GENE ACTIVATION: REGULATING GENES TO SLOW AGING
Slowing Aging: FOXO and Sirtuins (SIRT)
Factors which affect aging are many and complicated. What is known:
• Aging affects the entire body, including the skin. While the skin is the most recognizable sign of aging, simultaneous aging is also taking place internally.
• Genes, those segments of DNA which encode (manufacture) proteins, which affect the functioning of the body, can significantly alter the path of longevity. Sirtuins are the proteins which are produced by activation / expression of a SIRT gene. For example, expression of SIRT1 produces sirtuin 1.
Studies involving worms, mice and fruit flies, which have significantly shorter lifespans, have offered clues into the potential genes and gene activators (transcription factors) involved in the aging process. Transcription factors are the protein activators of genes, which is also termed as gene expression. The expression of a gene creates a gene specific protein which is involved in regulating metabolic pathways in the body, including glucose metabolism, energy homeostasis and longevity. FOXO transcription factors, for example, are expressed in response to specific environmental factors, which in turn activate specific genes.
FOXO (transcription factors) are involved in regulating genes involved in cellular growth and longevity. In studies with lab animals, FOXO has been shown to be a potent longevity extender. It is postulated that FOXO may be the most important gene factors involved in longevity promotion. Additionally, there also appear to be a regulatory relationship between SIRT longevity genes and FOXO transcription factors.
TETRAHYDROCURCUMIN- Regulator of FOXO / Skin Anti-Aging FOXO Activator
• Tetrahydroxycurcumin, a bioactive metabolite of curcumin, regulates oxidative stress and cellular aging by the activating FOXO transcription factors. Laboratory studies support the powerful anti-aging effects of tetrahydrocurcumin.(3)
• Tetrahydroxycurcumin extends the lifespan of lab animals.
o Increased the lifespan of Mice an average of 11.7%(1, 2)
o Increased the lifespan of Drosophila melanogaster (fruit fly) based on FOXO inhibition of oxidative stress (3)
• Tetrahydroxycurcmin promotes skin health and longevity
o Superb Antioxidant. Protects keratinocytes (skin cells) by the inhibition of superoxideradicals Keratinocytes are the predominant cell type in the outermost layer of skin (epidermis).
o Prevents cellular membrane lipid oxidation. o Anti-Inflammatory: Including inhibition of inflammatory 5-LOX and COX enzymes.
o Inhibits breakdown of connective tissue in skin by inhibiting the enzymes: Inhibits Collagenase (breaks down collagen) Inhibits Hyaluronase (breaks down hyaluronic acid)
• Tetrahydroxycurcumin activating FOXO transcription factors target genes:
o Enhancing DNA Repair o Detoxification of Reactive Oxygen Compounds – by increasing Catalase and MnSOD (Maganese Superoxide Dismutase). Both are enzymes which are powerful in breaking down toxic cell oxygen reactive molecules.
Sirtuins proteins (Genes SIRT1-7) regulate biological pathways, including energy metabolism. Calorie restriction, for example, is known to increase longevity. Under conditions of calorie restriction, metabolism pathways activate SIRT1 genes, to produce sirtuin 1 protein. The sirtuin 1 protein activates pathways which conserve energy and promote longevity. Resveratrol is perhaps the most well known SIRT1 gene activator, which is known as the “longevity gene”.
HYDROXYTYROSOL & PTEROSTILBENE – Sirtuin Activators / Skin Anti-Aging Sirtuin Activator
• Hydroxytyrosol - .Olive polyphenol which invokes SIRT1, SIRT3 and SIRT4 anti-aging gene expression and FOXO. (4)
o Promotes longevity via targeted gene expression.
o Enhances mitochondrial biogenesis (new mitochondria) by virtue of SIRT3 and SIRT4 expression.
• Pterostilbene – Invokes expression of the SIRT1 and other SIRT genes. Similar in structure and action as its related molecule resveratrol, but has a significantly longer bioavailability than resveratrol.
• Hydroxytyrosol – Protects against skin aging by increasing antioxidant levels. Hydroxytyrsol prevents skin aging in the outermost layer of skin, the epidermis and the layer containing the collagen and elastin extracellular martix, the dermis. In the dermal layer, hydroxytyrosol extends the replicative lifespan of the fibroblasts, the cells necessary for the production of connective tissue, collagen and elastic fibers as part of the skin extracellular structural framework.
o Skin fibroblasts synthesize the extracellular matrix in the dermal layer, which acts as the supporting structure for skin. Hydroxytyrosol extends the life of fibroblasts, including their ability to maintain and regenerate connective tissue, collagen and elastin as part of the extracellular matrix.
o Skin fibroblasts are therefore capable replenishing connective tissue, for longer periods of time. Hydroxytyrosol increases levels of antioxidant MnSOD activity thereby reducing mitochondrial oxidative damage.(5) MnSOD is a major free radical scavenger in the skin in both the epidermal kertinocytes and the dermal fibroblasts and helps prevent skin aging.
(1) Kitani K, et al. Interventions in aging and age-associated pathologies by means of nutritional approaches. Ann N Y Acad Sci. 2004 Jun;1019:424-6.
(2) Kitani K, et al. The effects of tetrahydrocurcumin and green tea polyphenol on the survival of male C57BL/6 mice. Biogerontology. 2007 Oct;8(5):567-73. Epub 2007 May 22.
(3) Xiang L, et al. Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor. Aging (Albany NY). 2011 Dec 8.
(4) Mukherjee S, et al. Expression of the longevity proteins by both red and white wines and their cardioprotective components, resveratrol, tyrosol, and hydroxytyrosol. Free Radic Biol Med. 2009 Mar 1;46(5):573-8.
(5) Sarsour EH, et al. MnSOD activity regulates hydroxytyrosol-induced extension of chronological lifespan. Age (Dordr). 2011 Mar 8. (6) Sarsour EH, et al. Manganese superoxide dismutase protects the proliferative capacity of confluent normal human fibroblasts. J Biol Chem. 2005 May 6;280(18):18033-41.