Supplemental Notes 1 - Anti-Aging Medicine

[1s] See The Aging Process by the Rubins & Theories of Aging and Anti-Aging Today.
Also see Wikipedia: Life Extension and Ben Best's Mechanisms of Aging, International Anti-Aging Systems, Longevity magazine, and Life Extension magazine & search engine together with their program for Anti-Aging Research. For links and references to other journals and sources, see footnote [57] from my file Anti-Aging Medicine.
Anti-Aging Glossary | Anti-Aging Conference Glossary | Anti-Aging Terms

[2s] Carnosine and the Proteasome: "Ageing and neurodegenerative conditions are often associated with proteasome dysfunction, possibly mediated by zinc and/or copper ions. Studies have shown that (i) the olfactory lobe is normally enriched in carnosine and zinc, (ii) carnosine can suppress copper and zinc toxicity in olfactory neurones, (iii) olfactory dysfunction is often associated with neurodegenerative conditions and (iv) elevated levels of zinc are found in brains of Alzheimer’s patients. It is suggested that nasal administration of carnosine should be explored as a possible way of suppressing zinc/copper-mediated proteasome inhibition and consequent neurodegeneration." - from Biogerontology, Volume 6, Number 2, pp 147-149, 2005.
Also see Google: Carnosine nasal spray, footnote [9s], and footnote [69] on Carnosine from Anti-Aging Medicine. Regarding the proteasomes, I note that they digest oxidized and ubiquitinated proteins, and that they fail in aging cells, resulting in the accumulation of damaged proteins into Lewis bodies. Lipofuscin may inhibit proteasomes. Dietary caloric restriction has restored proteasome function in old animals (pg.213, Aging at the Molecular Level, ed. T. Zglinicki). Caloric restriction modifies age-related accumulation of altered proteins damaged by oxidation, glycation, glycoxidation, and conjugation with lipid peroxidation products. 26S proteasomes were inactivated by carboxymethl-lysine, a glycoxidation product, and by conjugation with 3-hydroxy-2-noneal, a lipid peroxidation product in old lymphocytes. (pg.219, ibed). "Free radical mediated arachidonic acid oxidation can produce a mixture of gamma-isoketals capable of reacting with proteins to produce structures that are not only resistant to proteolysis but inhibit proteasome function." - pg. 160, Hipkiss in Aging at the Molecular Level, ed. T. Zglinicki." Arachidonic acid is found in meat, poultry, eggs, and wheat products. It can be avoided by substituting cold water fish. However, arachidonic acid is considered an essential fatty acid that should not be entirely missing from your diet. Over-consumption of arachidonic acid acts to produce inflammation, so that physicians treating arthritis often recommend substituting fish for red meat. Since free radicals mediate the process producing reactive gamma-isoketals from arachidonic acid leading to functional inhibition of proteasomes after further reactions with proteins, anti-oxidants can be used to control this result.
"Meat is rich in a twenty carbon fatty acid called arachidonic acid. This is the raw material for the inflammatory series two prostaglandins. These make blood platelets more sticky and likely to adhere together. The result can be a blood clot leading to a stroke or a heart attack. Cold water fish, rich in eicosapentaenoic acid (another twenty carbon fatty acid with less hydrogen atoms attached to it), is fuel for the production of the antiinflammatory series three prostaglandins. Lancet (1989;2;757) reported that patients who ate fatty fish had almost a thirty percent reduction in deaths over two years compared to those who were not so advised. This is because the eicosopentaenoic acid in the fish increased the production of series three prostaglandins and thus tilted the balance in the direction of less "sticky" platelets and less inflammation in the cardiovascular system." - from Essential Fatty Acids

[3s] The stationary phase model of aging in yeast for the study of oxidative stress and age-related neurodegeneration, by Quinghua Chen, Qunxing Ding and Jeffrey N. Keller, Biogerontology, Volume 6, Number 1, pages 1-13, 2005. Points out that aging effects can be opposed both by inhibiting Reactive Oxidative Species and by removal of the products of their oxidation of proteins and lipids, which cause further damage or carbonylation. The important role of the proteasomes in removal of oxidized proteins is reviewed, and the article supplies many valuable insights.

[4s] Testing the garbage accumulation theory of ageing: mitotic activity protects cells from death induced by inhibition of autophagy by Yuri Stroikin1 , Helge Dalen1, Ulf T. Brunk2 and Alexei Terman1, Biogerontology, Vol.6, No.1, jan 2005. Accumulation of garbage such as lipofuscin eventually results in cell death by apoptosis. The removal of oxidatively damaged cellular structures and garbage usually takes place via lysosomes, proteasomes, and cytosolic proteases, but this is inherently imperfect. Accumulation of lipofuscin and damaged mitochondria leads to enhancement of oxidative stress and damage to cellular DNA. Proteasome activity could be enhanced by repeated mild heat shock with life-extending effect. Another unusual scheme would transfect cells with genes encoding for xenohydrolases (enzymes found in bacteria and fungi) capable of degrading lipofuscin.
Piracetam as an effective lipofuscin formation blocker.
See books on Piracetam, Piracetam and aging.

[5s] Exercise and hormesis: oxidative stress-related adaptation for successful aging by Zsolt Radak , Hae Young Chung and Sataro Goto, Biogerontology, Vol.6, No.1, Jan 2005. "The hormesis theory purports that biological systems respond with a bell-shaped curve to exposure to chemicals, toxins, and radiation. Here we extend the hormesis theory to include reactive oxygen species (ROS). " Exercise champ Jack LaLanne is still alive, well, and pumping iron at 91! However, exercise generates Reactive Oxygen Species that shorten the life span of Drosophila by about 50% when it is allowed to fly, as opposed to when it is constrained not to fly. See Aging at the Molecular Level, edited by Thomas von Zglinicki, editor, Kluwer, 2003. Bodybuilders would be well-advised to keep their antioxidant levels high. Also, it has been shown that high anti-oxidant defense produces slower-rate telomere shortening in nuclear DNA. Finally, you may be suffering from hyperoxia by living at low altitude. "Culturing human WI-38 fibroblasts under high oxygen tension (40% O₂) causes telomeres to shorten prematurely and consequently the replicative life span of the cells is significantly reduced." - Petra Boukamp, Biological Clocks in the Aging Cell, from Zgliniki, pg. 81, ibed.
See books on Hormesis and Aging.

Finished current 2005 Biogerontology, working back through 2004.

[6s] Extending Life Requires NAD Synthesis. NAD (nicotinamide adenine dinucleotide), best increased in vivo with the B-vitamin nicotinamide (vitamin B3) and/or niacin, also becomes more abundant with Caloric Restriction, which makes more NAD available. See also NADPH and NADPH links.
"A large 5-year study in Finland (which has one of the world's highest heart-disease rates) showed that patients treated with the anticholesterol drug gemfibrozil had an 11% decrease in LDL, an 11% increase in HDL and 34% less heart disease. Niacin is reported to produce similar results." - Ben Best, Sudden Cardiovascular Death.

[7s] SENS - Strategies for Engineered Negligible Senescence, (Books), Aubrey de Grey.

[8s] Legendary Pharmaceuticals - Senescence | Dossier on Aging, Cellular Flowchart of Aging, Background: Introduction to the Biology of Aging and Senescence.
Senescence, books on senescence.

[9s] Carnosine: nature's pluripotent life extension agent. See Carnosine face serum from International Anti-Aging Systems. See the IAS interview with Marios Kyriazis, M.D., on carnosine, and the Kyriazis article on Carnosine. See also footnotes [2s] and [69] on carnosine. || Carnosine is anti-senescent and glycation-suppressing as are pyridoxamine and possibly kinetin. D-penicillamine, Aminoguanidine, and hydroxyamines are also anti-glycation medications. "Protein glycation may also create catalytic sites for free-radical generation, linking oxidative and non-oxidative aging theories." (pg.160, Hipkiss in Aging at the Molecular Level, ibed.) Carnosine (Books) may also be a protective agent against glutamine residue deamidation. (pg.157, ibed.) "Suppression of glycolysis rather than any decrease of mitochondrial function may explain the anti-aging effects of caloric restriction.... Furthermore, glucose is itself subject to metal-catalyzed auto-oxidation with concomitant generation of ROS and bicarbonyls." (pg.160, Hipkiss, ibed.)

[10s] Jean Calment took red wine (resveratrol), olive oil (hydroxytyrosol), chocolates (dark chocolate polyphenols) and smoked cigarettes for nicotine. Perhaps a combination of nicotinamide (vitamin B3) or niacin (an alternate form of vitamin B3 causing niacin flush) with resveratrol, hydroxytyrosol, and dark chocolate polyphenols would be as effective as her program. Both resveratrol and nicotinamide are associated with gene silencing of genes promoting aging. See vitamin B3 sources and the vitamin B3 description in The World's Healthiest Foods. The tolerable upper limit for niacin dosage is 35 mg. Vitamin B3 deficiency has been linked directly to DNA damage. "Those getting the most niacin from foods (22 mg per day) were 70% less likely to have developed Alzheimer's disease than those consuming the least (about 13 mg daily), and their rate of age-related cognitive decline was significantly less."
See books on Centennarians.

[11s] According to "Iron and Oxygen Free Radicals in Brain Aging" by Robert A. Floyd, M.M.Zaleska, and H.James Harmon in Aging 27, "Free Radicals in Molecular Biology, Aging, and Disease", edited by Donald Armstrong, et.al., Raven Press, 1989, dopamine ([97]) ligates iron that catalyzes the production of the hydroxyl radical from hydrogen peroxide, which peroxidizes lipids and cellular membranes. (See page 159.) Thus dopamine protects cellular membranes and prevents the peroxidation of lipids by ligating iron. Perhaps the life-extending effect of deprenyl (selegiline), a dopamine availability improver, is due to this. Other dopamine producers such as St. John's Wort might also show life-extending effects based on this mechanism, although without MAO-B dopamine uptake inhibition as produced by deprenyl, extra dopamine might be confined to the synapse and barely impact aging. See the James South article on Deprenyl. "Only one supplement, deprenyl [92], has so far been shown to increase any mammal's maximum life span without reducing caloric intake." - Aubrey D.N.J. de Grey, The Mitochondrial Free Radical Theory of Aging, pg.121, 131, 134. The same book details the branching chain reaction catalyzed by iron featuring oxygen and the superoxide radical yielding 2 lipid radicals out for each lipid radical in. (See pg. 42.) Vitamin E combats this iron-catalyzed reaction by hydrogenating the lipid radicals it produces. After vitamin E performs this function, it must be restored by vitamin C. So vitamin E supplementation is very attractive for warding off the chain reaction acceleration of free radical processes associated with the peroxidation of lipids. According to de Grey, the peroxidation of the mitochondrial membranes is in fact more impacting to mitochondrial functional decline than ensuing mutations to mitochondrial mtDNA. (pg. 131.) Curcumin can be used to chelate the iron involved in catalyzing the branching chain reaction, which yields lipofuscin and products that, if glycated by sugar (glucose), produce hard-to-remove Advanced Glycation End products (AGEs). CoQ10, DMAE, or centrophenoxine (DMAE+Auxin) are often prescribed to remove lipofuscin wastes associated with reaction hot spots. However, indigestible iron-rich lipofuscin wastes are finally locked up in lysosomes like garbage in bags. Eventually, the accumulation of such bagged material can result in retinal lift-off and macular degeneration [101]. Supplementation of the diet with phosphatidylserine or other phospholipids (such as phosphatidylserine-DHA in Cognitex) used by enzymes such as phospholipase to repair the mitochondrial membranes is also an attractive option. Treat with anti-oxidants like alpha lipoic acid ([70]), also with vitamin C, vitamin E, curcumin, deprenyl, CoQ10 [59], DMAE or centrophenoxine, and phosphatidylserine, phosphatidylcholine, phosphatidylinositol, or equivalent, avoiding both a glycemic load such as jelly bean pills (really a Mickey Finn leading to Alzheimer's) and treatment with pure oxygen. Anti-glycation medicine such as carnosine [69] or acetyl L-carnitine should be used to prevent AGEs. The peroxidation of lipids finally produces both atherosclerois leading to heart attack, stroke, and hypertension, and neural damage leading to old age cognitive decline and Alzheimer's Disease. There is evidence that both ROS and products of lipid peroxidation including reactive aldehydes (p.148) can damage DNA and DNA-maintenance enzymes. Also, it has been shown that lowering the double-bond index of cellular membranes with appropriate low-double-bond index dietary unsaturated fats protects post-mitotic cells against lipid peroxidation. (See Pamplona and Barja, Aging Rate, Mitochondrial Free Radical Production, and Constitutive Sensitivity to Lipid Peroxidation: Insights from Comparative Studies from Aging at the Molecular Level, ed. Thomas von Zgliniki, 2003.)

File indexed to this point.

[12s] 2-mercaptoethylamine was shown to increase the life span of mice by 30%, according to an Dr. Denham Harman in Aging 27, ibed.

[13s] Chelation of aluminum, which causes neuro-fibrillary tangles.
See books on chelation of aluminum and neurofibrillary tangles.

[14s] In yeast, extrachromosomal circular DNA (eccDNA, also termed small polydispersed circular DNA (spcDNA), ) is thought to contribute to aging by titrating away essential nuclear factors. Extrachromosomal circular DNA also exists in humans, worms, and flies. Its role in aging in these organisms is now being explored. See Gene Regulation in Senescence. Extrachromosomal circular DNA increases with cell stress or aging. I note that "In particular, the most common carrier of amplified oncogenes and drug resistance genes in human cancer cells in vivo are extrachromosomal circular DNA molecules, referred to as double minute chromosomes (dmin) and episomes.". Telomeric eccDNA has been observed. || See Aging at the Molecular Level by T. Zglinicki, pg.198 on eccDNA. Recombinant DNA can form eccDNA loops in the nucleolus region of aging cells. In yeast, eccDNA loops reproduce with each cell division, but stick with the mother cell, so that eccDNA accumulates in the nucleolus, finally exploding it. An extra copy of the gene Sir2 extends yeast life span 30% by suppressing DNA recombination. (pg.198) I note that Sir2 can be activated by caloric restriction or resveratrol. Sir2 requires NAD for its function, which can be obtained via niacin.
I note that mtDNA in mitrochondria has been observed to create eccDNA loops from the 16569 bp mitochondrial genome when mtDNA topoisomerase II is inhibited. See Principles of Neural Aging, ed. Dani, Hori, and Walter, 1997, chap.6. Genetic recombinations cause DNA errors with higher frequency than DNA replication. ibed, chap.1. Inhibition of DNA topoisomerases may be a factor in apoptosis, in which DNA is snipped between histone cores.

[15s] Glucose, glycation and aging, by George Suji and S. Sivakami, in Biogerontology, Volume 5, Number 6, November 2004. Good review.
Signs of premature aging in patients with diabetes, which is associated with high blood sugar and abnormally low production of insulin, led researchers to suspect that sugar damage and glycation of proteins is involved in the aging process. Obesity and lack of exercise correlate with diabetes.

[16s] Functional foods, herbs and nutraceuticals: towards biochemical mechanisms of healthy aging by Carlos K. B. Ferrari, Biogerontology, Volume 5, Number 5, October 2004.
CoQ10 content of foods:
Soy Oil - 92mg/100g
Mackerel fish - 43mg/100g, or 196.76 mg of CoQ10 per lb. of mackerel!
Meat - 32mg/100g, or 144 mg/lb of meat.
Peanuts - 27mg/100g, or 122.3 mg/lb of peanuts.
Pork - 25mg/100g, or 133.4 mg/lb of pork.
Fish filet - 24mg/100g, or 108.86 mg/lb of fish fillet.
Chicken - 21mg/100g, or 95.25 mg/lb of chicken.
Nuts - 19mg/100g, or 86.18 mg/lb of nuts.

[17s] Human Growth Hormone Replacement Therapy decreases fat, increases muscle, and improves bone mass, increases vigor, ambition, and sense of well-being. Perhaps this is best achieved by bodybuilding technique combined with skim milk blended with egg whites. "A few investigators have expressed concern that increased concentrations of GH and IGF-1 associated with GHRT may accelerate the maladaptive changes associated with aging. This view derives mostly from animal studies, which may have little or no relevance to the human condition. However in one clinical study, men with the highest levels of plasma IGF-1 had a 4.3-fold greater risk for prostate cancer than those with the lowest IGF-1 concentrations (72). (This increased risk of prostate cancer may be eliminated using Vitamin D3.) In another study, high concentrations of IGF-1 were associated with increased breast cancer (73). "

[18s] DHEA (IAS Bulletin) is another bone-mass improver opposing osteoporosis and sarcopenia (age-related decrease in skeletal muscle mass). "A group of researchers found that DHEA increased the growth of human brain cells in an in-vitro study. DHEA treatment caused as much as a 29% increase in the number of neurons produced by stem cells. Low endogenous levels of DHEA are found in a number of different dementias and AD."

[19s] Observations on The Neuroendocrine Theory of Aging (See also the chapter 4 article on the Neuroendocrine Aging Theory by Ward Dean and the subsequent chapter 5.)- Pacific salmon have an unusual programmed life span in which they swim upstream after several years in the ocean, mate, lay eggs, and then die after their glandular systems release massive amounts of corticosteroids. The wipe-out of the older generation prevents it from competing with the younger generation for resources in a way that would disfavor salmon in the overall process of evolution and species survival. In the human case, the adrenal gland hormone cortisol seems to play a similar role. (See books on cortisol and aging.) Therefore, attention is paid in the neuroendocrine theory of aging to medicines that reduce cortisol levels, including DHEA, Gerovital-H3, and Phenytoin. (Note Ashwagandha also lowers cortisol levels.) The premature aging sometimes reported after a hair-whitening period of intense strain is probably due to cortisol. Cortisol is supposed to attack the hypothalamus, which is anyway attacked by free radical reactions catalyzed by iron and copper that peroxidize lipid membranes in hypothalamic tissue. Dopamine, which ligates iron, removes the catalyst for these iron-catalyzed Fenton reactions, as does curcumin, which chelates iron and copper. The anti-aging drug Deprenyl makes dopamine available via a MAO-B uptake inhibitor effect. However, if cortisol plays a role similar to corticosteroids in salmon, then cortisol accumulation may trigger many aging problems we attack separately after they have been cortisol-triggered, rather as in salmon. Note that the anti-aging Human Growth Hormone (HGH) is released by the pituitary after bodybuilding exercises, so we will want to look into cortisol and exercise (Books). Overall, however, I get the impression that fiddling with our hormones is more dangerous than playing with anti-oxidant levels, because excess testosterone may be associated with cancer problems, and some of the mechanisms modifying cortisol levels modify testosterone levels. (Vitamin D3 reduces these dangers.) See Hormones & Health on hormonal carcinogenesis. Also see Life Extension magazine on the cortisol connection and related problems in brain aging.
See also books on hormonal carcinogenesis.

[20s] Phytoestrogens - "The low incidence of hormone-related cancers, osteoporosis, heart disease, and menopausal symptoms in certain populations with diets rich in phytoestrogens has led to renewed interest in the potential beneficial effects of phytoestrogens in treating and preventing disease. Asian populations consume a diet rich in soy products, which contain the phytoestrogens genistein and daidzein. Because of evidence of lesser incidence among such populations of hormonally related cancers, and because there is a greater incidence of hormonally related cancers among Asians who have migrated to the United States and consequently changed their dietary habits, it seems possible that phytoestrogens in the diet may be useful in the prevention of certain estrogen-related diseases. ".

[21s] Thymic Theory of Aging (Books) in Theories of Aging.
"Arginine: Fabris (1991) reported that treatment of healthy elderly people with arginine (no dose stated) resulted in restoration of blood thymic hormone levels to youthful values after several months. I believe a reasonable dose to accomplish this would be 1 to 3 grams daily, or about 90 grams/month. See NutraBio Arginine, 500 grams of bulk arginine for $25.66; roughly 5 dollars per month covers our 90 gram/month requirement. On the other hand, a typical $8.99 bottle 240 of 500 mg Best Vite arginine capsules amounts to 120 grams, so (90/120)$8.99 = $6.75 covers 90 grams/month with a more conventional source. Nobel prize winner Louis B. Ignarro suggests in his book NO More Heart Disease that nitric oxide is best boosted by 5-6 grams of arginine per day plus 200 mg to 1 gram of L-citrulline, plus antioxidants. The L-citrulline, which is found in watermelon rinds, extends the half-life of nitric oxide in the blood. Vasa, et al, 2000 and Hayashi, et al, 2006 showed in separate papers that NO activates telomerase in endothelial cells to refresh the vascular endothelium.
Zinc: Fabris, and colleagues (1990, 1991) showed that zinc supplementation in old age could restore thymic activity, and improve various immune parameters as well as some age-related hormonal deficits. " Zinc to 50 mg/day is good for telomere protection. [Links/Zinc and Telomeres, Links/Zinc Fingers and Telomeres; Links/Zinc Homeostasis, Wikipedia/Zinc(Biological role), Links/Zinc supplements, Links/Foods rich in Zinc, GovFactSheet/Zinc]. See Catia Cipriano, Silvia Tesei, Marco Malavolta, Robertina Giacconi, Elisa Muti, Laura Costarelli, Francesco Piacenza, Sara Pierpaoli, Roberta Galeazzi, Maria Blasco, Elsa Vera, Andres Canela, Fabrizia Lattanzio and Eugenio Mocchegiani, 2009, Accumulation of Cells With Short Telomeres Is Associated With Impaired Zinc Homeostasis and Inflammation in Old Hypertensive Participants, The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009, 64A(7):745-751. Note that semen, which perpetually contains cells with long telomeres, is rich in zinc, which is sometimes taken to increase the size of a semen load. Note that "oysters" are the food source richest in zinc. "Zinc deficiency is characterized by... impaired immune function." Zinc "is required for the catalytic activity of approximately 100 enzymes and it plays a role in immune function, protein synthesis, wound healing, DNA synthesis, and cell division." - GovFactSheet/Zinc. See books on arginine and aging.
See Google Arginine links.
See Thyroxine as a life extension drug. (Books) I think this last link is bad bait. Life span is inversely proportional to metabolic rate as determined by application of thyroxine. For instance, cooled rats increase their metabolic rate by supplying themselves with more thyroxine, and live shorter lifetimes. (See Hypothalamus Pituitary and Aging by Everitt and Burgess, pg.17.)

[22s] Death Hormone Theory (Books) involving DECO as described in Theories of Aging. Based on the research of W. Donner Denckla on replacing specific pituitary hormones after removing the pituitary without replacing the hormone DECO, which if included greatly decreased life span in lab rats. See alternate notes on the theory of aging including Denckla's model. "Denckla speculated that as we age the pituitary begins to release DECO which inhibits the ability of cells to use thyroxine, a hormone produced by the thyroid-governing basal metabolism, the rate at which cells convert food to energy. The metabolic rate brings on and accelerates the process of aging.". W. Donner Denckla seems to be German for "W. Thunder Thinks", however, which does little to establish confidence that he is playing with an honest deck. See Google links on thyroxine and aging. See Thyroxine as a life extension drug. I think this last link is bad bait. Life span is inversely proportional to metabolic rate as determined by application of thyroxine. For instance, cooled rats increase their metabolic rate by supplying themselves with more thyroxine, and live shorter lifetimes. (See Hypothalamus Pituitary and Aging by Everitt and Burgess, pg.17.)

[23s] According to research by Dr. Don Kleinsek of Gerigene, telomeres can be repaired by introduction of the relevant hormone. (Books on hormonal repair of telomeres, Papers.) See Theories of Aging from International Anti-Aging Systems. See also Hormones of the Human, and its Table of Hormones, and Wikipedia on Hormones. See the Google searches telomere repair and hormones and telomere lengthening and hormones. Also see the Google searches: HGH and telomere repair, HGH and telomere lengthening, HGH and telomere lengthening, DHEA and telomere repair, DHEA and telomere lengthening, melatonin and telomere repair, melatonin and telomere lengthening. (Most recently, I have seen evidence that Growth Hormone produces telomere-extending effects [Gomez-Garcia, et.al., 2005] or telomerase activation, and that antagonists of growth hormone dramatically decrease telomere growth [Jun-Ping Liu, FASEB Journal, 1999]. Also, IGF-1 was shown to increase telomerase activity in mice [Torella et.al., 2004].) Since stress has been linked to telomere shortening, cortisol elevation probably leads to shortened telomeres, and since cortisol is opposed by DHEA, perhaps DHEA is telomere-lengthening, or at least telomere-length preserving. (Note that DHEA improves IGF-1 levels, and that IGF-1 is now known to activate telomerase. Also, HGH is turned into IGF-1 in the liver, so that activates telomerase by this pathway.) Vitamin D3 helps reduce any associated cancer risks from using HGH or IGF-1. On the other hand, "Indeed, mice that overproduce growth hormone die sooner than normal mice, and fruit flies that under-produce growth hormone live longer than normal flies. In addition, some researchers suspect that supplementary growth hormone may increase the risk of cancer." Also, "researchers found that telomeres lengthened rather than shortened with age in Leach's storm-petrels, an extremely long-lived bird." This concordance suggests that a fundamental link between telomere length and organismal lifespan may exist, perhaps due to the same mechanisms that link telomere shortening to cell replicative life span."
Note that most rodent cells never turn off the gene for telomerase, and their telomeres do not shrink with age. - Page 474, Molecular Biology of the Cell, Alberts, Johnson, et. al. Therefore, the maximum life span of a rodent may be determined by a different mechanism.

[24s] Heat Shock protein overexpression via Hsp22 extends Drosophila lifespan 30%.
See books on Heat Shock proteins and aging, Hsp22 extends life span, Methuselah flies.
Perhaps anti-aging sauna treatments involving hormesis-response to heat treatment can be used to elevate heat shock protein levels in humans with good life extension effect. See books on heat shock proteins in humans.

[25s] SAMe and DNA methylation according to Life Extension Magazine. A SAMe source [Links/SAMe]. SAMe as an anti-depressant and regarding its impact on neurotransmitters. Life Extension brand SAMe. Quality Counts links on SAMe.
SAMe article by James South on its characteristics. I note that DNA methylation is not necessarily good, since it can silence a tumor-suppressor gene and induce cancer. However, SAMe (S-adenosylmethionine) may merely make methylation available to the DNA-maintenance machinery for silencing genes when they ought to be silenced. See A Simplified Description of DNA methylation. Life Extension magazine ads were promoting SAMe this month (Sept 2005) as substantially reducing peroxidation of lipids in experimental animals.
Reduction in methylation of DNA has been found with aging, and application of 5-azacytidine, a demethylation inducer, causes a decrease in DNA methylation and reduces the life span of cultured cells in vitro. See Principles of Neural Aging, chap.5, ed. Dani, Hori, and Walter, 1997. Note that methylation also detoxifies homocysteine, a fact used to measure methylation in the body.

"He don't plant tatters, and he don't plant cotton
And them what plants em, are soon forgotten
But ol' man river, he just keeps rollin' along...

I gets weary, and sick of tryin'
I'm tired of livin', but I'm scared of dyin'
But ol' man river, he just keeps rolin' along." - Old Man River, Frank Sinatra.

Astrophoto of Galaxy M51 courtesy Kitt Peak Observatories. Mythos: The Beyond Within.
John 1:51 "And he saith unto him, Verily, verily, I say unto you, Hereafter ye shall see heaven open, and the angels of God ascending and descending upon the Son of man. ". This passage probably influenced the choice of a number for M51. Subjectively, it looks like my 2nd coming to Tampa Bay in 1987 as a Principal Design Engineer to Honeywell DCPD.
The tortoise on the bottom left side of the whirlpool galaxy is marked with a factor of 4,
which may establish the connection of "eternal life" with "Astragaloside IV". - Jokerman

[26s] Sesame Lignans elevate gamma tocopherol levels. "Duthie et al. (1 ) and Saldeen et al. (2 ) have reported that the antioxidative effect of gamma-tocopherol on lipid peroxidation in vitro is more potent than that of alpha-tocopherol. Moreover, Cooney et al. (3 ) and Christen et al. (4 ) showed that gamma-tocopherol trapped reactive nitrogen oxide species generated during inflammation in vitro. ". See also Dietary Defatted Sesame Flour Decreases Susceptibility to Oxidative Stress... and Sesame Seeds and sesame oil with the sesame lignan sesamin lowers blood pressure. (I note that the copper in sesame seeds may be undesirable, since excessive copper and iron in beef contribute to the spread of cancer and Alzheimer's disease, respectively. Resveratrol chelates copper, curcumin chelates copper and iron.) The sesame lignans sesamin and episesamin are eliminated from rats in about 24 hours. Studies show that sesame lignans increase mitochondrial activity, and increase burning of fat by stimulating fatty acid metabolism in the liver. See Gamma E tocopherol with sesame lignans and fish oil with sesame lignans and olive fruit. See also Sesame Lignan links. Note that lowering salt (sodium) levels also reduces high blood pressure (hypertension). Salt can raise blood pressure, aggravating atherosclerosis and leading to stroke or heart attack. My favorite source of gamma tocopherol is sunflower seeds.

[27s] Gradual disruption of chromatin silencing may cause aging. "Experiments in which Drosophila Sir2 expression was quadrupled led to a 57% extension of lifespan". - Ben Best, Gene Silencing. Quercetin (primarily found in apples, onions, and black tea) and resveratrol, (found in red grape skins and Japanese Knotweed), are life-extending sirtuin-activating compounds that promote gene silencing by promoting Sir2. Sir2 and Aging: A Historical Perspective. NAD is high when calories are restricted and is required for Sir2 functioning. See NAD/NADH links. The gene for Sir2 produces the Sir2 histone deacetylase protein, which allows histones to bind to DNA thereby silencing gene expression. "Drosophila fed the histone deacetylase [inhibitor] 4-phenylbutyrate showed up to 52% longer maximum life span". See footnote [87] on sodium 4-phenylbutyrate.
See books on sirtuins, 4-phenylbutyrate, histone deacetylases, gene silencing, and chromatin remodeling. Note that the human homolog for yeast SIR2 is SIRT1.

[28s] The hormone DHEA counteracts the effects of cortisol and DHEA can be used to extend life span. DHEA protects against cancerous tumor formation. Cortisol is produced by the hypothalamus in response to stress, and is probably responsible for the greying and premature aging that sometimes results from high-stress situations, and for other aging phenomena. See Ben Best's Hormones and Aging and Chapter 32 by Vladimir M. Dilman in Pituitary Hypothalamus and Aging by Everitt. DHEA displays no hormonal carcinogenic properties, sometimes seen in cases involving the sex hormones or melatonin. I note that the free radical Fenton reactions catalyzed by iron damage the hippocampus of iron-supplemented rats via lipid peroxidation independently of cortisol, which may also damage the hippocampus to produce symptoms of old age cognitive decline. The iron may be ligated by dopamine (from MAO-B inhibition using deprenyl), carnosine, or turmeric root curcuminoids, while DHEA supplementation seems to be the cure for the cortisol part of the neuroendocrine aging program. The primary source of excess iron leading to old age cognitive decline seems to be beef. See Ben Best on the role of the hippocampus in memory and learning. Human Growth Hormone maintains muscle mass, low fat leanness, and bone density, and may be released via ingestion of arginine, via exercise, or by direct supplementation. On the other hand, ingestion of glucose inhibits the release of HGH by the pituitary via inhibitory receptors in the hypothalamus according to Dilman.

[29s] Ben Best's Dietary Program | Ben Best's Life Extension links | Best Best's Home Page.

[30s] DHA, an omega-3 fatty acid found in fish oil, is the primary fatty acid in the brain. I think Ben Best takes it for brain food. See Ben Best's DHA for Hearts and Minds. I note that supplementing DHA with arachidonic acid gives the best results for brain-building in infants. Human milk contains 0.6% arachidonic acid. See Google links on DHA supplements.
Also see FATS: Fats for the Brain from Fats You Need by Ben Best. According to Best, arachidonic acid should be used to supplement DHA when feeding infants, although it makes stroke worse and contributes to the peroxidation of lipids, toxic effects that can be blocked by NAC, or N-Acetyl-Cysteine. EPA lowers triglycerides but raises LDL cholesterol, and I suspect that to reduce peroxoidation of lipids the best for adults is to take brain-building DHA straight, rather than fish oil, which Best thinks should be taken with vitamin E to ward off lipid peroxidation. See also Fats & Cholesterol, Know Your Fats. See books on DHA and Aging.

[31s] Ben also takes NAC (N-Acetylcysteine) 3 times a day, 600mg. See Google links on NAC, and Quality Counts NAC links. NAC raises levels of the natural anti-oxidant Glutathione in the body, which is also achieved with Vitamin C. NAC (N-Acetyl_Cysteine) is also used to chelate heavy metals, including mercury from fish and fillings. See also Glutathione links from Quality Counts. Ben directs an institute for cryonics suspension, which keeps recently dead patients frozen in liquid nitrogen until they can be revived via the re-animation of dead tissue, perhaps somewhat as shown in Young Frankenstein. (Sounds of Young Frankenstein.)

[32s] Ben also takes TMG or TriMethylGlycine [Wikipedia], which is converted in the body to SAMe [Wikipedia], an anti-depressant, serotonin-booster and membrane detoxifier which may assist in the methylation of DNA for life extension via gene silencing. TMG is also useful for detoxifying homocysteine, which may come from methionine in red meat, and which attacks the lining of arteries prior to the formation of arteriosclerotic plaque. See books on trimethylglycine, and trimethylglycine and aging.

[33s] Life Extension magazine on Metformin. See footnote [65] on metformin, which mimics CR, caloric restriction. See also Links/metformin. Extra vitamin B12 may be required. See the Life Extension Magazine article on metformin therapy from Biomarker Pharmaceuticals. The drug is used in the USA to treat diabetes and has resulted in death in a few cases from lactic acidosis. It may be required by law to do Caloric Restriction with Adequate Nutrition (CRAN) for real, and skip metformin.

[34s] Telomere maintenance via ALT. (links), Books. This was mentioned in an article by Aubrey De Grey, et. al. from Cambridge: Time to talk SENS: Critiquing the Immutability of Human Aging. See also links on telomerase-independent telomere length maintenance. The Aubrey De Grey group uses a lingo of its own to describe certain things such as AGE/ALEs - Advanced Glycation End Products/Lipid oxidation End Products, so that searching on their keys yields clues originating from their group. Another such key would be SENS, or Strategies for Engineered Negligible Senescence or biogerontology.

[35s] Royal Jelly for anti-aging (Books). Aubrey De Grey mentioned it in a table in one of his articles as an anti-aging therapeutic method, along with some other novel approaches, which I have given below with search links on Google, including:

a) anti-aging hormonal manipulation | Royal Jelly for anti-aging.
Royal Jelly: Claims of the Hive Club. "Royal Jelly is another bee food. It contains components that can smooth the wrinkles in aging skin. Royal jelly is high in B vitamins and beneficial fatty acids. The antioxidant and antimicrobial activity of propolis and royal jelly make them awesome antibiotics. It is so valuable that it is fed exclusively to the queen bee. It is credited with maintaining the queen's larger size and extending her life. Queen bees live four to five years compared to worker bees, who live approximately 40 days." - from Food From Bees to Promote Longevity and Anti-Aging. | PDRhealth on royal jelly.

b) Enzymatic free radical scavenging | Superoxide dismutase
"Enzymatic reactions which serve as sources of free radicals include those involved in the respiratory chain, in phagocytosis, in prostaglandin synthesis and in the cytochrome P450 system." - from Free Radicals and Anti-Oxidants in Health and Disease.

c) Nonenzymatic free radical scavenging | EUK-134, a catalase mimetic, SOD mimetic.
"Free radicals also arise in non-enzymatic reactions of oxygen with organic compounds as well as those initiated by ionizing radiations. Some internally generated sources of free radicals are [1]: mitochondria, phagocytes, xanthine oxidase, reactions involving iron and other transition metals, arachidonate pathways, peroxisomes, exercise, inflammation, ischaemia/reperfusion. Some externally generated sources of free radicals are [1]: cigarette smoke, environmental pollutants, radiation, ultraviolet light, certain drugs, pesticides, anaesthetics and industrial solvents, ozone. " - from Free Radicals and Anti-Oxidants in Health and Disease.
See books on catalase mimetics, SOD mimetics, Wasabi and aging, Sprouts and endogenous anti-oxidants, [64s].

d) Enzymatic inhibition of glycation | Amadoriases, deglycating enzymes.
"Inhibition of advanced glycated end-products" | Metformin inhibition of glycation processes.
Pyridoxamine, an Inhibitor of Advanced Glycation Reactions, Also Inhibits Advanced Lipoxidation Reactions. | Chelating Activity of Advanced Glycation Inhibitors. | Enzymatic deglycation - a new paradigm or an epiphenomenon?
Tissue-Specific Variation in Glycation of Proteins in Diabetes: Evidence for a Functional Role of Amadoriase Enzymes . | Google links on deglycating enzymes and enzymatic deglycation of proteins. See books on Amadoriase enzymes, deglycating enzymes, deglycation and aging.

e) Nonenzymatic inhibition of glycation (Books) | Pyridoxamine, aminoguanidine
Inhibition of nonenzymatic protein glycation and lipid peroxidation by drugs with antioxidant activity. | Nonenzymatic glycation of collagen in aging and diabetes | Pyridoxamine, an Inhibitor of Advanced Glycation Reactions, Also Inhibits Advanced Lipoxidation Reactions.
Aminoguanidine in the prevention of diabetic complications | Aminoguanidine: AGES inhibitor.

f) Reversal of aging | Digestion of lysosomal aggregates (Books) | Bacterial/fungal hydrolases (Books).

g) Apoptosis of senescent cells (Books) | Senescence marker-targeted toxins

h) Killing of age-related tumors | Angiostasis, vaccination for age-related

i) Nuclear rescue of mtDNA mutations | Allotopic mt-coded proteins

j) Immune system restoration | IL-7-mediated thymopoiesis.

k) Cleavage of AGE cross-links | Phenacyldimethylthiazolium chloride

L) Clearance of extracellular aggregates | Immune-mediated phagocytosis

m) Cell replacement | Stem cell therapy

n) Hormone restoration | Genetically engineered muscle

[36s] Life Extension mix from Life Extension magazine with its many Life Extension products has some familiar ingredients and others that I have not seen elsewhere that seem worth investigating:

a) Ascorbyl Palmitate (fat-soluble vitamin C) protects against lipid peroxidation, "is a synthetic ester comprised of the 16-carbon chain saturated fatty acid palmitic acid and L-ascorbic acid." - PDRhealth on ascorbyl palmitate. The Life Extension brand of ascorbyl palmitate, products containing ascorbyl palmitate.

b) Phosphatidylcholine [lecithin] (from Soy), the "phospholipid that is a major constituent of cell membranes". - PDRhealth on phosphatidylcholine.

c) Dilaurylthiodipropionate (an anti-oxidant effective when dissolved in fats and oils.)

d) Thiodiproprionic acid (an anti-oxidant), available from Life Extension Foundation all by itself.

e) Broccoli sprout concentrate (anti-cancer sulphoraphane)
"Sulforaphane is found in large quantities in broccoli and increased levels of 30-50 times the potency are found in broccoli sprouts, thus making broccoli sprouts among the most potent anticarcinogens in the food area." - Handy Pantry on Broccoli Sprouts

f) Ginger or ginger extract, anti-inflammatory, inhibits NFκB | Dr.Ray Sahelian on ginger research.

g) Luteolin (combats proliferation of undesirable cell colonies), found in high amounts in parsley, sage, and peppermint along with basil, celery and artichoke.
Luteolin deactivates TNF-alpha. It is found in green peppers and celery.

h) Pantethine may enhance cognitive abilities and increase energy levels. It is the biologically active form of vitamin B5, also termed pantothenic acid.

i) Pyridoxal 5-phosphate, or the active co-enzyme form of vitamin B6, which increases the production of serotonin, norepinephrine, GABA, dopamine, & other neurotransmitters. The pyridoxine HCL form of vitamin B6 is inactive, though frequently given. Without adequate vitamin B6, the amino acids in dietary protein are not absorbed properly. Vitamin B6 controls amino acid absorption, metabolism & associated transformations. It also directly participates in carbohydrate & fat metabolism, as well as the formation of red blood cells & antibodies. It is necessary for the absorption & utilization of certain minerals & is required for the proper functioning of more than sixty human enzyme systems.

j) PABA, para-aminobenzoic acid

k) Taurine - "Taurine supplements may be important to counteract the effects of human aging on the natural taurine production process. As humans age, hepatic taurine production can fall or fail completely, producing low to no energy, cardiac, digestive, and mental problems, and premature death." - Wikipedia

L) boron citrate

m) Links/Magnesium oxide, Links/magnesium citrate, Links/magnesium glycinate, Links/magnesium tarinate, Links/magnesium arginate, Links/magnesium ascorbate.

n) Cholinergic complex - choline
Dr. Ray Sahelian's remarks on choline.

o) Inositol.

p) Bromelain.
Anti-cancer, found in pinapple. "Pineapples contain bromelain, a sulfur-rich proteolytic enzyme that has been investigated for antitumor effects. U.S. and French research shows oral bromelain can reduce cancer in animals. Some documented cases show cancerous tumors regressing as a result of bromelain therapy." from Cancer Prevention Diet

q) silymarin (Milk thistle) | Dr.Sahelian's remarks on silymarin research.
Anti-Oxidant, liver protective, neuro-protective, UV-protective, anti-cancer, inhibits apoptosis, retards alcohol-induced hepatic fibrosis, combats colon cancer, exerts an anti-atherosclerotic activity.

[37s] Life Extension magazine (site map) article on European therapies with European anti-aging drugs, including extensive collections of links to abstracts on drugs such as:
Aminoguanidine, centrophenoxine, deprenyl, hydergine, isoprinosine, KH3 (procaine with procaine-enhancing hematoporphyrin), picamilon, piracetam, ect.. Most of these can be obtained through International Anti-Aging Systems. These European treatments can be compared with the short Life Extension list of USA-available Anti-Aging therapies, Top Ten Therapies, and their Popular Formulas. They also support an extensive collection of references, anti-aging clinics, anti-aging doctors, consumer alerts, Forum, and Newsletter Archive, and explanations of their Funded Research.

[38s] Anti-Aging Pharmaceutical Vendors. || Now a file unto itself.

[39s] Breeding for longevity: it has been shown that siring offspring from the later-life-cycle eggs of females produces longer-lived offspring as time goes on. Breeding of longer-lived species of rodents and flies has been demonstrated with this approach, which should also be applicable to humans. I saw a study promoting this approach that followed 19 generations. (Ref misplaced. [Ben Best].)

[40s] It seems Jean Calment's program of smoking cigarettes ought to have been replaced by ingestion of niacin or a related vitamin-B3 compound or NAD (nicotinamide adenine dinucleotide), best increased in vivo with the B-vitamin nicotinamide (vitamin B3) and/or niacin. See Modulatory effects of curcumin on lipid peroxidation and antioxidant status during nicotine-induced toxicity. See also Curcumin in anti-aging medicine at Quality Counts. See Google Links/Curcumin and Ray Sahelian's Curcumin Research. Wikipedia: Curcumin, Turmeric. Life Extension magazine: LE Magazine February 2004 Curcumin Update, Anti-Cancer Effects of Curcumin.

[41s] Phytochemicals as Nutraceuticals by Ben Best. See also Best's Nutraceuticals Topic Index, the Linus Pauling Micronutrient Information Center, and The World's Healthiest Foods. Also see Google Links/phytochemicals, Links/Phytochemicals and Aging, Links/nutraceuticals, and Links/nutraceuticals and aging. Also, see footnote [44s] based on Handbook of Nutraceuticals and Functional Foods, ed. Robert E.C.Wildman, 2001.
Also see Sigma Aldrich's BIOACTIVE NUTRIENT EXPLORER.

[42s] See Links/Bioavailability and Wikipedia/Pharmacokinetics with Links/Pharmacokinetics. See The Merck Manual on Bioavailability. See also the journal of Chemical Speciation and Bioavailability, the NIH page on Bioavailability of Nutrients and Supplements. Also see links of The USC Laboratory of Applied Pharmacokinetics and Boomer's Phamacokinetic Resources with A First Course in Pharmacokinetics and Biophamaceutics by David Bourne, PhD.

[43s] Building a Better Brain (from L.E. Kurzweil article) | 1st, Aging Brain & Old Brains
Free Radical Theory of Aging | Mitochondria and Aging || Glycation Theory of Aging
Molecular Mechanisms of Alzheimer's Disease & Advanced Glycation End Products
Smart Drugs and the Aging Brain by Ben Best | Neuroprotective supplements | [2]
Neuroactive drugs | Smart pills | Memory pills | Nooptropics | Anti-Aging Recommendations

Vinpocetin and with Ginko Biloba - memory improver. Google Links/vinpocetin | BrainQuicken.
Phosphatidylserine - reverses memory loss. Links/Phosphatidylserine.
Acetyl L-Carnitine - improves mental energy, mood, concentration. See Links/Acetyl L-Carnitine.
Acetyl L-Carnitine Arginate promotes faster neutrite growth | Anti-Aging Effects
Acetyl L-Carnitine with Alpha Lipoic Acid - Makes old rats behave like young rats.
Ginko Biloba - improves brain function, brain blood flow. Links/Ginko Biloba.
Pregnenolone - enhances memory. See Links/Pregnenolone.
EPA - fish oil contains EPA & DHA.
DHA - brain food. | Brain-building supplements. "In studies with aged and young rats, DHA supplementation significantly decreased free-radical levels of lipid peroxide in the hippocampus, a brain region involved in memory, and also reduced errors in maze learning."
Phosphatidylcholine - improves memory, learning, reverses damage. See Links/Phosphatidylcholine.

More Neuroprotective Supplements or old age cognitive decline inhibitors.
Curcumin, curcuminoids, turmeric root - neuroprotective curcumin links
CoQ10 - Links/neuroprotective CoQ10, CoQ10 as an anti-cancer agent, anti-lipofuscin, prescribed for cardiovascular health, Links/CoQ10.
Centrophenoxine - Links/neuroprotective Centrophenoxine.
Deprenyl - neuroprotective dopamine booster via MAO-B inhibition.
Hydergine - Links/neuroprotective hydergine, blood flow enhancing.
DMAE - Links/neuroactive DMAE, cleans out lipofuscin wastes, centrophenoxine = DMAE + Auxin.
DHEA - DHEA opposes cortisol, the strain-aging corticosteroid. "DHEA (dehydroepiandrosterone) improves brain cell activity and facilitates changes in nerve cells, allowing them to record new memories. Remarkably, DHEA added to human brain stem cells in the laboratory dramatically increased their growth rate".
"Phosphatidylserine restored mental function in older animals to levels exceeding those found in some younger animals." - L.E.magazine, 1995, and L.E. phosphatidylserine (PS) product. Phosphatidylserine is an acetylcholine booster.
Glycerophosphocholine, an acetylcholine booster, (Links/Glycerophosphocholine) and
Ashwagandha (Links/Ashwagandha) are both described in Life Extension magazine, Oct.2005.

Memories are formed in CREB protein at the synapse, as discovered by Nobelist Eric R. Kandel of Memory Pharmaceuticals, which is doing pre-release tests on their drug MEM 1414 to improve memory. Helicon Therapeutics is also working on memory-improvers based on CREB. Other memory-improving drugs are based on NMDA receptors and nootropes, or nootropic drugs. Jerome Yesavage worked on donepezil, a memory-improver with the brand-name Aricept. Also see Ritalin. - based on Scientific American article, Oct.2005.

Anti-depressants.

Contrast: Psychedelic Drugs & Psychoactive Substances
Dr. Albert Hoffman | LSD neurophysiology | LSD - Wikipedia | Synthesis || Dr. Leary in the Sky
Erowid and the Psychoactives || MAPS | Psychedelic Review | Psychedelic Library | Psychedelics.
Alcohol | Alcoholism | Drug Abuse | Controlled Substances | DEA || NORML - Marijuana Reform
LSD | Aging LSD Brains | Pioneers | Hospitalization & drug use || Medicines and Contraindications

Basic Neurotransmitters and Neuropeptides | Neurotransmitter images | Neurotransmitter Biochem
Physiological Psychology | Medical Physiology & Pathophysiology || Good Drug Guide | Drugs

Green plumes and girlfriends from 1987, 20 years after graduation. 'It was 20 years ago today, Sargent Pepper taught the band to play, they've been going in and out of style, but they're guaranteed to raise a smile, so may I introduce to you, the act you've know for all these years...'

" It was 20 years ago today, Sgt. Pepper taught the band to play, they've been going in and out of style, but they're guaranteed to raise a smile, so may I introduce to you, the act you've known for all these years, Sgt. Pepper's Lonely Hearts Club Band..."

Disclaimer: Psychedelic and psychoactive substances should always be used with appropriate caution, and the safest course may be not to take them, especially if they are not available with a precisely specified dosage from a reputable pharmaceutical firm. Also, local folkways and the legal environment must be considered when we contemplate their use, as the spirit of the law is to safeguard good health. I note that toxic side effects may sometimes manifest themselves or accumulate when such drugs are used with too high a dosage or with too high a frequency. For example, this may happen with repeated use of morning glory seeds, which might afflict an experimenter with a miserable case of neurotoxic cyanide poisoning lasting more than a month.

[44s] Handbook of Nutraceuticals and Functional Foods, ed. Robert E.C.Wildman, 2001.
See also Phytochemicals as Nutraceuticals by Ben Best | Micronutrients at Linus Pauling and
Phytochemicals and Foods they are Prominent In | Phytochemicals: Nutrients Of The Future
For food content, see The World's Healthiest Foods and Essential Nutrients.
Also see Life Extension magazine's search engine and Bioactive Nutrient Explorer.

Anti-Cancer Nutraceuticals
Capsaicin, Genestein, Daidzein, alpha-Tocotrienal, gamma-Tocotrienal, CLA (beef & dairy), Lactobacillus acidophilus, Sphingolipids, Limonene, Diallyl sulphide, Ajoene, alpha-Tocopherol, Enterolactone, Glycyrrhizin, Equol, Curcumin (curry, turmeric root), Ellagic acid, Lutein, Carnosol, L. bulgaricus, sulphoraphane (broccoli)

Positive Influence on Blood Lipid Profile
beta-Glucan, gamma-Tocotrienol, delta-Tocotrienol, MUFA, Quercetin, omega-3 PUFAs (DHA & EPA), Resveratrol (grape skins), tannins, beta-Sitosterol, Saponins

Antioxidant
CLA, Ascorbic Acid (vitamin C, green peppers), beta-Carotene, Polyphenolics, Tocopherols, Tocotrienols, Indole-3-Carbinol, alpha-Tocopherol, Ellagic Acid, Lycopene, Lutein, Glutathione, Hydroxytyrosol, Luteolin, Oleuropein, Catachins, Gingerol, Chlorigenic acid, Tannins

Anti-Inflammatory
Linolenic acid, EPA, DHA, Capsaicin, Quercetin, Curcumin.

Osteogenetic or Bone Protective
CLA, Soy protein, Genestein, Daidzein, Calcium.

"In time the Rockies may crumble, Gibraltar may tumble
They're only made of clay
But our love is here to stay..."

Nutraceutical/Food/(for Application, see above).

Allyl sulfur compounds/Onions, garlic/anti-cancer, anti-heart disease.
Isoflavones/Soybeans and other legumes, apios
Quercetin/Onions, red grapes, citrus fruit, broccoli, Italian yellow squash.
Capsaicinoids/Pepper fruit/anti-cancer, anti-inflammatory.
EPA and DHA/Fish oils/EPA anti-trigycerides, raises LDL cho.; DHA brain food.
Lycopene/Tomatoes and tomato products
Isothiocyanates/Cruciferous vegetables/sulforaphane anti-cancer.
Beta-glucan/Oat bran
CLA/Beef and dairy
Resveratrol/Grapes (skin), red wine
Beta-Carotene/Citrus fruit, carrots, squash, pumpkin
Carnosol/Rosemary/anti-oxidant.
Catechins/Teas, berries
Adenosine/Garlic, onion
Indoles/Cabbage, broccoli, cauliflower, kale, Brussel sprouts
Curcumin/Turmeric, curry
Ellagic acid, usually ingested as ellagitannin/Grapes, strawberries, raspberries, walnuts, blackberries/anti-cancer.
Anthocyanates or anthocyanides/Red wine, blueberries
3-n-Butyl phthalide/Celery/anti-cancer.
Cellulose/Most plants, from cell walls

[45s] Tuna contains varying amounts of mercury, several times more in Albacore tuna than in chunk light tuna. Perhaps the best idea is to take most protein from skim milk or no-fat yogurt. See Life Extension magazine, Oct. 2005.

[46s] Head off Alzheimer's Disease - dispense with that jelly bean dish. Sugar, by producing glycation of proteins and AGEs (advanced glycation end products) that excite the RAGE receptor of the immunoglobin protein superfamily, leads to the accelerated generation of ROS (reactive oxygen species) leading to neural damage and Alzheimer's Disease. For instance, perhaps President Reagan's habit of eating jelly beans resulted in Alzheimer's Disease. In a case like this, the RAGE immunoglobin activation occurs via glycated skeletal proteins, leading to free radical damage to neural tissues, producing inflammation. RAGE may also be activated by by inflammation-associated amyloid proteins in an accelerating cascade. - See Richard J. Epstein, Human Molecular Biology, Cambridge U. Press, 2003, page 130.

[47s] "Ascorbate doses exceeding 500mg per day may have a pro-oxidant effect, which induces mutagenic 8-oxo-adenine DNA lesions." - pg.150, Human Molecular Biology, Richard J. Epstein, 2003. Perhaps Vitamin C dosage should be limited to 500 mg/dose and other anti-oxidants should also be relied on for the task. I note that the large doses used by Linus Pauling of 20,000 mg/day were based on the amount of vitamin C produced per kg of body weight by gorillas, which manufacture vitamin C in their livers. Recently, "The National Institutes of Health found that vitamin C should be taken in divided doses throughout the day, as urinary excretion increases rapidly when individual doses exceed 500 mg." - Quantum Health. It seems to me that vitamin C overdose scares have been largely discredited, but that it only makes sense to take about 500 mg/dose based on the excretion argument. Perhaps it should be taken with vitamin E and iron-chelating curcumin, as vitamin C restores vitamin E after it fixes products of a branching chain reaction catalyzed by iron that peroxidizes lipids.

[48s] Bioavailable SOD, Links/Bioavailable SOD. The life spans of animals are roughly proportional to their SOD production, and coincidentally to their levels of carnosine, which has anti-glycation properties. "Humans, for example, produce twice as much SOD as chimpanzees and live twice as long. In one study, fruit flies genetically altered to make more SOD, lived 40% longer." Mitochondrial SOD is probably essential for protecting the mitochondrial membranes and mtDNA, and it is the kind that incorporates mangansese. The SOD in the cytosol uses copper and zinc. Bioavailable mitochondrial SOD and bioavailable cytosolic SOD may both be desirable supplements. See Life Extension Mitochondrial Energy Optimizer with Sodzyme, which includes carnosine, and also Sodzyme with GliSODin. See also a Life Extension magazine search on SOD. See Superoxide Dismutase [52], SOD-booster Ashwagandha, which generally boosts endogenous antioxidant levels [63s], SOD-booster and nootropic agent Huperzine A [65s], SOD-rich Wheat Sprouts [64s], and SOD-rich Wheat Grass [66s]. Wasabi (Japanese Horseradish) contains a SOD-mimetic isothiocyanate that processes superoxide like SOD.

Close encouters of the toured kind. Press for Visionary.swf on constellation-theme-synchronous mythically imageing nebulae on the celestial sphere, including S. Monocerotis and the Knee of Orion.

On our way to SOD in S.Monocerotis in NGC 2264 between Procyon and Orion.
Is SOD the key to eternal life beyond Jean Calment's 122 years and 164 days? 122.45 < 123.
("Ash-wah-gander" at Green: Ashwaganda is a SOD and Acetylcholine [ass-seat-L-coal-lean] booster.)
Astrophoto courtesy Siding Spring Observatory, Anglo-Australian Telescope. See page 123, Colours of the Stars by David Malin and Paul Murdin, Cam. U. Press.
The scene reminds us of Hayflick and Moorhead's paper on cell division limits and
physicist George Gamow's title One, Two, Three...Infinity. Perhaps
the 21st Century will break the 123 year limit in human life span in 2072 when I turn 123.
Telomerase has been isolated as a 123-kilodalton molecule, p123, from a protozoan,
Euplotes aediculatus.
The image also reminds us of "Piracetam with choline", or "astragaloside IV with chitosan",
or perhaps "astragaloside IV with sodium deoxycholate".

MUSIC - "Hey, doll, you're bound to fall, you thought they were all kiddin' you..." {56}

"I am I, Don Quixote,
The Lord of La Mancha,
My destiny calls and I go,
And the wild winds of fortune
Will carry me onward,
Oh whithersoever they blow.
Whithersoever they blow,
Onward to glory I go!"

"And I'll tell it and think it and speak it and breathe it,
And reflect it from the mountain so all souls can see it,
Then I'll stand on the ocean until I start sinkin',
But I'll know my song well before I start singin'..."
- Bob Dylan, A Hard Reign's A-Gonna Fall

Picasso's Don Quixote The Man of La Mancha

[49s] The life span of fruit flies decreases 80% when the gene for cytosolic SOD is knocked out, and increased 40% when SOD is over-expressed. Drosophila, incidentally, has no mitochondrial gene for glutathione peroxidase. Knockout of the the mtDNA gene for mitochondrial SOD in mice causes early death. On the other hand, the knockoutof cytosolic SOD does not much impact mouse life span. - see Aubrey D.N.J. de Grey, The Mitochondrial Free Radical Theory of Aging, pg.134, pg.131. Extra-Cellular SOD (EC-SOD, or SOD3) can exist on external cell surfaces and in the extra-cellular matrix, being expressed highly in the lungs to protect against hyperoxia. Structurally, it contains a heparin-binding domain sensitive to proteolysis differentiating it from cytosolic SOD or mitochondrial SOD. When EC-SOD was applied to cells in culture, telomeres shortened only 5-20 bp per population doubling, as opposed to 50-100 bp under standard conditions. - from "Telomeric Damage in Aging" by Thomas von Zglinicki, in Aging at the Molecular Level, ed. T.Zglinicki, pp 124-125. See Google's Links/Extracellular SOD.

[50s] Over-expression of the protein oxidative damage repair enzyme peptidyl S-methione sulfide reductase (MsrA) was found to increase Drosophila life span 85%. p.133, Aging at the Molecular Level, ed. Zglinicki and also Ruan, Tang and Chen's article "High quality life extension by the enzyme peptide methionine sulfoxide reductase" in Proc. Natl. Acad. Sci. USA 99: 2748-53. Note 70 x 1.85 = 129.5 > 123. It was shown that reducing the amino acid methionine in the diet to 1/5 the normal level increased life span 30% in rats. (from Ben Best, Protein Damage and Maintenance in Aging.) High levels of methionine, an essential amino acid, can be found in cheddar cheese, eggs, chicken, beef, bass, trout, cod, sirloin, spinach, green peas, corn, navel and mandarin oranges, peanuts, pistachios, macadamia nuts, kidney beans, black turtle beans, tofu, and tempeh. For a description of food contents, see The World's Healthiest Foods. See also the amounts of amino acids in dog food ingredients, amino acids in bodybuilding, and amino acid food sources in Gym Addiction.

[51s] Knockout of the gene p66shc extends the life span of mice 30%! (pg.137, Zglincki, ibed.)

[52s] DNA repair declines during aging, probably due to the short one-day deamidation half-life of uracil DNA-glycosidase. (pg. 155, Hipkiss, T. Zglinicki, ibed.) See a uracil DNA-glycosidase in cellular homolog (pg.148, ibed.). I note that lipid peroxidation is a major source of reactive aldehydes that can react with DNA, and that other sources of DNA damage exist that can be repaired by gene-encoded DNA repair enzymes. Note that uracil DNA-glycosidase may be obtained commercially via genetically engineered E. Coli bacteria.

[53s] Hypoxia, oxygen shortage in tissue, may be due to artherosclerosis, arterial blockage, correlates to mtDNA⁴⁹⁷⁷ deletions, Alzheimer's Disease, and other diseases of neurological aging. See Ch.6 Deletions of Mitochondrial Genome and Neurodegenerative Diseases in Principles of Neural Aging, ed. Dani, Hori, and Walter, 1997. See also Mitochondrial mtDNA Deletions with references on-line.

[54s] Autoimmune theory of aging [Links/autoimmune theory of aging, Books, LifeExtension, Amazon]. Auto-antibody levels increase with age in man, but the autoimmune pathology is not thought to be the primary cause of aging. ibed, chap.1. Note that rheumatoid arthritis and psoriatic arthritis are autoimmune diseases [Wikipedia/Autoimmune disease, Books] in which the body attacks itself [Wikipedia/Arthritis]. Note that stress on the immune system due to antigens or infections can prematurely exhaust lymphocytes with replicative senescence, so that the immune system can become a weak link in our defenses against aging.

[55s] tRNA isoacceptor loss (more than 60 types of tRNA are known) progressively restricts the readability of DNA codons in aging specimens, resulting in inefficiency and inaccuracy of protein synthesis. (Bernard Strehler, 1970s.) tRNA synthetases were also implicated. Some codons for an amino acid are used more than others, and small genes display more codon usage bias than large ones, so that small gene products might be more damaged by specific tRNA shortages. [53s], chap.1, from Principles of Neural Aging. Perhaps tRNA levels could be boosted by supplementation somehow to improve the quality of aging protein synthesis. Not all proteins become aberrant with age. Accumulating protein modifications seen in aging specimens are of several types:
a) Nonenzymatic glycosylation, b) Cross-linking, c) amino acid sidechain modification due to reactive oxygen radicals, d) spontaneous deamidation of glutamine and asparagine residues, e) proteolytic clips in peptide backbones, f) conformational alterations without covalent changes. (Principles of Neural Aging, ch.1). The accumulation of abnormal proteins may be explained by reduced rates of proteolysis. I note that "Free radical mediated arachidonic acid oxidation can produce a mixture of gamma-isoketals capable of reacting with proteins to produce structures that are not only resistant to proteolysis but inhibit proteasome function." - pg. 160, Hipkiss in Aging at the Molecular Level, ed. T. Zglinicki." Arachidonic acid is found in meat, poultry, and eggs. It can be avoided by substituting cold water fish. [2s].

[56s] DNA Translation error catastrophe results in accelerated cell senescence because of positive feedback yielding exponentially increasing error rates. (Orgel, 1963.) The problem may get started via oxidative stress curable with inducible SOD or other enzymatic anti-oxidants or non-enzymatic anti-oxidants.

Continued in Supplemental Notes 2