Anti-Aging Gene Regulation / Cellular Senescence

Genes and Aging

Aging is significantly influenced by our genetic codes (our genes). Genes are segments of DNA which contains genetic information upon which are body relies to function. Anti-aging gene regulation is the ability to control the expression of the gene which maximizes the cellular environment for health and longevity. Cells normally regulate gene expression to ensure that it can properly respond to changes in the cell, such as inflammation or damage to the cell. In response to these events, the cell will send gene activators which will cause the gene to be expressed and gene products (normally proteins) produced. Transcription factors are the activators of the gene expression and are responsible for producing the gene product.

As cells age, however, cellular regulation may make become more problematic. Aging results in damaged DNA being less able to be properly repaired and restored. Thusly, aged genes may not be correctly expressed or not expressed at all. Subsequently, the cells may become dysfunctional, and become unable to properly regulate gene expression. Eventually this leads to cellular senescence (cellular death).

 Anti-aging gene expression may also involve the inhibition of certain genes, especially those involved with the dysfunction of the inflammatory response(an over expression of these genes), creating chronic inflammation, which is a primary cellular aging mechanism. Furthermore, inflammatory gene activation is involved with disease processes such as carcinogenesis, and blocking the inflammation can help modulate the disease process.

Anti-Aging Gene Expression:

• Anti-Aging Expression of a gene which has either an anti-aging or other health promoting effect to targeted areas in the body. The effect may be throughout the body, or emphasized within a specific area. 

1. SIRT1 gene – When activated, the SIRT1 gene product is a protein (enzyme) referred to as sirtuin1. Sirtuin 1 is involved in metabolic and energy regulatory functions, and has been shown to promote health and longevity is laboratory animals. Activators of SIRT1:  pterostilbene and resveratrol

2. FOXO (Transcription Factor) – FOXO are proteins which regulate the expression of genes. FOXO both contributes to increased lifespan, activation of detoxification genes and tumor suppression. Increases antioxidant enzymes (1,2) Anti-aging and autophagy include the SIRT1and FOXO involvement(6). Curcumin and resveratrol can enhance autophagy and increase lifespan through these gene activating processes.(3)

3. P53 Tumor Suppressor Protein (Gene Product) – Encoded by the T53 gene. As a tumor suppressor, plays a major role in cancer prevention. o UpRegulators (Increase Activity of P53): curcumin(5,6), apigenin(17,18,19)

4. Nrf2 (Transcription Factor) – Master regulator of the antioxidant response system. As such, Nrf2 is key to the anti-aging activation of the endogenous antioxidant system in the body. This includes significant induced gene expression of antioxidant enzymes heme oxygenase-1 (HO-1) and glutathione reductase (GR). In the brain, gingerols (from ginger) have been shown to protect neurons from the oxidative stress created by the cytotoxicity of amyloid deposits by restoring depleted glutathione via the nrf2 pathway.(15)  Also, nrf2 INCREASES its own expression by binding to ARE (antioxidant response element). The action of some flavonoids (e.g. luteolin) is to enhance this binding, and the result is an even greater antioxidant response.(14) Nrf2 is VERY IMPORTANT in the gene response to oxidative stress and inflammation. By reducing cellular oxidative stress, it also prevents cellular senescence. Increasing Nrf2 activity has also been shown as a potential neuroprotection mechanism in laboratory research by preventing neuron death. o Upregulators (Increase Activity of Nrf2): pterostilbene(8), andrographolide, curcumin(11,12,13), Luteolin(14), ginger(15), EGCG(16) Andrographolide has been discovered to be one of the MOST ROBUST activators of Nrf2.

5. Enhances Mitochondria Function by Upregulating Gene Expression. The mitochondria are the energy engines of the cell, and decreased functioning of the mitcohondria isa prime indicator of cellular aging. Pterostilbene has been shown to significantly enhance gene expression of the mitochondria, improving function and energy generation.(24)

6. Curcumin - Anti-Aging Life Extension and Health Improvement. System-Wide Healthy Gene Expression.
LIFESPAN EXTENSION STUDIES:

     CURCUMIN AND D. MELANGASTER (FRUIT FLY): 
     STUDY 1: Curcumin extended the lifespan of two different strains of D. melanogaster. Not only was the
     lifespan extended, but the quality of life was also significantly improved (including locomotion).
     Authors of the study report that a critical component of curcumin's life extending actions was the ability
     to modulate a number of age-related genes.(27)
    STUDY 2: Curcumin also boosted the lifespan of  D. melanogaster in a second study, by significantly
    increasing gene expression of SOD (Superoxide Dismutase) and drecreasing lipid oxidation.(30)

    CURCUMIN AND C. ELEGANS (WORM)
    In other longevity research, curcumin extended the lifespan of c. elegans and at the same time reduced
    the accumulation of lipofuscin - a substance which is associated with aging that builds up in aging
    cells. Curcumin's powerful antioxidant properties (by enhancing the expression of antioxidant genes)
    was believed to be a major contributor to observed increase in lifespan.(29)

 Slowing Down of Aging Processes by Inflammation (Gene Inhibition)

• Chronic Inflammatory processes in the body significantly accelerate the aging process. Reducing the gene expression associated with inflammation, including inhibition of the transcription factors, is a target of many of the yellow flavonoids.

1. NF-kB (Transcription Factor) – An important part of the immune system. Stimulates inflammatory response. However, over expressed and dysregulated NF-kB Increases pro-inflammatory gene expression and is linked to cancer, autoimmune disease and accelerated aging. NF-kB is also chronically active in arthritis, inflammatory bowel disease, sepsis and cardiovascular disease. Low grade chronic inflammation is believed to be a significant contributor to the aging process.(4) NF-kB is also the key gene activator of other inflammatory products such as COX-2 and TNF-alpha. • NF-kappaB Inhibitors: curcumin(21), fisetin(7), apigenin(25), luteolin(26)

2. Cox-2 Expression Inhibition – An inflammatory gene product resulting from NF-kB transcription. • Cox-2 Inhibitors: fisetin, apigenin, luteolin(9), curcumin(20,21)

Carcinogenesis: Inhibiting the Wingless (Wnt) Signaling Pathway (Gene Inhibition)

• Wnt Signaling. Is an important protein signaling system that is key in the development of carcinogenesis (Cancer). Natural compounds, including curcumin, fisetin, querectin and resveratrol have been shown to inhibit the gene expression of an important protein in this cascade. Fisetin treated cells have been shown to inhibit components of this pathway in both melanoma and colon cancers.(22)

• Wnt Inhibitors: fisetin, curcumin, quercetin, resveratrol (23)

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References

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2. Zhang X, et al. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011 Mar 30.

3. Petrovski G, et al. Does autophagy take a front seat in lifespan extension? J Cell Mol Med. 2010 Nov;14(11):2543-51.

4. Chung HY, et al. Molecular Inflammation as an Underlying Mechanism of the Aging Process and Age-related Diseases. J Dent Res. 2011 Mar 29.

5. He ZY, et al. Upregulation of p53 expression in patients with colorectal cancer by administration of curcumin. Cancer Invest. 2011 Mar;29(3):208-13.

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7. Li J, et al. Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol. 2011 Feb;108(2):84-93.

8. Chiou YS. Et al. Pterostilbene is more potent than resveratrol in preventing azoxymethane (AOM)-induced colon tumorigenesis via activation of the NF-E2-related factor 2 (Nrf2)-mediated antioxidant signaling pathway. J Agric Food Chem. 2011 Mar 23;59(6):2725-33.

9. Tahanian E, et al. Flavonoids targeting of IκB phosphorylation abrogates carcinogen-induced MMP-9 and COX-2 expression in human brain endothelial cells. Drug Des Devel Ther. 2011;5:299-309.

10. Lee SE, et al. Fisetin induces Nrf2-mediated HO-1 expression through PKC-δ and p38 in human umbilical vein endothelial cells. J Cell Biochem. 2011 Apr 25.

11. Scapagnini G, et al. Modulation of Nrf2/ARE Pathway by Food Polyphenols: A Nutritional Neuroprotective Strategy for Cognitive and Neurodegenerative Disorders.

12. Zhao J, et al. Curcumin and Nrf2 Protect against Neuronal Oxidative Stress and Delayed Death Caused by Oxygen and Glucose Deprivation. Curr Neurovasc Res. 2011 Jun 15.

13. Yang C, et al. Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res. 2009 Jul 28;1282:133-41. Brain Res. 2009 Jul 28;1282:133-41.

14. Kin CW, et al. Neurotrophic and cytoprotective action of luteolin in PC12 cells through ERK-dependent induction of Nrf2-driven HO-1 expression. J Agric Food Chem. 2010 Apr 14;58(7):4477-86

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19. Shukla S, et al. Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation. Free Radic Biol Med. 2008 May 15;44(10):1833-45.

20. Tan X, et al. Regulation of the expression of cyclooxygenases and production of prostaglandin I and E in human coronary artery endothelial cells by curcumin. J Physiol Pharmacol. 2011 Feb;62(1):21-8.

21. Wilken R, et al. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol Cancer. 2011 Feb 7;10:12.

22. Sved DN, et al. Inhibition of Human Melanoma Cell Growth by the Dietary Flavonoid Fisetin Is Associated with Disruption of Wnt/β-Catenin Signaling and Decreased Mitf Levels. J Invest Dermatol. 2011 Jun;131(6):1291-9.

23. Teiten MH, et al. Targeting the Wingless Signaling Pathway with Natural Compounds as Chemopreventive or Chemotherapeutic Agents. Curr Pharm Biotechnol. 2011 Apr 5

24. Pan Z, et al. Identification of molecular pathways affected by pterostilbene, a natural dimethylether analog of resveratrol. BMC Med Genomics. 2008 Mar 20;1-7.

25. Kang OH, et al. Apigenin inhibits release of inflammatory mediators by blocking the NF-κB activation pathways in the HMC-1 cells. Immunopharmacol Immunotoxicol. 2010 Dec 13. 

26. Zhu LH, et al. Luteolin inhibits microglial inflammation and improves neuron survival against inflammation. Int J Neurosci. 2011 Jun;121(6):329-36. 

27. Lee KS, et al. Curcumin extends life span, improves health span, and modulates the expression of age-associated aging genes in Drosophila melanogaster. Rejuvenation Res. 2010 Oct;13(5):561-70.  

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29. Liao VH, et al.  Curcumin-mediated lifespan extension in Caenorhabditis elegans. Mech Ageing Dev. 2011 Oct;132(10):480-7. doi: 10.1016/j.mad.2011.07.008.

30. Shen LR, et al. Curcumin-supplemented diets increase superoxide dismutase activity and mean lifespan in Drosophila. Age (Dordr). 2012 Jun 1.