Health Support Criteria

In most species, including primates, caloric restriction appears to extend lifespan and delay the onset of age-related diseases.¹ Autophagy, an evolutionarily conserved cellular mechanism for the degradation of damaged proteins and organelles, is induced as a response to caloric restriction and acts to recycle damaged molecular components in order to provide fuel and recycled structural materials for the cell. Consequently, the cell is able to maintain its energy needs during a period of low supply and, at the same time, rid itself of accumulated molecular debris that can compromise future cellular function. Over the last decade, we have learned that the health advantages and extension of lifespan associated with caloric restriction can also be positively influenced by specific dietary factors.

Polyphenols

Emergent research shows that plant-derived polyphenols, a nutrient class with over 8,000 known molecular species, can regulate the genes encoding the production of endogenous antioxidant enzymes; they also play an evolutionarily conserved role in mimicking the cellular and physiological effects of calorie restriction.2;3 In particular, recent studies confirm that a vast number of polyphenols are involved in regulating the signalling pathways of autophagy. To date, however, only a handful of the thousands of polyphenols have been studied extensively in this regard.

While much has been learned over the last decade, we have only begun to understand just how important this nutrient class is to our current health and long-term survival. For a more complete review of the role that polyphenols play in the health giving processes of autophagy and mitophagy (the maintenance and renewal of damaged mitochondria), please read Chapter 6 of the guide and Appendix III: Healthy Aging Support.

Resveratrol (3,5,4’ – trihydroxystilbene)

Resveratrol has been of great scientific interest due to the large number of studies suggesting its preventive and protective effects against cancer and heart disease.⁴ Found in grape skins, red wine, and a large variety of berry fruits, resveratrol mimics the effects of calorie restriction by favourably modulating gene expression to increase cell autophagy.^5;6 By directly influencing the SIRT1 longevity gene, resveratrol favourably influences other genes that positively affect lifespan.

Epigallocatechin gallate (EGCG)

Only recently was the most abundant green tea polyphenol, epigallocatechin gallate, definitively shown to induce autophagy.⁷ Numerous recent studies confirm the polyphenol’s ability to induce both autophagic and apoptotic cell death in various cancers.^8-11 EGCG has been found to increase available beclin 1, a protein encoded in an autophagy-related gene that plays a critical role in inducing autophagy and cell death in cancer cells.¹²

Silibinin

Milk thistle (Silybum marianum), a stout plant found in the dry rocky soils of southern Europe and western North America, contains silymarin, a mixture of flavonoids of which silibinin is the major constituent. There is strong evidence that the extract is hepato (liver)-protective and demonstrates anti-cancer properties. It has been shown to induce cell death triggered by reactive oxygen species. Several recent studies confirm that these properties are enacted through the nutrient’s ability to induce autophagic and apoptotic responses and reduce metastasis (spreading) of cancerous growths.^13-16

Quercetin

One of the most abundant of the flavonoid class of polyphenols, quercetin is present in a wide range of dietary sources, such as berries, apples, onions, broccoli, kale, grapes, and tea. Its antioxidant and anti-inflammatory properties have long been recognized as a benefit to longevity. The flavonoid has recently been shown to down-regulate the actions of mTOR (mammalian target of rapamycin), an enzyme encoded by the mTOR gene that is responsible for controlling cellular growth, proliferation, protein synthesis, nuclear transcription, and autophagy.^17;18 Quercetin also activates sirtuin (SIRT1), a protein encoded by the silent information regulator gene, to influence cell survival, stress resistance, inflammation, immune function, and mitochondrial biogenesis.^19;20

Curcumin

Curcumin is the yellow-coloured phenolic pigment obtained from the powdered root of Curcuma longa, an herb native to India, where the powdered root is used extensively in the diet. Curcumin demonstrates varied therapeutic effects as an anti-inflammatory, antibacterial, antiviral, antifungal, antitumor, and antispasmodic agent.²¹ It is also an important player in cell-signalling processes and the modification of the expression of several genes related to longevity.²²

A growing body of evidence indicates that mitochondrial dysfunction is the main culprit in several chronic afflictions such as certain cancers, Alzheimer’s disease, Parkinson’s disease, cardiovascular disease, and type 2 diabetes.^23-26 Chronic oxidative stress associated with a deficiency in endogenous enzymes leads to cumulative damage in the mitochondrial membrane, with resultant mitochondrial dysfunction. Curcumin exerts strong antioxidant effects upon mitochondria, dampening the production of reactive oxygen species by up-regulation of cellular antioxidant defences.^27-29

Other Nutrients

Apart from the polyphenols, other dietary antioxidants play direct roles in modulating both autophagy and mitophagy. One of the most important of these is alpha lipoic acid.

Alpha Lipoic Acid (ALA)

Alpha lipoic acid plays an essential role in supporting mitochondrial health. In its reduced form (DHLA), it neutralizes reactive oxygen species such as the superoxide radical, the hydroxyl radical, hypochlorous acid, peroxyl radicals, and singlet oxygen. In animal-model studies, ALA and acetyl-l-carnitine (ALC), at miniscule concentrations within the cell, can dramatically increase mitochondrial mass, oxygen consumption, and fatty acid oxidation. Acting together, ALA and ALC appear to promote mitochondrial synthesis and enhance cellular metabolism.³⁰

Selenium

Modulation in mitochondrial function plays a key role in the regulation of apoptosis; it is also one of the targets of selenium compounds.^31;32 As well, sodium selenite exerts antitumor effects in several cancer cell types by inducing autophagic cell death and apoptosis.³³ Mitochondrial dysfunction is one of the major events responsible for activation of neuronal cell death pathways during cerebral ischemia (temporary loss of oxygen to the brain); selenium has been shown to protect neurons in such conditions. The antioxidant-like mineral preserves mitochondrial function, activates mitochondrial biogenesis, and prevents cell damage.³²

Vitamin D₃

Vitamin D plays an important role in providing immune support through its ability to enhance autophagy.³⁴ It maintains normal immune function and controls crosstalk between the innate (mature) and adaptive (naïve) immune systems.³⁴ Autophagy is an important mechanism for cellular homeostasis and survival during pathologic stress in the liver; vitamin D, acting through autophagy-dependent pathways, can preserve liver function.³⁵ Its ability to induce both autophagy and apoptosis through various cell-signalling pathways also provides a protective effect in other organs.^36;37

n-Acetylcysteine

The sulfhydryl (sulfur-containing) antioxidant n-acetylcysteine (NAC) appears to play a prominent role in modulating autophagic and apoptotic responses in cells and organelles. This action involves its dual role as a free radical antagonist and as a redox-signalling agent. The relationship is complex: in cases involving heavy metals and other environmental toxins NAC can reduce autophagy and increase cellular apoptosis;^38-40 in other cases, NAC plays a protective role inhibiting pro-inflammatory messengers and activating the signalling pathways important in regulating cell growth and proliferation.⁴¹ Several recent studies confirm NAC’s dual role in modulating both cellular and mitochondrial-based responses to oxidative, environmental, and physiological stressors that can damage important biomolecules and cellular components.^42-48

Summary of Intakes

Alpha lipoic acid, selenium, vitamin D, and n-acetylcysteine have recommended daily intakes for supplementation described in our Blended Standard; resveratrol, EGCG, silibinin, quercetin, and curcumin do not. For each of these nutrients, NutriSearch has reviewed the literature to determine a suggested daily intake within the physiological range known to elicit a cellular response. These daily values, while not specifically shown in the Blended Standard (pages 84-86 of the printed guide in English, French, and Spanish—pages 70-73 in the Chinese translation), are embedded in our analytical model. For more information on the suggested intakes for these nutrients, please read Appendix III, available online at www.nutrisearch.ca.

This new criterion assesses the product for the presence of these nutrients and compares their potencies to the suggested values of intake as determined from the literature and our Blended Standard.