

 Immune System

• Immune Allergic Response. Mast cells are primary to the immune allergic response which then releases a potent inflammatory response. Luteolin exhibits a modulatory effect on mast cell induced inflammatory response. (14) 
• Immunity Balanced Restoration. Inflammation disrupts the balance of the immune system function. Apigenin via an effective anti-inflammatory response, is capable of restoring  the immune response.(15)

Anti-Cancer

• Both apigenin and luteolin display potent ant-cancer properties.
• Apigenin:
  • Prostate Cancer Cells. Studies indicate that apigenin may inhibit the progression of prostate cancer including tumor growth and invasiveness. (16)
  • Colorectal Cancer Cells. Treated human colorectal cancer cells with apigenin, with extended exposure,  resulted in senescence of the cancer cells and attenuation of tumor formation. (17)
  • Cancer Stem Cells. Apigenin inhibits the stimulation and self renewal of ovarian cancer stem cells.(18)  Furthermore, apigenin may inhibit other cancer stem cells via inhibition of the same chemical promoter (casein kinase 2α) thereby inhibiting other cancer stem cell self-renewal.(19)
• Luteolin:
  • Anti-angiogenic - Cancer tumors grow by the creation of new bloods vessels, a process called angiogenesis. Luteolin inhibits the growth of new blood vessels in tumors.(20)
  • Cancer Stem Cells.  Certain breast cancers have a high rate of recurrence due to the continued growth from cancer stem cells. Research indicates that luteolin blocks the pathway for cancer stem cell maintenance and may eliminate cancer stem cells.(21)
  • Non-Small Cell Lung Cancer - Lab studies (in vitro) demonstrated the ability of luteolin to cause the cellular death of the cancer cells as well as inhibit migration.(22)

Anti-Diabetic Activity

• Apigenin and luteolin both inhibit gluconeogenic (glucose producing) and lipogenic (fat producing) gene expression.(23) 
• Apigenin improves glucose and lipid homeostasis.

Skin Rejuvenation

• Apigenin induces dermal collagen production, thereby serving as a potential agent improving collagen depleted skin. Collagen provides skin with youthful structure. Wrinkles are skin aging are the result of the loss of the collagen infrastructure.(24)

Hypertension

• Hypertension and low grade inflammation. Specifically, the link involves TLR4 - a protein involved with activation of  the innate immune response. Research indicates that TLR4 inflammatory response is key in the development and maintenance of hypertension.
• Apigenin was shown to significantly lower blood pressure in hypertensive rats, as well lowering inflammation, including reducing expression of TLR4 and inflammatory NF-KB and TNF-alpha.(25).

YELLOW LONGEVITY  (15 mg Apigenin plus 15mg Luteolin)

YELLOW NATURALLY  (10 mg Apigenin plus 10 mg Luteolin)

LONGEVITY NATURALLY (10 mg Apigenin plus 10 mg Luteolin)

CARTILAGE MAX (15 mg Apigenin plus 15 mg Luteolin)

REFERENCES:

1. Escande C, et al. Flavonoid Apigenin Is an Inhibitor of the NAD(+)ase CD38. Diabetes. 2013 Apr.

2. Braidy N, et al. Mapping NAD(+) metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence. Biogerontology. 2014 Apr;

3. Blackwell TK, et al. SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans. Free Radic Biol Med. 2015 Aug.

4. Paredes-Gonzalez X, et al. Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos. 2015 Apr 

5. Wang Q, et al. Inhibition of autophagy ameliorates atherogenic inflammation by augmenting apigenin-induced macrophage apoptosis. Int Immunopharmacol. 2015 Jul;

6. Zeng P, et al. Apigenin Attenuates Atherogenesis through Inducing Macrophage Apoptosis via Inhibition of AKT Ser473 Phosphorylation and Downregulation of Plasminogen Activator Inhibitor-2. Oxid Med Cell Longev. 2015

7. Yuan Y, et al. Anti-inflammatory effects of Edaravone and Scutellarin in activated microglia in experimentally induced ischemia injury in rats and in BV-2 microglia. BMC Neurosci. 2014 Nov

8. Wang S, et al. Neuroprotection of Scutellarin is mediated by inhibition of microglial inflammatory activation. Neuroscience. 2011 Jun

9. Theoharides TC, et al. Brain "fog," inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin. Front Neurosci. 2015 Jul

10. Huang F, et al. The inhibitory effect of luteolin on inflammation in LPS-induced microglia. Zhong Yao Cai. 2011 Nov

11. Taupin P. Neurogenic drugs and compounds. Recent Pat CNS Drug Discov. 2010 Nov

12. Li R, et al. The effects of apigenin on lipopolysaccharide-induced depressive-like behavior in mice. Neurosci Lett. 2015 May

13. Liu R, et al. The flavonoid apigenin protects brain neurovascular coupling against amyloid-β₂₅₋₃₅-induced toxicity in mice. J Alzheimers Dis. 2011

14. Kritas SK, et al. Luteolin inhibits mast cell-mediated allergic inflammation. J Biol Regul Homeost Agents. 2013 Oct-Dec

17. Banerjee K, et al. Oxidative stress triggered by naturally occurring flavone apigenin results in senescence and chemotherapeutic effect in human colorectal cancer cells. Redox Biol. 2015 Apr

18. Tang AQ, et al. Apigenin inhibits the self-renewal capacity of human ovarian cancer SKOV3‑derived sphere-forming cells. Mol Med Rep. 2015 Mar.

19. Liu J, et al. Apigenin inhibits HeLa sphere-forming cells through inactivation of casein kinase 2α. Mol Med Rep. 2015 Jan

21. Ma L, et al. Luteolin exerts an anticancer effect on NCI-H460 human non-small cell lung cancer cells through the induction of Sirt1-mediated apoptosis. Mol Med Rep. 2015 Sep

22. Davies AH, et al. Inhibition of RSK with the novel small-molecule inhibitor LJI308 overcomes chemoresistance by eliminating cancer stem cells. Oncotarget. 2015 Aug

23. Bumke-Vogt C, et al. The flavones apigenin and luteolin induce FOXO1 translocation but inhibit gluconeogenic and lipogenic gene expression in human cells. PLoS One. 2014 Aug 

24 Zhang Y, et al. Apigenin induces dermal collagen synthesis via smad2/3 signaling pathway. Eur J Histochem. 2015 Apr 

25. Chen X, et al. Scutellarin attenuates hypertension-induced expression of brain Toll-like receptor 4/nuclear factor kappa B. Mediators Inflamm. 2013