Index to Anti-Aging Medicine
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M: Ma - Mc
Maca Root Extract [Links/Maca Root Supplements, Images, Video, Papers, Patents, Books; Links/Maca Root Extract, Images]. Maca Root Extract (145) (Lepidium Meyenii) was shown to be effective at lengthening dermal fibroblast telomeres in Product B literature.
Macular degeneration [LifeExtension/MD, Wikipedia/MD; Links/Macular Degeneration, Images, Video, Papers, Patents, Books, LibCong, Amazon/Macular degeneration; Books/treating macular degeneration, IAAS/Macular Degeneration, MD Foundation; Index/Eye Problems of Aging (Taurine); Lutein; Zeaxanthin; Polyunsaturated Fats] [101].
Macular Degeneration Inducers [Links, Papers, Patents, Books, LifeExtension].
Diets high in polyunsaturated fats increase the risk of age-related macular degeneration (AMD). High levels of polyunsaturated fats double the rate of macular degeneration in women [1], [2].
Free radicals producing lipid peroxidation by operating on PUFAs (polyunsaturated fatty acids) gives rise to aldehydes producing lipofusin wastes impacting to macular degeneration [12].
"Female cigarette smokers are 2.4 times more likely to develop macular degeneration." [7], [8].
High homocysteine correlating to cardiovascular disease also correlates to macular degeneration.
Inhibitors of Macular Degeneration [Links, Papers, Patents, Books, LifeExtension].
"Studies have shown that bilberry [Index, Wikipedia, LifeExtension] can reduce or reverse effects of degenerative eye disorders such as macular degeneration. The overall therapeutic use of bilberry is still clinically unproven." The carotenoids zeaxanthin, lutein, (found in spinach, collard greens, and other vegetables) and mesozeaxanthin are thought to inhibit macular degeneration. Small molecule telomerase activators [81s/6b, (7)] are thought to be promising in connection with the treatment of macular degeneration [6]. "Some evidence points to the senescence of retinal pigment epithelial cells as the cause of macular degeneration. We may be able to cure macular degeneration by lengthening telomeres in these cells. Similarly, the senescence of ocular keratocytes correlates with the development of cataracts @ and may be another target for a telomere relengthening drug [Notes]." - Sierra Sciences. It has recently been pointed out that macular degeneration is associated with low levels of DHEA [Index, Links, Papers, Patents, Books, LifeExtension, [5]], a precursor of testosterone, an androgenic telomerase activator. Note that testosterone also produces reverse transport of cholesterol associated with atherosclerotic plaque and cardiovascular disease that can also interfere with the veinous system of the choroid of the eye. Anti-inflammatory omega-3 fatty acids useful in lowering inflammation have been shown to be useful in preventing macular degeneration. The eye is rich in DHA, an omega-3 fatty acid found in fish oil, and with higher density in salmon oil or pure DHA [7]. Factors such as high homocysteine that correlate to cardiovascular disease also correlate to macular degeneration, so that B-vitamins like Vitamin B6 and Vitamin B12 that are used in homocysteine shields also protect against macular degeneration. "A growing number of scientists believe that macular degeneration is related to the slow degeneration of blood vessels in the eye, specifically behind the layer behind the retina, known as the choroid [Images], which contains the blood supply to the retina." [8]. Therefore factors that defend us against atherosclerosis and arteriosclerosis (hardening of the arteries in general) also help defend us against macular degeneration, now seen by many to be a consequence of vascular disease [Index]. Note that elevated testosterone from DHEA or other testosterone-boosters such as Fenugreek or Forskolin work against atherosclerosis in the choroid by promoting the reverse transport of cholesterol. However, DHEA elevates testosterone even in castrated males, while drugs like Forskolin work by acting on the gland of Leydig in the testicles to elevate testosterone. High vitamin K2 (found in natto, Swiss cheese, peas and green beans) works against the calcification of atherosclerotic plaque, returning calcium to the bones, for which high vitamin D3 is also useful by promoting the formation of bone matrix. Polyunsaturated fats increase the risk of AMD, but monounsaturated fats in meat and milk were observed to decrease AMD risks. (LEF, June 2010; Arch Opthamol. 2009 Nov;127(11)1483-93). It is probably true that telomerase activators such as astragaloside IV or astragalus extract can prevent the senescence of the vascular endothelium in the choroid of the eye, decreasing the adhesion of monocytes to vessels there and preventing atherosclerotic plaque leading to macular degeneration. Ginkgo Biloba may help decrease the adhesion, as it reduces the stickiness of platelets. Nitric oxide-producing L-arginine (at 5-10 grams/day, with gamma tocopherol to limit lipid peroxidation) with citrulline is also useful for rejuvenating the vascular endothelium in the choroid of the eye. Anti-angiogenic substances are used to treat wet macular degeneration and prevent neovascularization obstructive to central vision. Note that DHA makes up 30% of the brain, and 50% of the retina (Russell L. Blaylock, 2008). DHA deficiency has been linked to Alzheimer's Disease, and is associated with macular degeneration. See DHA and Macular Degeneration [Links, Images, Video, Papers, Patents, Books].
"Participants among the top one-fifth in terms of omega-3-rich fish consumption had a 42% lower risk of early AMD compared to those whose fish intake placed them in the lowest fifth. Enjoying omega-3-rich fish at least once a week provided a a 42% reduction in risk for early AMD. Eating omega-3-rich fish at least three times a week was associated with a 75% reduction in late AMD." - The World's Healthiest Foods/Halibut. Melatonin is useful in preventing age-related macular degeneration [10], [11]. Lipid peroxidation from free radicals operating on PUFAs (polyunsaturated fatty acids) gives rise to aldehydes producing lipofusin wastes impacting to macular degeneration [12]. Astaxanthin and other antioxidants have been used to neutralize these free radicals. "AGE inhibitors (e.g., pimagedine or pyridoxamine) have been shown to reduce the severity of diseases involving advanced glycosylation (glycation) and could offer potential treatment targets for currently untreatable blinding retinal diseases."
Taurine provides retinal protection [Links, Images/Taurine Supplements]
Taurine, abundant in fish, is found at high concentrations in the retina that decline with age. Taurine defends against age-related vision loss, retinal ganglion degeneration, retinal dysfunction, and macular degeneration, and taurine deficiencies can induce vision problems [3], [4].
Stem Cell Therapy for Macular Degeneration
Induced pluripotent stem cell (iPS cell) technique may be used in therapy for macular degeneration. Biotime Inc's subsidiary Cell Cure Neurosciences, Ltd., has developed a OpRegenTM retinal cell product for treatment of age-related macular degeneration based on stem cell technology. Recently human embryonic stem cells [Images] have been used to restore the retina in cases of macular degeneration [9]. See Human Embryonic Stem Cells used to Cure Macular Degeneration [Images, Papers, Patents, Books].
References
[1] Diets High in Fat Increase Risk of Macular Degeneration, Life Extension Magazine, June 2010.
[2] Arch Opthamol 2009 Nov;127(11):1483-93.
[3] Ian Macleavy (2013),
The Forgotten Longevity Benefits of Taurine, Life Extension Magazine, June 2013.
[4] Froger N, Cadetti L, Lorach H, et al. (2012),
Taurine provides neuroprotection against retinal ganglion cell degeneration, PLOS One, 2012;7(10):e42017.
[5] Tamer C, Oksuz H, Sogut S (2007),
Serum dehydroepiandrosterone sulphate level in age-related macular degeneration, Am J Ophthalmol 2007 Feb;143(2):212-16.
[6] Allan L. Goldstein, Frontiers in Biomedicine by p.15.
[7] Debora Yost (2008),
Preventing Macular Degeneration A New Theory, Life Extension Magazine, December, 2008.
[8] Julius Goepp (2009),
Halt the Leading Cause of Age-Related Blindness, Life Extension Magazine, December 2009.
[9] Michelle Roberts (2012),
Advanced Cell Technology: Stem cell retinal implants safe, BBC News, Jan 23, 2012.
[10] Yi C, Pan X, Yan H, Guo M, Pierpaoli W. (2005),
Effects of melatonin in age-related macular degeneration,
Annals of the New York Academy of Sciences, 2005 Dec;1057:384-92.
[11] Claudia Kelley (2012),
Beyond Sleep: 7 Ways Melatonin Attacks Aging Factors, Life Extension Magazine, Sept. 2012.
[12] Florian Schutt, Marion Bergmann, Frank G. Holz and Jurgen Kopitz (2003),
Proteins Modified by Malondialdehyde, 4-Hydroxynonenal, or Advanced Glycation End Products in Lipofuscin of Human Retinal Pigment Epithelium [full text online], Investigative Opthamology and Visual Science, August 2003 vol. 44 no. 8 3663-3668.
Maillard reaction [IAAS/Maillard reaction, Wikipedia, Links, Images, Video, Papers, Patents, Books, Amazon, LibCong, LifeExtension]. The Maillard reaction is the "browning process" following glycation, which may produce AGES (Advanced Glycation End Products) in cooked food [Links, Links/AGES in cooked food]. (4).
Magnesium [Telomerase Activators/Magnesium (183), Links, Images/magnesium supplements, Video, Papers, Patents, Books, Life Extension/magnesium, Links/magnesium cofactor; LifeExtension/Magnesium deficiency linked with cellular aging, Links, Images, Papers, Books; LifeExtension/Magnesium deficiency, Links, Images, Papers, Patents, Books]. Magnesium deficiency accelerates cellular senescence. Magnesium deficiency of 13% of normal magnesium causes fibroblasts in culture to loose 6 population doublings, degrading cellular lifespan by 10%. 50% of normal magnesium may result in the loss of 4 population doublings, degrading lifespan by 6.7%. "IMR-90 fibroblast populations cultured in magnesium-deficient conditions had increased senescence-associated beta-galactosidase activity and increased p16INK4A and p21WAF1 protein expression compared with cultures from standard media conditions. Telomere attrition was also accelerated... Thus, the long-term consequence of inadequate magnesium availability in human fibroblast cultures was accelerated cellular senescence, which may be a mechanism through which chronic magnesium inadequacy could promote or exacerbate age-related disease." (David W. Killilea and Bruce N. Ames, 2008). See also Ferre S, Mazur A, Maier JAM (2007), Low magnesium induces senescent features in cultured human endothelial cells, Magnesium Research, 20:66-71. Close inspection reveals that the magnesium ion is a necessary cofactor for telomerase:
"TERT active site motifs shared with other protein-only RTs (Reverse Transcriptases)
play an essential role (Lingner et al. 1997), consistent with their expected function
in binding the magnesium ions that activate the deoxynucleoside triphosphate for incorporation
".
- from Elizabeth H. Blackburn and Kathleen Collins (2010),
Telomerase: An RNP Enzyme Synthesizes DNA,
Cold Spring Harbor Perspectives in Biology, July 21, 2010.
According to Life Extension magazine, low levels of magnesium are chronic in the US population, and magnesium should be supplemented. Otherwise, consequences include hypertension and higher rates of sudden death [Images]. Magnesium reduces blood pressure, inhibits platelet stickiness, and reduces platelet aggregation, making it useful for inhibiting leukoaraiosis and hypoperfusion, factors in several neurodegenerative disorders. ATP is combined with magnesium in the body to make Mg-ATP. Otherwise, ATP is not bioavailable in the body, leading to muscle fatigue or exhaustion. There are 5 RecQ DNA helicase genes [Wikipedia/Helicases, Books/DNA helicases, Books/RecQ DNA helicase genes] used to unwind DNA, some or all requiring Mg+2 as a cofactor [Hu & Ellis, Bloom Syndrome, in Chromosomal Instabilty and Aging, by Hisama, et al, 2003]. Therefore, it may be that deficiencies in dietary magnesium are connected with genomic instabilities in aging cells via the malfunctioning of DNA helicases. The WRNp helicase associated with Werner Syndrome, for instance, is localized to the telomere, and may malfunction if sufficient magnesium is not available as a cofactor [Links, Papers, Magnesium and Aging]. I note that magnesium is also listed as a necessary cofactor for DNA polymerase, which controls DNA replication. In 1961 Arthur Kornberg [Images] discovered that DNA from E. Coli can be synthesized only in the presence of
(1) DNA polymerase I,
(2) all 4 deoxynucleotide triphosphates (dNTPs)
(3) a double-stranded DNA template, and
(4) the magnesium ion Mg++.
Later on, it was determined that E. Coli could also synthesize DNA if (1) is replaced by DNA polymerase III (pol III), the primary DNA polymerase used by E. Coli. In other words Mg++ is not only important for DNA helicase function, but is also crucial for DNA synthesis. In telomeric DNA extension, telomerase adds a hex repeat to the opened telomere loop, then a DNA polymerase extends the lagging strand, using Mg++ as a cofactor. (Magnesium is also a cofactor for RNA polymerases.) So telomerase activators [List] do best with Mg++ available, otherwise a single-strand tail develops. (The single-strand part of the telomere is typically 50-100 bp long and is bound to the shelterin protein POT1.) Chlorophyll contains magnesium, and perhaps man suffered less from dietary magnesium shortages earlier in his evolution, when he ate more grasses. See King DE, Mainous AG 3rd, Geesey ME, Woolson RF (2005), Dietary magnesium and C-reactive protein levels, Journal of the American College of Nutrition 2005 Jun 24(3):155-71.
Magnesium L-Threonate [Links, Images, Papers, Patents, Books, LifeExtension].
The highly absorbable magnesium L-threonate protects the integrity of cellular synapses in the brain and increases synaptic density, boosting short- and long-term memory scores and fighting the loss of synaptic density seen in Alzheimers Disease. It boosts the level of magnesium found in cerbrospinal fluid effectively, unlike conventional magnesium supplements. 2000 mg/day of magnesium L-threonate [Images, Papers, Books] is recommended, awaiting FDA approval, and is sourced by the Life Extension Foundation and other vendors [Images]. See William Falloon (2012), Reversing Brain Decay, Life Extension Magazine, January 2012 and Slutsky I, et al. (2010), Enhancement of learning and memory by elevating brain magnesium, Neuron, 2010 Jan 28;65(2):165-77. See also Martin Alessio (2012), Novel Magnesium Compound Reverses Neurodegeneration, Life Extension Magazine, Feb 2012. There are no natural food sources of Magnesium L-Threonate.
Milk of Magnesia (MgOH) must be a useful source of magnesium, as well as serving as a laxative (2-4 tablespoons) and antiacid (1-3 teaspoons/dose, up to 4 times per day). I note that too much Milk of Magnesia taken to implement a low-calorie diet can burn your bottom enough for your rear end to appear in cloud cover weathervisions over your state of the union, as shown below.
Shatner Methods: Soul to Heaven on Last Magnesia Day. Press for Weather Visions.
Red Star on the Britches Award for too much Milk of Magnesia Taken.
I might add I have had dreams featuring advice whispered from Sierra Sciences top brass William Andrews claiming [Index] that Milk of Magnesia has a good effect on telomere length.
References
[1] Slutsky I. (2010), Enhancement of learning and memory by elevating brain magnesium, Neuron 65(2):2010;165-77.
Makeup Technique [Links, Images, Papers, Patents, Books, LibCong, Amazon, Makeup Tips, Cosmo Virtual Makeover Software, Makeover Solutions, Salon Syler Pro, EBAY Makeover, YouTube Makeover, Airbrush Makeover, Tips, Cyber Imaging, Makeup, Makeup Tips, In 10 Steps, Secrets of Makeup, Gillette, Luscious Lipstick, YouTube Makeup, Wikipedia/Cosmetology, Wiki/Cosmetics; Index/Skin; Index/Age Progression and Regression; Index/Antiaging Skin Care Products]. See Wigs and The Erotic Hots Study Guide for other supporting materials.
Malondialdehyde [Links, Images, Video, Papers, Patents, Books, LifeExtension, Amazon]. Malondialdehyde is a toxic end product of lipid peroxidation producing cross-linking, used as a marker for oxidative stress [Index/Oxidative Stress, Links, Books].
Mammalian Telomere Protein Factors
[Index/Telomere Loop Control Proteins; Refs7.8, Links, Images, Video, Papers, Patents, Books, LifeExtension, Amazon; Links/Telomere plus Telomeric Proteins, Images, Video, Papers, Patents, Books, LifeExtension, Amazon; hTERT, hTERT promoter, hTERT protein phosphorylation]. See also Genes and Senescence, Longevity Genes, The Telomere Interactome [Figure, Links, Images, Video, Papers, Patents, Books], GenomeBio, and Titia de Lange (2005), Shelterin: the protein complex that shapes and safeguards human telomeres (Full PDF), Genes and Development 2005, 19: 2100-2110.
(1) According to GeneCards, the shelterin complex [Index, Images, Video, Papers, Patents, Books], also termed the telosome [Index, Images, Video, Papers, Patents, Books] is composed of the 6 proteins:
___TRF1 [Shelterin, Index, Links/TRF1 telomere, Images, Video, Papers, Patents, Books],
________[Index, Links/TRF1 promoter, Images, Video, Papers, Patents, Books],
________[Links/Poly(ADP-ribo)sylation of TRF1, Images, Video, Papers, Patents, Books].
_________"Human telomere length is regulated by the TTAGGG-repeat-binding protein
_________TRF1 and its interacting partners tankyrase 1, TIN2 and PINX1...
_________The TRF1 complex interacts with a single-stranded telomeric
_________DNA-binding protein—protection of telomeres 1 (POT1)— (such) that
_________human POT1 controls telomerase-mediated telomere elongation.
"
_________(Diego Loayza & Titia de Lange, 2003). Telomerase installs GGTTAG repeats.
___TRF2 [Shelterin, Index, Links/TRF2 telomere, Images, Video, Papers, Patents, Books],
________[Index, Links/TRF2 promoter, Images, Video, Papers, Patents, Books],
___TIN2 [Shelterin, Links/TIN2 telomere, Images, Video, Papers, Patents, Books],
________[Links/TIN2 promoter, Images, Video, Papers, Patents, Books],
__________Inhibiting TIN2 enlongates telomeres by reducing TIN2 interference
__________with tankyrase 1. See TIN2 inhibitors [Links, Images, Papers, Patents, Books].
___RAP1 [Shelterin, Links/RAP1 telomere, Images, Video, Papers, Patents, Books],
________[Links/RAP1 promoter, Images, Video, Papers, Patents, Books],
___TPP1 [Shelterin, Links/TPP1 telomere, Images, Video, Papers, Patents, Books],
________[Links/TPP1 promoter, Images, Video, Papers, Patents, Books],
___POT1 [Shelterin, Links/POT1 telomere, Images, Video, Papers, Patents, Books],
________[Links/POT1 promoter, Images, Video, Papers, Patents, Books],
________[Links/POT1a telomere (mice), Images, Video, Papers, Patents, Books],
________[Links/POT1b telomere (mice), Images, Video, Papers, Patents, Books],
(2) Other Telomere Management Proteins.
___Tankyrase 1 [List, Links/Tankyrase 1, Images, Video, Papers, Patents, Books],
_____________[Links/the Tankyrase 1 promoter, Images, Papers, Patents, Books].
_____________[Links/Phosphorylation of Tankyrase 1, Images, Papers, Patents, Books].
_____________[Links/Poly(ADP-ribo)sylation of TRF1, Images, Papers, Patents, Books].
______Tankyrase 1 localizes where TRF1 is located in the cell.
______Tankyrase 1 does not itself contain a nuclear localization signal.
______Usually, overexpressed Tankyrase 1 remains in the cytoplasm and does not touch TRF1.
______Perhaps Tankyrase 1, like hTERT, is transported into the nucleus when phosphorylated.
______Tankyrase 1 includes 24 ANK repeats [Wiki] that fold into five ARCs with
_______scaffolds at each end structured so that each ARC can recognize TRF1.
______Perhaps a single tankyrase 1 molecule can bind several TRF1 molecules.
______3 of 5 ARCs can bind to either TAB182 or TRF1.
________(Sbodio, Lodish, and Chi, 2002), (Hiroyuki, et. al., 2004).
______Tankyrase 1 binds to both TRF1 and IRAP (Insulin-responsive aminopeptidase),
_______ like Tankyrase 2.
______Poly(ADP-ribo)sylation of TRF1 by tankyrase 1 using a NAD+ substrate
______strips TRF1 from telomeres, allowing them to open for access by the
______telomerase holoenzyme. Tankyrase 1 may be phosphorylated for this
______reaction by insulin stimulation at cell surface insulin receptors, or by EGF or PDGF.
________Insulin, EGF, and PDGF stimulate MAP kinase serine-phosphorylation of Tankyrase 1.
________Fenugreek or 4-hydroxyisoleucine or Gymnema sylvestere may be used
________to elevate insulin for tankyrase 1 phosphorylation to open telomere loops.
__________"Long-term overexpression of tankyrase in telomerase-positive
__________human cells resulted in a gradual and progressive elongation of telomeres.
"
__________"...Tankyrase-mediated ADP-ribosylation of TRF1 opens the
__________telomeric complex, allowing access to telomerase.
"
____________(Susan Smith and Titia de Lange, 2000).
______Telomere enlongation by tankyrase 1 depends on telomerase activity
_______and is blocked by telomerase inhibition (Hiroyuki Seimiya, et al, 2005).
______Tankyrase 1 is serine-phosphorylated by MAP kinases, enhancing its PARP activity.
________(Sbodio, Lodish, and Chi, 2002).
________This is important for MAP kinase-activated telomerase activators, including
________TAT2 (cycloastragenol), astragalus extract, and progesterone,
________ which open t-loops for telomerase.
______Tankyrase 1 also interacts with insulin-responsive peptidase (IRAP),
______and the telomerase binding protein TAB182, a nuclear protein including 2
______nuclear localization signals which is also referred to as tankyrase-binding protein.
______TAB182 may function to block some of 5 ARC binding sites on tankyrase 1 for TRF1.
______TAB182 is highly acidic and may tether tankyrase 1 to chromosomes during mitosis
_______via stong binding to histones. (Sbodio, Lodish, and Chi, 2002).
______IRAP moves from secretory membranes to the plasma membrane after insulin stimulation.
______See Poly(ADP-ribo)sylation by Alexander Burkle on Tankyrase 1.
______Also see TAB182 antibody. TAB182 is most highly expressed in testis, ovary, and lung.
______Knockdown of TIN2 by siRNA derepresses tankyrase 1 at telomeres, removing TRF1,
_______allowing the telomerase holoenzyme to lengthen telomeres (Ye and de Lange, 2004).
______Tankyrase 1 is found at multiple sites in the cell and has several functions.
______Tankyrase 1 catalytic efficiency (kcat/Km) is 150-fold lower than PARP 1.
_______(Rippmann, Damm, and Schnapp, 2002).
___Tankyrase 2 [Links, Images, Video, Papers, Patents, Books],
_____________[Links/the Tankyrase 2 promoter, Images, Papers, Patents, Books].
_____Tankyrase 2 might also poly(ADP-ribo)sylate TRF1. (Sbodio, Lodish, and Chi, 2002).
_____Tankyrase 2 exhibits intrisic PARP activity after all,
_____and may have a role in telomere homeostasis. (Sbodio, Lodish, and Chi, 2002).
_____Tankyrase 2 binds to both TRF1 and IRAP (Insulin-responsive aminopeptidase),
_____ like Tankyrase 1.
_____Tankyrase 2 contains multiple binding sites for IRAP from 5 of 24 ankyrin repeat domains.
_____Tankyrase 2 associates and colocalizes with Tankyrase 1. (Sbodio, Lodish, and Chi, 2002).
_____Tankyrase 2 and Tankyrase 1 may function as a complex. (Sbodio, Lodish, and Chi, 2002).
_____Grb14 binds to ARC III of tankyrase 2 but not ARC V of 5 ARCs (op cit).
_____When overexpressed, Tankyrase 2 causes telomere enlongation, releases TRF1.
_____(Wikigenes/Tankyrase 2).
_____When highly overexpressed, Tankyrase 2 causes rapid cell death in yeast.
_____(Kaminker, et al, 2001), (Patrick G. Kaminker,..,Judith Campisi, 2001).
___PARP [Wikipedia, Links, Images, Video, Papers, Patents, Books],
______[Links/the PARP promoter, Images, Papers, Patents, Books].
______The Poly (ADP-ribose) polymerase (PARP) family is involved in DNA repair
______ (detects single-strand DNA breaks) and in programmed cell death.
______There are 17 PARP family members including Tankyrase 1 & Tankyrase 2.
______PARP enzymes are essential for expression of inflammatory genes.
______The PARP catalytic domain is responsible for poly (ADP-ribose) polymerization,
______producing a polymer (up to 200 bp long) synthesized using nicotinamide.
___the MRN complex [Links, Images, Video, Papers, Patents, Books],
_____MRN functions together with ATM to phosphorylate TRF1.
_____(Xin, Liu, and Songyang, 2008).
_____MRN is a protein mediating the repair of double-strand breaks.
___the RecQ helicase WRN [Links, Images, Video, Papers, Patents, Books],
_____WRN facilitates replication fork progression after DNA damage
_____ or after replication fork arrest. More WRN seems to speed up DNA repair.
_____Mutations of WRN are associated with Werner Syndrome and
_____symptoms of old age, including premature greying, hair loss,
_____cancer, osteoporosis, type 2 diabetes and atherosclerosis.
_____Cigarette smoke induces down-regulation of WRN, producing senescence.
_____(Toru Nyunoya, et al, 2009).
___the RecQ helicase BLM [Wikipedia, Links, Images, Video, Papers, Patents, Books],
_____BLM drives DNA and RNA unwinding by metabolizing ATP.
_____Mutations of BLM are associated with Bloom Syndrome and
_____symptoms of old age, including premature greying, hair loss,
_____cancer, osteoporosis, type 2 diabetes and atherosclerosis.
_____Of 5 the RecQ helicase genes, mutations in WRN, BLM, and RECQ4
_____are associated with premature aging.
___KU70 [Links, Images, Video, Papers, Patents, Books],
_____Ku70 and Ku80 (Ku86) make up the Ku heterodimer, which
_____binds to DNA double-strand break ends and is needed for
_____non-homologous end joining (NHEJ) in DNA repair.
_____KU70 is required for V(D)J recombination, which utilizes the NHEJ pathway
_____to promote antigen diversity in the mammalian immune system.
_____In addition, Ku is required for telomere length maintenance
_____and subtelomeric gene silencing. - Wikipedia/Ku70.
_____"Ku70 and Ku80 (Ku86)... form a heterodimer (Ku) that can bind to free
_____double-stranded DNA ends. Inactivation of Ku leads to various defects
_____including telomere length deregulation and end-to-end chromosome fusions...
_____During normal senescence, Ku protein declines in abundance...
_____SIRT1 is able to deactylate and activate Ku70.
".
_____(Choi, Cho, Kang, Lee, Kaeberlein, Suh, Chung, and Park, (2011)).
_____Also see (Indivglio SM, Bertuch AA (2009)),
_____(Jeong J, Juhn K, Lee H, Kim SH, Min, Lee KM, Cho, Park, Lee KH, (2007)),
_____and (Seluanov A, Danek J, Hause N, Govbunova V (2007)).
___KU86 [Links, Images, Video, Papers, Patents, Books],
_____"Ku86 (Ku80) together with Ku70, DNA-PKcs, XRCC4 and DNA ligase IV forms
_____a complex involved in repairing DNA double-strand breaks (DSB) in mammals."
_____(Enrique Samper, et al, 2000)
_____See Espejel, S et al. (2002), Mammalian KU86 mediates chromosomal fusions
_____ and apoptosis caused by critically short telomeres
, EMBO Journal 21, 2207-2219.
___DNA-PK [Links, Images, Video, Papers, Patents, Books],
______TRF2 interacts with DNA-PK, a protein mediating the repair
______of double-strand breaks, like MRN. (Xin, Liu, and Songyang, 2008).
___ATM [Links, Images, Video, Papers, Patents, Books],
_____Protein kinase ATM is a sensor of DNA damage, and can phosphorylate TRF1,
_____impairing TRF1's capacity to interact with DNA.
_____(Xin, Liu, and Songyang, 2008).
_____TRF2 protects chromosome ends by repressing DNA damage signaling
_____by the ATM kinase. (Denchi and de Lange, 2007).
___ATR [Links, Images, Video, Papers, Patents, Books].
_____ATR kinase is controlled by POT1.
_____TRF2 and POT1 protect chromosome ends by repressing DNA damage signaling
_____by the ATM kinase and the ATR kinase, respectively.
_____See Denchi, E.L., and de Lange, T. (2007),
_____Protection of telomeres through independent control of
_____ATM and ATR by TRF2 and POT1
,
_____Nature 448, 1068-1071.
___ERCC1 [Links, Images, Video, Papers, Patents, Books],
____ERCC1/XPF is the nucleotide excision repair protein.
___XPF [Links, Images, Video, Papers, Patents, Books],
____ERCC1/XPF is the nucleotide excision repair protein.
___RAD51D [Links, Images, Video, Papers, Patents, Books],
_____RAD51 family members such as RAD51D are highly similar to bacterial RecA
_____and yeast Rad51, both involved in the homologous recombination and
_____repair of DNA. RAD51D complexes with RAD51 family members including RAD51L1,
_____RAD51L2, and XRCC2. This protein complex catalyzes homologous pairing between
_____single- and double-stranded DNA
, and plays a role in the early stage
_____of recombinational repair of DNA.
___Nucleostemin [Links, Images, Video, Papers, Patents, Books],
_____Nucleostemin enhances TRF1 degradation by a ubiquitination-independent pathway.
_____(Xin, Liu, and Songyang, 2008).
_____Nucleostemin is upregulated by FGF (Fibroblast Growth Factor).
_____"Nucleostemin expression in cardiomyocytes is induced by FGF2 and
_____accumulates in response to Pim-1 kinase activity." - (Sailay Sidiqi, et al, 2008).
_____FGF2 (FGFb, basic FGF) is upregulated by testosterone (ref).
_____Epidermal Growth Factor Receptor (Wikipedia/EGFR) upregulates Pim-1 kinase.
_____EGFR is upregulated by EGF, found in colostrum and colostrum skin creams.
_____"FGF-2 increases nucleostemin in adult bone marrow stem cells..." FGF-2 prompts
_____induction of nucleostemin immunoreactivity in mouse cariomyocytes.
_____after (Sailay Siddiqi, et al, 2008).
_____D1 and D2 dopamine receptors upregulate FGF2 expression
_____in the prefrontal cortex and hippocampus when stimulated by dopamine
_____or dopamine receptor agonists for test purposes only such as
_____quinpirole, SKF38393 and 7-OH-DPAT. (Fabio Fumagalli, et al, 2003).
___FBX4 [Links, Images, Video, Papers, Patents, Books],
_____FBX4 is an E3 ligase specific for TRF1 ubiquitination via the
_____Cul1-containing SCF complex, which leads to proteasomal TRF1 degradation.
_____(Xin, Liu, and Songyang, 2008), (Ming Lei, 2012).
_____"The Small Heat-shock Protein alphaB-Crystallin Promotes FBX4-dependent
_____Ubiquitination" - (John den Engelsman, et al, 2002).
_____"Overexpression of Fbx4 reduces endogenous TRF1 protein levels
_____and causes progressive telomere elongation in human cells.
_____Inhibition of Fbx4 by RNA interference stabilizes TRF1
_____and promotes telomere shortening, thereby impairing cell growth.
"
_____(Lee TH, Perrem K, Harper JW, Lu KP, Zhou XZ (2006)).
___ORC complex [Links, Images, Video, Papers, Patents, Books],
_____TRF2 associates with the origin of replication protein ORC1,
_____so that the ORC complex may be involved in telomere replication.
_____See Zhong Deng, et.al, 2007, The Origin Recognition Complex Localizes to Telomere
_____Repeats and Prevents Telomere-Circle Formation
, Current Biology 17, Nov.20,2007.
_____6 ORC complex subunits exist: ORC1, ORC2, ORC3, ORC4, ORC5, & ORC6.
_____3 ORC subunits bind to telomeric DNA: ORC1, ORC2, and ORC4.
_____ORC2 depletion increases telomeric circle (eccDNA) formation.
(3) Telomerase Protein and RNA components.
___hTERT protein [Index, Links, Images, Video, Papers, Patents, Books].
___hTR RNA [Index, Links, Images, Video, Papers, Patents, Books].
___Dyskerin [Index, Links, Images, Video, Papers, Patents, Books].
(4) The Telomere Interactome [Images, Papers, Pats, Books, Refs7.8], (GenomeBio F1)
surrounding the 6-protein TRF1, TRF2, TIN2, RAP1, TPP1, POT1 shelterin complex [Index]. See Huawei Xin, Dan Liu, and Zhou Songyang (2008) The telosome/shelterin complex and its functions, Genome Biology, 2008, 9:232. More recently, about 320 proteins were detected interacting with the 6 core shelterin proteins, including 44 DNA binding proteins and chromatin regulators. See Ok-Hee Lee, Hyeung Kim, Quanyuan He, Hwa Jin Baek, Dong Yang, Liuh-Yow Chen, Jiancong Liang, Heekyung Kate Chae, Amin Safari, Dan Liu and Zhou Songyang (2011), Genome-wide YFP Fluorescence Complementation Screen Identifies New Regulators for Telomere Signaling in Human Cells, Molecular and Cellular Proteomics, 2011, 10, M110.001628. See also Marco Folinia, Paolo Gandellinia and Nadia Zaffaroni (2009), Targeting the telosome: Therapeutic implications, Biochimica et Biophysica Acta, April 2009, 309-316.
(4a) Complexes interacting with TPP1 [Images, Video, Papers, Patents, Books]
include the telomerase holoenzyme complex.
Proteins interacting with telomerase [Images, Video, Papers, Patents, Books] include
__hnRNPs [Links, Images, Video, Papers, Patents, Books;
____Links/hnRNP telomerase interactions, Images, Video, Papers, Patents, Books].
____hnRNP A1 and a derivative UP1 = UAGGGU enlongate telomeres.
____hnRNP A1 [Links, Images, Papers, Patents, Books, GeneCards, Wikipedia],
____hnRNP A1 enlongates telomeres [Links, Images, Papers, Patents, Books].
_______Note c-Myc upregulates the transcription of hnRNP A1. (Charles J. David, et al, 2010).
_______Note that c-Myc is upregulated by EGF, Colostrum, and PDGF.
____UP1 [Links, Images, Papers, Patents, Books]
____enlongates telomeres [Links, Images, Papers, Patents, Books].
"A model has been proposed for how hnRNP A1/UP1 contributes to enhancement of the telomerase activity through recruitment and unfolding of the quadruplex of telomeric DNA." (Takashi Nagada, et al.,2008).
__Dyskerin complex [Index, Links, Images, Video, Papers, Patents, Books;
____Links/interactions with telomerase, Images, Video, Papers, Patents, Books].
____Dyskerin is a component of the telomerase holoenzyme.
__La protein [Links, Images, Papers, Patents, Books;
____Links/interactions with telomerase, Images, Papers, Patents, Books].
____The La antigen associates with telomerase and influences telomere length.
"Overexpression of La in both experimentally immortalized human cells and prostate cancer cells results in gradual telomere shortening." - L P Ford, J W Shay, and W E Wright (2001), The La antigen associates with the human telomerase ribonucleoprotein and influences telomere length in vivo, RNA 7:168-175.
Try La protein inhibitors [Images, Papers, Patents, Books].
__hStau protein [Links, Images, Papers, Patents, Books;
____Links/interactions with telomerase, Images, Papers, Patents, Books].
See Siyuan Le, Rolf Sternglanz, and Carol W. Greider (2000), Identification of Two RNA-binding Proteins Associated with Human Telomerase RNA, Molecular Biology of the Cell, March 2000 (11):999-1010.
__L22 protein [Links, Images, Papers, Patents, Books; OMIM/L22 protein; GeneCards/L22;
____Links/interactions with telomerase, Images, Papers, Patents, Books].
See Siyuan Le, Rolf Sternglanz, and Carol W. Greider (2000), Identification of Two RNA-binding Proteins Associated with Human Telomerase RNA, Molecular Biology of the Cell, March 2000 (11):999-1010.
__Sm protein [Links, Images, Papers, Patents, Books;
____Links/interactions with telomerase, Images, Papers, Patents, Books].
Sm protein is a telomerase accessory factor in yeast, but not in mammalian genomes, which instead use dyskerin. See Agata Smogorzewsk and Titia de Lange (2004), Regulation of Telomerase by Telomeric Proteins, Annual Review of Biochemistry, 2004, 73:177-208.
__14-3-3 protein [Links, Images, Papers, Patents, Books; OMIM; GeneCards;
____Links/interactions with telomerase, Images, Papers, Patents, Books].
____The 14-3-3 proteins promote the nuclear localization of hTERT.
_____(Cong, Wright, & Shay, 2002).
_____14-3-3 protein binds FOXO transcription factors, sequestering them away from the nucleus.
_______inhibiting caveolin-1 transcription to inhibit senescence. [See Longevity Genes]
____"In the absence of growth factor signaling and Akt activity, FOXO is released from
____14-3-3 and translocates to the nucleus, stimulating transcription of genes that
____inhibit cell proliferation and induce cell death.
" - Geoffrey M. Cooper and
____Robert E. Hausman, The Cell: A Molecular Approach, 4th edition (2007), p. 624.

__MKRN1 protein [Links, Images, Papers, Patents, Books;
____OMIM/MKRN1; iHOP/interactions; iHOP most recent; Gene Cards/MKRN1;
____Links/interactions with telomerase, Images, Papers, Patents, Books].
____The Makorin RING finger protein 1 (MKRN1) binds hTERT. "MKRN1 encodes an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length." - Jun Hyun Kim, et al (2005), Ubiquitin ligase MRKN1 modulates telomere length homeostasis through a proteolysis of hTERT, Genes and Development, 2005 19:776-781. See MKRN1 inhibitors [Papers, Patents, Books].
__TEP1 protein [Links, Images, Papers, Patents, Books;
____Links/interactions with telomerase, Images, Papers, Patents, Books].
"TEP1 is a component of the telomerase ribonucleoprotein complex that is essential for the replication of chromosome termini. Also component of the ribonucleoprotein vaults particle, a multi-subunit structure involved in nucleo-cytoplasmic transport. Responsible for the localizing and stabilizing vault RNA (vRNA) association in the vault ribonucleoprotein particle. TEP1 binds to TERC (By similarity)" - UniProtKB/Swiss-Prot: TEP1_HUMAN. See Vault organelles [Wikipedia/Vault_(organelle), Links, Images, Papers, Patents, Books].
__EST1 protein [Links, Images, Papers, Patents, Books; OMIM; GeneCards;
____Links/interactions with telomerase, Images, Papers, Patents, Books] interacts with
______SMG5, SMG6, and SMG7 proteins [Links, Images, Papers, Patents, Books] interacts
__________UPF1 protein [Links, Images, Papers, Patents, Books] interacts with
______________UPF2 protein [Links, Images, Papers, Patents, Books].
__9-1-1 complex [Links, Images, Papers, Patents, Books].
...Findings suggest that the 9-1-1 clamp is a multifunctional complex that is loaded onto DNA at sites of damage, where it coordinates checkpoint activation and DNA repair. (Parilla-Castellar ER, Arlander SJ, Karnitz L, 2004).
__PINX1 protein [Links, Images, Papers, Patents, Books, Gene Cards/PINX1].
____PINX1 mediates TRF1 and hTERT accumulation in the nucleolus and enhances
____TRF1 binding to telomeres with telomerase-inhibiting effect. PINX1 may inhibit cell
____proliferation and act as tumor suppressor. PINX1 also binds for reliable
____chromosome segregation. See PINX1 inhibitors [Links, Images, Papers, Patents, Books].
__NS protein [Links, Images, Papers, Patents, Books].
__Taz1 protein (fission yeast) [Links, Images, Papers, Patents, Books].
___Taz1 is a fission yeast ortholog of human TRF2.
___Miller, K.M., Rog, O., and Cooper, J.P. (2006),
___Semiconservative DNA replication through telomeres requires TAZ1,
___Nature, 440, 824-828. See also (Maria A. Blasco, 2007).
(4b) Proteins interacting with TRF1 [Images, Video, Papers, Patents, Books].
__PINX1 protein [Links, Images, Papers, Patents, Books].
____PINX1 mediates TRF1 and hTERT accumulation in the nucleolus and enhances
____TRF1 binding to telomeres with telomerase-inhibiting effect. PINX1 may inhibit cell
____proliferation and act as tumor suppressor. PINX1 also binds for reliable
____chromosome segregation. See PINX1 inhibitors and
____supplements inhibiting expression of PINX1 [Links, Images, Papers, Patents, Books].
____PINX1 (a putative tumor suppressor gene) is absent in a wide variety of malignancies.
__NS protein [Links, Images, Papers, Patents, Books].
__FBX4 protein [Links, Images, Papers, Patents, Books].
_____FBX4 is an E3 ligase specific for TRF1 ubiquitination via the
_____Cul1-containing SCF complex, which leads to proteasomal TRF1 degradation.
_____(Xin, Liu, and Songyang, 2008), (Ming Lei, 2012).
_____"The Small Heat-shock Protein alphaB-Crystallin Promotes FBX4-dependent
_____Ubiquitination" - (John den Engelsman, et al, 2002).
_____"Overexpression of Fbx4 reduces endogenous TRF1 protein levels
_____and causes progressive telomere elongation in human cells.
_____Inhibition of Fbx4 by RNA interference stabilizes TRF1
_____and promotes telomere shortening, thereby impairing cell growth.
"
_____(Lee TH, Perrem K, Harper JW, Lu KP, Zhou XZ (2006)).
__Tankyrase 1 protein [List, Links, Images, Papers, Patents, Books] interacts with
___________IRAP protein [Wikipedia, Links, Images, Papers, Patents, Books].
_____________IRAP = Interleukin 1 receptor antagonist, anti-inflammatory,
_____________encoded by the IL1RN gene. Also termed IL-1 inhibitor. It binds
_____________to the IL-1 receptor, preventing IL-1 activation.
___________Mcl-1 protein [Links, Images, Papers, Patents, Books].
_____________Mcl-1 (a Bcl-2 family gene), has 2 isoforms.
_____________Isoform 1 enhances cell survival by inhibiting apoptosis.
_____________Isoform 2 promotes apoptosis and is death-inducing.
___________NuMA protein [Wikipedia, Links, Images, Papers, Patents, Books].
_____________Nuclear mitotic apparatus protein 1 is encoded by NuMA1.
___________TAB182 protein [Links, Images, Papers, Patents, Books; Bethyl].
_____________TAB182 may act as a scaffold to mediate higher order protein
_____________complex formation at telomeres, interacting with TRF1.
__EB1 protein (with TRF1) [Links, Images, Papers, Patents, Books].
__ATM protein (with TRF1) [Links, Images, Papers, Patents, Books] interacts with
___________CHK1 protein [Links, Images, Papers, Patents, Books].
___________CHK2 protein [Links, Images, Papers, Patents, Books].
___________p53 protein [Index, Links, Images, Papers, Patents, Books].
___________MDM2 protein [Links, Images, Papers, Patents, Books].
___________SMC1 protein [Links, Images, Papers, Patents, Books].
___________Histone [Links, Images, Papers, Patents, Books] interacts with
_____________HP1 protein [Links, Images, Papers, Patents, Books].
_____________MDC1 protein [Links, Images, Papers, Patents, Books].
_____________53BP1 protein [Links, Images, Papers, Patents, Books].
___________Mre11 (with ATM,NBS1,Rad50) [List, Links, Images, Papers, Patents, Books]
_____________Rad50 protein [Links, Images, Papers, Patents, Books].
_____________NBS1 protein (with ATM,TRF2,Rad50,Mre11)
_____________[Links/NBS1, Images, Papers, Patents, Books].
__MMS21 (with TRF1 and TRF2) [Links, Images, Papers, Patents, Books].
_____SMC5/6 Complex (with MMS21) [Links, Images, Papers, Patents, Books].
(4c) Proteins interacting with TRF2 [Images, Video, Papers, Patents, Books].
__MMS21 (with TRF1 and TRF2) [Links, Images, Papers, Patents, Books].
_____SMC5/6 Complex (with MMS21) [Links, Images, Papers, Patents, Books].
__KU70 (with TRF2, KU86, and DNA-PKcs) [Links, Images, Papers, Patents, Books].
_______KU86 (with KU70 and DNA-PKcs) [Links, Images, Papers, Patents, Books].
_______DNA-PKcs (with KU70 and KU86) [Links, Images, Papers, Patents, Books].
________DNA-PK is a protein mediating repair of double-strand breaks.
__BLM (with TRF2) [Links, Images, Papers, Patents, Books].
____BLM is a DNA helicase recruited to telomeres.
__APOLLO (with TRF2) [Links, Images, Papers, Patents, Books].
____"Apollo knockdown with RNA interference resulted in senescence and the
____activation of a DNA-damage signal at telomeres as evidenced by
____telomere-dysfunction-induced foci (TIFs) [Images, Papers, Patents, Books].
____See Megan van Overbeek and Titia de Lange (2006),
____Apollo, an Artemis-Related Nuclease, Interacts
____ with TRF2 and Protects Human Telomeres in S Phase
,
____Current Biology 16, 1295–1302, July 11, 2006.
__WRN (with TRF2) [Links, Images, Papers, Patents, Books].
_____WRN is a DNA helicase recruited to telomeres.
__DDX19B, 21, 23, 24, 38 RNA/DNA helicases [Links, Images, Papers, Patents, Books].
_____DDX19B is an ATP-dependent RNA helicase enzyme. These are involved in altering
_______RNA secondary structure: translation initiation, nuclear splicing,
_______mitochondrial splicing, ribosome assembly, and splicosome assembly.
_____DDX21 (Nucleolar RNA helicase 2) is encoded by the DDX21 gene.
_____
DDX23 (an ATP-dependent RNA helicase) is encoded by the DDX23 gene.
_____DDX24 (an ATP-dependent RNA helicase) is encoded by the DDX24 gene.
_____DDX38 is a pre-mRNA splicing factor ATP-dependent RNA helicase.
__DNMT3A DNA methyltransferase [Links, Images, Papers, Patents, Books].
_____All known DNA methyltranferases use SAMe as the methyl donor.
_____DNMT3a methylates CpG dinucleotides in various native DNA substrates.
__PRMT7 protein methyltransferase [Links, Images, Papers, Patents, Books].
_____PRMT7 is a mammalian arginine N-methyltransferase using SAMe for a methyl donor.
__RECQL4 helicase [Links, Images, Papers, Patents, Books].
_____ATP-dependent DNA helicase Q4 is an enzyme encoded by the RECQL4 gene.
__POLD1 DNA polymerase [Links, Images, Papers, Patents, Books].
____The POLD1 gene encodes DNA polymerase delta catalytic subunit,
____a component of the DNA polymerase delta complex.
__APEX1 DNA base excision enzyme [Links, Images, Papers, Patents, Links Books].
_____APEX1 (DNA-(apurinic or apyrimidinic site) lyase) is the primary base excision repair
_____(BER) endonuclease used in human cells to repair abasic sites.
__FEN1 endonuclease [Links, Images, Papers, Patents, Books] is described as
____Flap endonuclease 1, or Flap structure-specific endonuclease 1.
____FEN1 and AP endonuclease 1 interact during long-patch base excision repair.
__PARP1/2 (with TRF2) [Links, Images, Papers, Patents, Books].
_____PARP1 protein [Wiki, Links, Images, Papers, Patents, Books].
_____PARP2 protein [Wiki, Links, Images, Papers, Patents, Books].
_____MSH2 [Links, Papers], a DNA mismatch repair protein, and
_______PARP1 [Index, Links, Images, Papers, Patents, Books]
_______play a role in maintaining telomere capping function
_______[Links, Images, Papers, Patents, Books]
________in which a telomere t-loop configuration many thousands of base pairs long
________is believed to protect chromosome ends from being recognized as broken DNA.
__ORC1 (with TRF2) [Links, Images, Papers, Patents, Books].
_____TRF2 associates with the origin of replication protein ORC1,
_____so that the ORC complex [Images, Papers, Patents, Books] may be involved in
_____telomere replication [Images, Papers, Patents, Books].
The 6-protein shelterin/telosome complex also interacts with
__ERCC1 (with Shelterin) [Wiki, Links, Images, Papers, Patents, Books].
____ERCC1 protein acts primarily in nucleotide excision repair (NER) of damaged DNA.
__RAD51D (with Shelterin) [Links, Images, Papers, Patents, Books].
__RIF-1 (with Shelterin) [Links, Images, Papers, Patents, Books].
__Protein phosphorylation regulators - serine threonine kinases:
____AKT1 [Index/Akt, Links, Images, Papers, Patents, Books],
____CAMK1D [Links, Images, Papers, Patents, Books],
_______"CAMK1D (CaMK1 delta) is a serine/threonine kinase
_______that is a member of the calcium/calmodulin-dependent
_______protein kinase family
. CAMK1D is expressed in polymorphonuclear
_______leukocytes
and may be part of the chemokine signal transduction
_______pathway that regulates granulocyte function. It may also
_______be involved in modulation of neuronal apoptosis." - Invitrogen
____CLK3 [Links, Images, Papers, Patents, Books],
____MAP2K3 [Links, Images, Papers, Patents, Books],
____MAPK2 [Links, Images, Papers, Patents, Books],
____MAPK12 [Links, Images, Papers, Patents, Books],
____PAK4 [Links, Images, Papers, Patents, Books].
__Protein phosphatase catalytic and regulatory subunits:
____PPM1G [Wikipedia, Links, Images, Papers, Patents, Books],
______A member of the PP2C family of Ser/Thr protein phosphatases,
______negative regulators of cell stress response pathways.
______Dephosphorylates pre-mRNA splicing factors important for spliceosome formation.
____PHPT1 [Links, Images, Papers, Patents, Books],
____PTPN5 [Links, Images, Papers, Patents, Books],
____SAPS3 [Links, Images, Papers, Patents, Books],
____PPP1R2 [Links, Images, Papers, Patents, Books].
__Ubiquitin E3 ligases [Links, Images, Papers, Patents, Books].
Telomere DNA Damage Response (DDR) proteins (Markers of DDR)
localizing to dysfunctional telomeres [Images] to form telomere-induced-foci (TIFs).
Inactivation of these proteins in senescent cells restores cell-cycle progression into S-phase.
______Phosphorylated gamma-H2AX [Wiki/H2AFX, Images, Papers, Patents, Books],
________"H2AX becomes phosphorylated on serine 139, then called gamma-H2AX,
________as a reaction on DNA Double-strand breaks (DSB)
". - Wikipedia/H2AFX
______p53-binding protein 1 (TB53BP1) [Uniprot/p53BP1, Images, Papers, Patents, Books],
________Thought to function as a transcriptional coactivator of the p53 tumor suppressor.
______NBS1 (nibrin) [Wiki/Nibrin, Images, Papers, Patents, Books],
________A member of the NBS1/hMre11/RAD50 double strand DNA break repair complex.
______MDC1 [Images, Papers, Patents, Books],
________Mediator of DNA damage checkpoint protein 1 encoded by the MDC1 gene.
________Facilitates recruitment of the ATM kinase and
________meiotic recombination 11 protein complex to DNA damage foci.
______CHK2 [Images, Papers, Patents, Books],
__"Results suggest that dysfunctional telomeres are recognized
__as DNA double-strand breaks that impinge on p53 and/or RB tumor suppressor pathways
__to induce expressions of their regulators
______p21 (encoded by CDKN1A) and
______p16INK4A (encoded by p16) to initiate replicative senescence."
__after (Yibin Deng, Suzanne S. Chan, and Sandy Cheng, 2008). See Fig.2,
Telomere dysfunction activates the p53 and RB pathways [Images, Papers, Patents, Books].
___Telomere shortening activates a DNA damage response,
_____activating ATM kinase, then downstream kinase CHK2, phosphorylating p53,
_____leading to apoptosis or activation of p21-mediated senescence. Alternatively,
_____ATR kinase is activated, then downstream kinase CHK1, phosphorylating p53,
_____leading to apoptosis or activation of p21-mediated senescence.
_____p21 from telomere shortening can interact with RB to induce senescence from RB.
___Uncapped telomeres activate a DNA damage response.
___TRF2 loss associated with a double-strand DNA break activates ATM kinase,
_____interacting with downstream kinase CHK2 to phosphorylate p53,
_____leading to apoptosis or activation of p21-mediated senescence.
___POT1 loss associated with a single-strand DNA break activates ATR kinase,
_____interacting with downstream kinase CHK1 to phosphorylate p53,
_____leading to apoptosis or activation of p21-mediated senescence. (op.cit.)
_____Note that loss of p21 inhibits the p53-induced senescence that inhibits lymphomas, while
_____p53-induced apoptosis is important for tumor suppression of sarcomas. Note
_____BCL2-overexpression prevents the p53-induced apoptosis that suppresses sarcomas.
RHPS4 can induce G-quadruplex folding of single-stranded DNA, producing
_______a strong telomeric DNA damage response in fibroblasts characteristic of melanoma. (op.cit.)
Mandibular Cancer [Links, Images, Video, Papers, Patents, Books; Anticancer Nutraceuticals, Anti-Inflammatory Drugs, Bone Cancer, Cancer, Facial Anatomy, Metastasis, NF-KB inhibitors, Telomerase Inhibitors (List), TNF-alpha inhibitors, Angiogenesis Inhibitors; Garlic, Ginger].
Mandibular Infections [Links, Images, Video, Papers, Patents, Books, Antibiotics, Facial Anatomy; Links/Facial Swelling from Infected Teeth, Images, Video, Papers, Patents, Books;
Links/Odontogenic Facial Swelling, Images, Video, Papers, Patents, Books;
Links/Oral and Maxillofacial Infections, Images, Video, Papers, Patents, Books;
Links/Anatomy of Maxillofacial Infections, Images, Video, Papers, Patents, Books;
Links/Pharmacology for Maxillofacial Infections, Images, Video, Papers, Patents, Books]. Mandibular infections may originate in an abcess treatable with garlic at 3 servings of 3-5 cloves per day, taken on crackers with artifical sweetener and barbeque sauce or a salad dressing. Garlic is a powerful antibiotic that works well against most bacterial pathogens and against many viral pathogens. Ramesses II appears to have died from an abcess curable with garlic, and in his time doctors swore by it. Instead, he had it drilled out to drain. Garlic defends the population against epidemics such as the Black Death, as well as against common bacterial infections. Ginger, which contains zerumbone and gingerol, may be useful if cancer is suspected. Chopped ginger can be pouched in the cheek against a swollen bony area, and taken orally, to reduce a bony mandibular lump. Garlic is also anticancer.
Manganese [Links, Images, Video, Papers, Patents, Books, LifeExtension, Amazon]. Manganese is a primary component of MnSOD (SOD2) found in mitochondrial SOD [Index/SOD].
MAP Kinase Pathway [hTERT promoter/Map Kinase Pathway, Links, Images, Video, Papers, Patents, Books, Amazon]. MAP Kinases are mitogen-activated protein kinases [Wikipedia]. "A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis. A mitogen is usually some form of a protein. Mitogens trigger signal transduction pathways in which mitogen-activated protein kinase is involved, leading to mitosis." - Wikipedia/Mitogens. Kinases phosphorylate proteins. Telomerase may be activated via the Map Kinase Pathway to lengthen telomeres in a program of treatment for cellular rejuvenation. This is true for TAT2 (cycloastragenol), for instance, the smallest-molecule astragaloside, a metabolite of astragalus extract. See activation of hTERT mRNA transcription via the Map Kinase Pathway [Images, Papers, Patents, Books]. Also see the MAPK/ERK pathway. Progesterone and ligands of the progesterone receptor also activate transcription of hTERT mRNA via the MAP kinase pathway. MAPK signaling cascades can influence transcription via direct phosphorylation of Sp1, and via the transcription factors c-Myc, AP-1, and Ets in the core promoter region of the hTERT gene [Links]. See Davis, R.J. (1993), The mitogen-activated protein kinase signal transduction pathway, Journal of Biological Chemistry 268, 14553-14556. Note that "...Tankyrase is quantitatively phosphorylated on certain serine residues by MAP kinase upon stimulation with insulin, PDGF, and EGF." (Chi and Lodish, 2000). The phosphorylation of tankyrase 1 enhances its poly(ADP-ribo)sylation activity on TRF1 telomere loop closure protein, allowing t-loops to open for access by the telomerase holoenzyme.
Note that all hTERT mRNA is transported from the nucleus into the cytoplasm to make hTERT protein, which requires phosphorylation to be transported into the nucleus. hTERT phosphorylation might be provided by exercise via IGF-1 and IL-2 or from telomerase activator supplements functioning via phosphorylation of hTERT. On the other hand, hTERT mRNA must be transcribed to be translated into the catalytic component of telomerase before hTERT protein exists to be imported into the nucleus.
"Our initial investigations into the mechanism of action of TAT2 suggest that telomerase activation, which typically peaks 24-48 h after TAT2 treatment, is preceded by early activation of the MAPK/ERK pathway (within minutes of TAT2 exposure), followed by increased production (or reduced turnover) of hTERT mRNA transcripts (peaking around 12 h). Interestingly, the main nuclear effectors of the MAPK pathway include the ETS transcription factors (37), which are known to play a major role in the transcriptional regulation of telomerase activity (38). The MAPK pathway has also been implicated in posttranslational up-regulation of telomerase activity through phosphorylation of hTERT (14), but the effects of TAT2 on this pathway have not been investigated. Thus, although the direct binding partner of TAT2 is not known, our data suggest that TAT2 up-regulates telomerase activity via activation of the MAPK pathway and subsequent increase in hTERT mRNA and/or active phosphorylated forms of hTERT protein." - from Steven Russell Fauce, Beth D. Jamieson, Allison C. Chin, Ronald T. Mitsuyasu, Stan T. Parish, Hwee L. Ng, Christina M. Ramirez Kitchen, Otto O. Yang, Calvin B. Harley, and Rita B. Effros, (2008), Antiaging Therapy with TAT2: Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ T Lymphocytes, The Journal of Immunology, Nov 2008, 181: 7400-7406.
MAP kinases include the ERK family, which is driven by growth factors, and JNK and p38 MAP kinases, which are driven by inflammatory cytokines and cell stress. Growth factors cascading through the ERK family MAP kinases produce cell proliferation, differentiation, and cell survival. Inflammatory cytokines cascading through JNK or p38 produce inflammation or cell death. (G.Cooper and R.E.Housman, p.632.)
Markers of Longevity [Index/Biomarkers of Longevity, Index/Biomarkers of Aging, Index/Biomarkers of Cellular Senescence, LifeXLabs/Measuring Cellular Senesence; Links, Images, Video, Papers, Patents, Books, LifeExtension, Amazon/Longevity markers, Books/Longevity markers, LibCong/Markers of Senescence, LibCong/Markers of Longevity, Books/Longevity biomarkers, Links/Longevity biomarkers, Amazon/Longevity biomarkers, LifeExtension/longevity biomarkers, Ben Best] [77].
Markers of Aging [Index/Biomarkers of Aging, Index/Biomarkers of Longevity, Index/Biomarkers of Cellular Senescence, LifeXLabs/Measuring Cellular Senesence; Links, Images, Video, Papers, Patents, Books, LibCong, LifeExtension]. Senescence-associated increases in levels of β-galactosidase [Wikipedia, Links, Papers, Patents, Books] are seen in both rodent and human tissues. In addition p16INK4a [Wikipedia, Links, Papers, Patents, Books] expression levels may increase by a factor of 10 in senescent cells. p16INK4a is a cyclin-dependent kinase inhibitor [Links, Papers, Patents, Books], functions as an effector of senescence [Links, Papers, Patents, Books], and should be regarded as a senescence marker [Links, Papers, Patents, Books] in physiological aging. Many other aging-associated markers are described in Senescence Pathway. Markers of aging include measures of mobility and cognition. Reduced mobility is a good marker of aging because animals move less and sleep more as they age. "Reduced mobility is... closely linked to overall metabolic rate, feeding, fat storage, brain neurotransmitter levels, mitochondrial function, and cardiovascular and muscular systems. And loss of mobility in humans is associated with muscle wasting, bone thinning, and other changes that increase the risk of other negative outcomes, such as factures, pneumonia, and skin infections." See Susan Machado (2012), Nutrient Cocktail Delays Aging and Extends Life Span, Life Extension Magazine, May 2012. Higher dopamine levels are associated with improvements in mobility, as are increased measures of mitochondrial activity and declining levels of protein carbonyls symptomatic of glycation. Reduced cognition is a good marker of aging because "cognition declines with aging in all animal species". Young animals learn faster, remember better, and "preserving cognitive function into older ages is associated with longer life spans." Increased mitochondrial performance produced by drugs such as CoQ10 is associated with better cognition and learning. Ceramide levels decline with age in the skin, but oral phytoceramides may be used to restore ceramide elastase inhibitors, also restoring hydration, and producing other improvements in stratum corneum top skin layer cell binding leading to apparent facial rejuvenation.
Matrix, Extracellular [Index/Extracellular Matrix, Wikipedia, Links, Images, Video, Papers, Patents, Books, LifeExtension, LibCong, Amazon]. The extracellular matrix turns over slowly, thus collagen and elastin in the matrix are only slowly replaced [Links, Books] by rejuvenated fibroblasts with telomerase-enlongated telomeres after gene expression is reset to the expression characteristic of the youthful phenotype. On the other hand, if skin fibroblasts are senescent, they secrete matrix metalloproteinases such as collagenase (MMP-1) and stromelysin (MMP-3) that attack collagen and extracellular matrix proteins. MMP-3 and other matrix metalloproteinases promoting skin wrinkling are stimulated by UV and IR radiation. Senescent fibroblasts also show reduced expression of TIMP1 and TIMP3, tissue inhibitors of matrix metalloproteinases [Links, Books, Papers, Patents, Amazon, LifeExtension, Wikipedia]. See Links/treating the extracellular matrix, Index/Telomerase Activators, Terraternal Astragaloside IV skin cream, IndexW/Wrinkles, IndexM/Matrixyl 3000, and Index/Skin.
Matrix Metalloproteinases [Wikipedia, Links, Images, Papers, Patents, Books/Matrix Metalloproteinases and Aging, Amazon LibCong/Matrix Metalloproteinases, Links, Images, Video, Papers, Patents, Books, Amazon LifeExtension; Sigma_Aldrich/Matrix Metalloproteinases and Their Inhibitors; Sigma_Aldrich/Matrix Metalloproteinases]. Senescent dermal fibroblasts, which have a Hayflick limit of about 50, express matrix metalloproteinases collagenase (MMP-1) and stromelysin (MMP-3) which degrade collagen and extracellular matrix proteins. "Moreover, chronic IR treatment increased MMP-3 and MMP-13 mRNA expressions significantly in hairless mouse skin and augmented UV-induced MMP-3 and MMP-13 mRNA expressions and UV-induced MMP-2 and MMP-9 activities. From these results, we demonstrate that IR alone induces skin wrinkling and augments UV-induced wrinkle formation." [Hyeon Ho Kim, et al., 2005]. Senescent fibroblasts also show reduced expression of TIMP1 and TIMP3, tissue inhibitors of matrix metalloproteinases [Links, Images, Books, Papers, Patents, Amazon, Wikipedia]. See Robert Visse, Hideaki Nagase (2003), Matrix Metalloproteinases and Tissue Inhibitors of Matrix Metalloproteinases, Circulation Research, 2003;92:827.
MMP-1 (Collagenase) degrades collagen.
_______MMP-1 Inhibitors [Images, Papers, Patents, Books].
MMP-2 (Gelatinase A) and MMP-9 (Gelatinase B) attack gelatin.
_______MMP-2 Inhibitors [Images, Papers, Patents, Books].
MMP-3 (Stromelysin) degrades extracellular matrix proteins.
_______MMP-3 Inhibitors [Images, Papers, Patents, Books].
MMP-8 (MEROPS/MMP-8)), attacks collagens.
_______MMP-8 Inhibitors [Images, Papers, Patents, Books].
MMP-9 inhibits TIMP-1 and TIMP-2 MMP inhibitors in cancer cells, attacks gelatin.
_______MMP-9 Inhibitors [Images, Papers, Patents, Books].
MMP-12 (Metalloelastase, Elastase)] attacks elastin.
_______MMP-12 Inhibitors [Images, Papers, Patents, Books].
MMP-13 (Collagenase 3) dissolves cartilage, attacks collagens, fibrillar collagens (Article).
_______MMP-13 Inhibitors [Images, Papers, Patents, Books].
MMP-1, MMP-8, MMP-13, and MMP-18 (Xenopus) attack collagens.
TIMP-1 and TIMP-3 are tissue inhibitors of matrix metalloproteinases.
Tissue Inhibitors of Matrix Metalloproteinases TIMP-1,TIMP-2, TIMP-3, TIMP-4.
TIMP-1 - human collagenase inhibitor. TIMP-1 "complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor... Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13 and MMP-16. Does not act on MMP-14." - GeneCards/TIMP1.
______TIMP-1 transcriptional activators: Leptin [Leptin Supplements].
TIMP-2 - Acts on MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13, MMP-14, MMP-15, MMP-16 and MMP-19. - GeneCards/TIMP2.
______TIMP-2 transcriptional activators.
TIMP-3 "complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. May form part of a tissue-specific acute response to remodeling stimuli. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, MMP-14 and MMP-15." - GeneCards/TIMP3.
______TIMP-3 transcriptional activators: Bovine lactoferricin supplements [Ref].
TIMP-4 acts on MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9. - GeneCards/TIMP4.
______TIMP-4 transcriptional activators.
See Dong Z, Nemeth JA, Cher ML, Palmer KC, Bright RC, Fridman R (2001), Differential regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression in co-cultures of prostate cancer and stromal cells, International Journal of Cancer 93:507-515. Note that hyaluronic acid inhibits the cartilage-dissolving enzyme MMP-13 to protect joints in therapy for arthritis, and is best given with pain-relieving krill oil (300 mg/day), fish oil (2400 mg/day), and astaxanthin, which also inhibits MMP-13.
Note that doxycycline, a tetracycline family antibiotic, is a matrix metalloprotease inhibitor. - Wikipedia/Doxycycline. See
Matrix Metalloproteinase Inhibitors defending Elastin - (Test Techniques [Ref]),
MMP-12 inhibitors, supplements inhibiting MMP-12:
____Ilomastat (GM6001 [Enzo Ref]): TruthInAging: Marta remarks.
____Hydroxamate inhibitors of MMP-12.
____Leptin [Leptin Supplements], via TIMP-1 transcriptional activation.

Matrix Metalloproteinase Inhibitors defending Collagen
MMP-1 inhibitors, supplements inhibiting MMP-1:
___Doxycycline hyclate (Periostat) [Ref].
___Mepacrine inhibits up-regulation of MMP1, MMP2 and MMP8. [Ref].
___EGCG inhibited the IL-1beta-induced expression of MMP-1 and MMP-13. [Ref].
___Leptin [Leptin Supplements], via TIMP-1 transcriptional activation.
___Bovine lactoferricin supplements by TIMP-3 transcriptional activation.
___Mepacrine inhibits up-regulation of MMP1, MMP2 and MMP8. [Ref].
MMP-8 inhibitors, supplements inhibiting MMP-8:
___Mepacrine inhibits up-regulation of MMP1, MMP2 and MMP8. [Ref].
___Leptin [Leptin Supplements], via TIMP-1 transcriptional activation.
___Mepacrine inhibits up-regulation of MMP1, MMP2 and MMP8. [Ref].
MMP-13 inhibitors, supplements inhibiting MMP-13:
___Hyaluronic Acid, given with krill oil 300 mg/day or fish oil 2400 mg/day.
___Astaxanthin.
___Apigenin [Ref].
___Wogonin [Ref].
___EGCG inhibited the IL-1beta-induced expression of MMP-1 and MMP-13. [Ref].
___Leptin [Leptin Supplements], via TIMP-1 transcriptional activation.
___Bovine lactoferricin supplements by TIMP-3 transcriptional activation.
MMP-18 inhibitors, supplements inhibiting MMP-18.

Matrix Metalloproteinase Inhibitors defending Gelatin
MMP-2 inhibitors, supplements inhibiting MMP-2:
___GSH (glutathione) [Ref].
___NAC (N-acetyl-cysteine) [Ref].
___Mepacrine inhibits up-regulation of MMP1, MMP2 and MMP8. [Ref].
___Leptin [Leptin Supplements], via TIMP-1 transcriptional activation.
___Bovine lactoferricin supplements by TIMP-3 transcriptional activation.
MMP-9 inhibitors, supplements inhibiting MMP-9:
___Lipoic Acid [Ref].
___Leptin [Leptin Supplements], via TIMP-1 transcriptional activation.
___Bovine lactoferricin supplements by TIMP-3 transcriptional activation.
See Matrix Metalloproteinases as Clinical Targets [Links, Images, Papers, Patents, Books].
Matrixyl 3000 (palmitoyl tetrapeptide-3) [LifeExtension, Links, Images, Papers, Patents, Books; Truth in Aging]. Matrixyl 3000 is a fatty acid mixed with amino acids, a lipo-peptide, shown to increase collagen synthesis [Links, Images, Video, Papers, Patents, Books] overall by up to 117% and collagen IV synthesis [Links, Images, Papers, Patents, Books] by up to 267%. It also stimulates the healing of lower skin layers, dimenishing the appearance of wrinkles, and increases hyaluronic acid synthesis [Links, Images, Papers, Patents, Books; Index/Hyaluronic Acid] up to 267%. Noticibly younger skin with wrinkles half as deep is typically obtained within 2 weeks. See also Life Extension's New Face Solution. Note that colostrum skin creams can reconstruct both collagen and elastin in the extracellular matrix with TGF-beta while also lengthening dermal telomeres with growth factor telomerase activators IGF-1, IGF-2, EGF, TNF-alpha, FGF (FGF-2 and FGF-4), PDGF, VEGF, and TGF-alpha. . Syn-Tacks, a skin formula I found in Truth in Aging a year or two ago, improves the expression of integrins to boost skin elasticity. Hexapeptide-10 (serilesene), described in neck rejuvenation, can restore hemidesmosomes, alpha6-integrin, and laminin-5 to revive skin elasticity and firmness. Genistein and daidzein from soy extract, when mixed with skin creams, inhibit elastase and improve the expression of elastin. A good quick fix for wrinkles is found in Instant Face Lift Serum [Index, Links, Images, Video, Papers, Patents, Books], which dramatically removes wrinkles for twelve hours or more. Such formulas often seem to feature hyaluronic acid with retinol in a suitable transporter such as isopropyl alcohol, glycerin, or milk lipid liposomes, perhaps with other components of the extracellular matrix, such as collagen. Recently, oral phytoceramides have been used to implement facial rejuvenation.
MCP, Modified Citrus Pectin [Links, Images, Papers, Patents, Books, LifeExtension, LibCong]. Modified citrus pectin is a galectin-3 antagonist that interferes with cancer metastasis as a cancer metastasis inhibitor. (Note that agonistic drugs are those that work to mimic the effect of a signaling molecule such as a neurotransmitter, while antagonistic drugs work by blocking signaling molecules such as neurotransmitters.) NF-kB inhibitors are cancer metastasis inhibitors. Modified Citrus Pectin is made by chopping up longer chains of citrus pectin, which also has anticancer, anti-metastasis properties to a lesser degree. See how to manufacture modified citrus pectin.


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