Press for Jim Green's Home Page.Press for Jim Green's Home Page.
Astragaloside IV, a telomerase activator [81s/TA], is still described by Chinese
as being a medicine for correcting a deficiency in chi, the life force.

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(8) Stem cell technology [Refs8, Wiki/Adult Stem Cell; Index, Links, Papers, Patents, Books, Amazon, Video Lectures, LifeExtension]. Stem cell technology for replacing old cells with embryonic stem cells or modified adult stem cells [77s] has been developed that is available now for tissue repair and treatment. For example, see Stem Cell Therapy for Kidney Disease. Infarcted heart tissue may be rebuilt from stem cells. Cord blood transplants from umbilical cords of newborns have been useful in providing new sources of red blood cells, hematopoietic stem cells, and immune system cells after burrowing into bone marrow [5,56], although autologous treatment using cells equipped with the patient's own DNA is clearly preferable. See (11) on the immunological theory of aging. Studies show that circulating adult stem cells decrease in number and in clonogenic capacity with age. Note that stem cells can typically divide more than the 50 times granted to ordinary human somatic cells, however, because stem cells may from time to time express telomerase to lengthen their telomeres and allow more cell divisions. For instance, the keratinocyte stem cells beneath the epidermis may divide up to a 1000 times in the course of a lifetime, a mature epidermal keratinocyte enduring for about a month and contributing to a topmost layer of dead cells. On the other hand, germ cells express the most telomerase of all cells, protecting sperm cells and egg cells from senescence and maximizing genomic stability, whereas stem cells designed to replace cells in the body intermittantly express a lesser amount of telomerase to ensure genomic stability adequate for them to fulfill their role as replacement parts. Normal human somatic cells like dermal fibroblasts seem not to express telomerase at all, enabling them to play the role of expendable parts that may be replaced as they count towards their ceiling of about 50 cell divisions. New classes of adult stem cells, such as the skin-derived precursors (SKPs), are still being discovered. See Shuang Liu, Shu Liu, Xinyue Wang, Jiaxi Zhou, Yujing Cao, Fei Wang and Enkui Duan (2011), The PI3K-Akt pathway inhibits senescence and promotes self-renewal of human skin-derived precursors in vitro, Aging Cell (2011), 10, pp661-674. See The Institute for Cellular Medicine, the A4M on stem cell therapeutics, the journal Stem Cells, and NIH Stem Cell Information. The meristematic stem cells [Links] of the bristlecone pine [Links] are responsible for its potentially 5,000 year life span, and comparison with other pines suggests that humans may need to apply anti-aging stem cell technology [Links] [5] for long range life extension. It may be a good idea to have skin cells and other cells containing your DNA cultured, perhaps telomere-extended with telomerase [71s], and cryopreserved, so that they can be used to create autologous cells later that will not be rejected by the immune system. Note that it has recently been possible to prepare embryonic stem cells or induced pluripotent stem cells (iPS cells) from skin cells, so that all stem cells used can be perfectly DNA-matched for autologous treatment and legally derived without disturbing embryos. The results were seperately published by Dr. Shinya Yamanaka [Links, Images, refs1c] of Kyoto University and UCSF in Cell [Papers, Links, Images, refs1c] and James Thomson of the University of Wisconsin in Science [Papers, Links, Images, refs1c]. Dr. Yamanaka showed that pluripotent stem cells can be induced [Links, Images, Papers, Patents, Books] from mouse embryonic fibroblasts and adult mouse tail tip fibroblasts by the retrovirus-mediated transfection of four transcription factors [Links, Papers, Patents, Books], Oct3/4, Sox2, c-Myc, and Klf4. Evidently, these iPS cells [Links/induced Pluripotent Stem cells, Images, Papers, Patents, Books] usually have short telomeres if derived from cells with short telomeres, according to the June 10, 2010 LEF interview with Dr. Michael West, Immortal Stem Cells for Anti-Aging Therapies. Dr. West, who (as mentioned below) was one of the first to identify "reset" cells with long telomeres in clones from senescent cells, has been doing research on obtaining iPS cells with long telomeres, identifying 4 transcription factors Oct4, Sox2, Lin28, and Nanog. See H. Vaziri, K. B. Chapman, and A. Guigova (2010), Spontaneous reversal of the developmental aging of normal human cells following transcriptional reprogramming, Regenerative Medicine, March 16, 2010. Embryonic stem cells may also start from youthful cellular DNA cloned by nuclear transfer technique from the cryopreserved cellular DNA of older specimens. The embryonic stem cells could then be differentiated to create younger bone marrow (or any other tissue that may be required) to be implanted in the body and find its way into the bones to ultimately rejuvenate the vascular endothelium and immune system via rejuvenated bone marrow stem cells functioning like the meristematic stem cells of the bristlecone pine. If a bristlecone pine can live 5,000 years, why not us? "Bone marrow cells lose approximately 40% of their replicative capacity during culturing. This problem becomes even more pronounced when the cells are first genetically engineered from a single cell using gene therapy procedures. By the time the cell population is sufficient for transplantation, the cells have gone through the equivalent of 50 years of aging. A telomerase inducing drug may eliminate the loss of replicative capacity, greatly extending their useful life span and effectiveness." - Sierra Sciences. At the present time, most telomerase-inducing drugs are too slow to be used to adequately life extend a culture prepared for transplantation applications in a reasonable time frame. Perhaps targeted gene editing using zinc finger nucleases inserting extra copies of hTERT, or hEST1A, or dyskerin in bone marrow cell cultures would suitably eliminate loss of bone marrow transplant replicative capacity. Although one may not interfere with microscopic embryos containing one's own DNA, one's own skin cells may now be subjected to nuclear reprogramming [Links, Images, Video, Papers, Patents, Books] to create induced pluripotent stem cells (iPS cells). See West MD, Vazin H. (2010), Back to Immortality: The restoration of embryonic telomere length during induced pluripotency, Regenerative Medicine, 2010; 5(4):485-8. Also, samples of one's own adult stem cells may be obtained, perhaps from a cell-sorting machine [Images, Papers, Patents, Books], cultured and multiplied, optionally telomere-extended [Links, Papers, Patents, Books, LifeExtension, Frontiers in Biomedicine, p.16], and cryopreserved for use later in autologous transplants. Otherwise, stem cells may be obtained from an identical twin in syngenetic treatment. Most alternatives using someone else's DNA seem unattractive at this time. I note that some stem cells have been dried and stored on a shelf rather than cryopreserved. See books on regenerative medicine, regenerative medicine and gene therapy, and stem cell transplantation [Links, Images, Video, Papers, Patents, Books]. The drugs Neupogen [filgrastim], Neulasta [pegfilgrastim] and Leukine [sargramostim] may be used to coax hemopoietic stem cells out of bone marrow into the blood, so that you may collect a sample of your own blood that is stem cell enriched, freeze it [Links, Images, Papers, Patents, Books], and use it later for autologous stem cell transplant procedures [Links, Images, Papers, Patents, Books]. These compounds have been available since the 1980s. Stem cells may then be collected from the blood by a cell sorting machine [Links, Images, Papers, Patents, Books]. Also, bone marrow containing hemopoietic stem cells may be collected from hip bones or from bones in the lower back with a hypodermic needle to harvest bone marrow [Links, Images, Papers, Patents, Books] for bone marrow transplants or bone marrow culturing [Images, Papers, Patents, Books]. Typically, up to 1000 mL of bone marrow is taken. As early as 2002, adult stem cells from mice were treated to behave like embryonic stem cells, and now human skin cells may be reprogrammed to yield an acceptable supply of embryonic stem cells for human tissue transplant applications. Recently there are indications that T-lymphocytes resulting from hematopoietic stem cell transplants rich in telomerase show telomere extension of about 50% when activated by an antigen.. Perhaps cord blood transplants accompanied by antigentic stimulation would be effective for lengthening telomeres in T-lymphocytes. TA-65 from TA Sciences may be used for this, or perhaps other astragalus extracts [81s/6b, Vendors/Astragalus] or could be used. Furthermore, it has been shown that astragalus root extracts can be used to increase the numbers of stem cells in bone and in lymphatic tissues [article, Links, Books]. Telomerase activation (7) has been achieved in cord blood using IGF-1 in the presence of PHA (phytohaemagglutinin; 1 μg/ml, Sigma, St Louis, Mo., U.S.A.). Heat shock proteins Hsp90 and P23 facilitate the assembly of telomerase [Links, Papers, Patents, Books]. Clones of animals with normal life spans are usually prepared via nuclear transfer from embryonic tissues [Images, Papers, Patents, Books]. Cloning from animal tissues taken at mid-life produced offspring with shorter lives, as in the case of Dolly the Sheep, but recently we have found out that cloning from senescent cells at the end of their lifespan can produce strong telomerase activation in a way that produces potentially very long-lived offspring in cows with telomeres longer than ever! [Links, Images, Papers, Patents, Books]. See Dr. Michael West's interview, Conquering Aging with Cloning, in LifeExtension, June 2000, and Michael D. West PhD (2013), How Engineered Stem Cells May Enable Youthful Immortality, Life Extension Magazine, February 2013. Dr. West was the founder of Geron and Advanced Cell Technology. Also see Lanza, Cibelli, and Blackwell (2000), Extension of cell life-span and telomere length in animals cloned from senescent somatic cells, Science, 2000, Apr 28;288(5466):665-9.
It seems hTERT may be transfected into stem cells in a way that produces hTERT-immortalized primary cells from the stem cells after a stem cell transplant. This may lead to immortalized tissues in the human body requiring less medicine to maintain than ordinary primary cells. See Transplants of Immortalized (Stem) Cells. Other transfections or medicine may be required to hTERT-immortalize all primary cells in the body. Perhaps eventually all primary cells in the body could be replaced by establishing populations of hTERT-transfected stem cells or something similar.

The Role of Increasing DNA strand separation temperature in aging and cloning
Perhaps the steadily increasing cross-linking of aging DNA with proteins [Books], which causes the strand separation temperature of DNA to rise in old DNA, will turn out to be an inhibiting factor in cloning from adults. [See S. Dani, A. Hori and G. Walter, Principles of Neural Aging, Elsevier Press, 1997.] I have not determined whether or not cross-link breakers like Alagebrium (ALT-711, Links) exist that can be used to alleviate this problem, and the role of rising DNA strand separation temperature from DNA-protein cross-linking in aging remains somewhat unclear to me at this time. [See Books/DNA-protein crosslink repair, Aging Processes, DNA Damage, and Repair, and Papers/aging and DNA strand separation temperature]. Protein-DNA crosslinking characteristic of increasing DNA strand separation temperature is typically caused by reactions with hydroxyl radicals and is prevented by application of antioxidants and anti-glycating drugs that oppose escalating generation of free radicals by Advanced Glycation End products. For example, DNA-protein crosslinking is mitigated in experimental animals with carnitine and lipoic acid. [See Papers/repairing DNA-protein crosslinks, Books/repairing DNA-protein crosslinks, and associated Links]. Cat's Claw extract [Links, Images, Papers, Books] may assist with DNA-protein crosslink repair [Links], a hypothesis which requires more specific testing. Measurements done in the future may determine that Cat's Claw extract can be used to prevent and treat rising DNA strand separation temperature. A good treatment of DNA-protein crosslinking in connection with DNA strand separation temperature is contained in The Membrane Hypothesis of Aging by Imre Zs-Nagy. Zs-Nagy believed that age-dependent decreases in the rate of protein synthesis were perhaps associated with increasing DNA strand separation temperature, leading to the accumulation of damaged proteins as the protein turnover rate changes.


(9) Age comes through lack of exercise theory [Refs9, Index, Telomerase Activators/Exercise, Links, Images, Papers, Patents, Books, Amazon, LifeExtension/Aging and Exercise]. "Exercise can help you stave off a premature death due to your weight woes, researchers finding that working out for just 1/2 hour a day can increase your chances of reaching age 90 by up to 31%." "Grip strength is a predictor of premature mortality in men who are older than 60 years of age." [Robert Arking, Biology of Aging, 2006, p.75]. Exercise tends to correct an abnormal level of lipoproteins. "Even a small amount of exercise [Index] at low or moderate intensity (equivilant to walking or jogging 12 miles per week) is associated with beneficial changes of the lipoprotein profile in the plasma [Links, Images, Papers, Patents, Books]. There is actually a graded response of the plasma lipoprotein [Links, Images] almost parallel with increasing levels of exercise,", explaining the progressive decrease in cardiovascular risks [Images, Papers, Patents, Books] associated with increasing levels of muscular activity [Physiological Basis of Aging and Geriatrics, 4th edition, 2007, p.388]. Other researchers speculated that exercise stimulates the pituitary gland into preserving subjects for their social value. [84]. Lack of exercise may reduce the population of muscle satellite stem cells [Images, Papers, Patents, Books], which have telomeres that shorten with age, so that they should senesce. These cells should be treatable with small molecule telomerase activators such as the androgens, including testosterone from DHEA. [M. Fossel, Cells, Aging, and Human Disease, 2004, pp.256-257]. Fossel suspects that the bulk of muscle tissue regeneration and repair derives from the hyperplastic cell division of muscle satellite stem cells [Images], rather than from classical hypertrophy [Images, Papers, Patents, Books]. It seems muscle stem cell myoblasts senesce and induce age-related changes in functioning myocytes [M.Fossel, ibid, p.257]. With the correct amino acids as precursors, exercise improves HGH, IGF-1, androgen levels, and the levels of exercise-induced telomerase activators such as epiregulin, amphiregulin, HIF-1, PDGF, testosterone, estrogen, HSP90, TNF-alpha, IL-2, nitric oxide, TGF-alpha, and VEGF. Most of these may be further boosted during exercise by applying a suitable supplement. Some of these behave like endocrine hormones that circulate everywhere through the blood, while others have semi-localized paracrine or highly localized autocrine effect. Also, the range of targeted tissues varies. Note that HIF-1 transcription factor improves hTERT transcription in every cell in the body, while IGF-1 improves hTERT transport into the nucleus in every cell. HIF-1 can be boosted by hypoxia from exercise, and additionally by ginkgo biloba or diosgenin from fenugreek seeds or wild yam. IGF-1 levels can be improved by creatine monohydrate and other supplements, while HGH, which improves hTERT transcription and is partially converted to IGF-1 in the liver, is boosted by whey protein and HGH secretagogues such as alpha-GPC, 1500 mg arginine + 1500 mg lysine.
Telomerase ActivatorNotes on Fifteen Exercise-Induced Telomerase Activators
HGH [Index]HGH is an endocrine hormone upregulating hTERT transcription converted to IGF-1 in the liver. HGH is upregulated by HGH secretagogues including alpha-GPC, CDP-choline, GABA (Gamma-aminobutyric acid), Mucuna Pruriens, glutamine, glycine, ornithine alpha-ketoglutarate, whey protein, 1500 mg arginine + 1500 mg lysine, arginine + ornithine supplements, and by exercise. HGH is a ligand of the Growth Hormone Receptor. See cell types expressing GHR. Transient overexpression of HIF-1A or exposure to the hypoxia mimetic CoCl2 significantly increases GHR mRNA levels and promoter activities. See supplements increasing GHR mRNA levels. Drugs promoting the expression of HIF-1 [Images, Papers, Patents, Books] include ginkgo biloba, ginkgolides, and diosgenin (from fenugreek seed, fenugreek extract, or wild yam).
IGF-1 [Index]Upregulates hTERT phosphorylation for for hTERT protein transport into the nucleus. It may be obtained from conversion of HGH in the liver, and is boosted by creatine monohydrate, colostrum, cottage cheese, acetyl L-carnitine plus alpha lipoic acid, animal protein or soy protein at a gram per pound of bodyweight, essential amino acids at 7.5 grams, and IGF-1 supplements. The expression of IGF-1 is inhibited by cortisol, which may be inhibited with ashwagandha. All cells have IGF-1 receptors.
PDGFTelomerase activator, upregulates c-Myc. PDGF is upregulated 1.55-fold by exercise and is contained in colostrum and in many growth factor skin creams. PDGF increases the expression of c-Myc, a transcription factor activating the hTERT promoter [NK Banskota, et al., 1989]. PDGF activates the PI3K (Phosphoinositide 3-kinase) pathway.
IL-6Telomerase activator [PDF] and inflammatory cytokine, activates STAT3. IL-6 is upregulated 15-fold by 30 minutes of exercise (and up to 105-fold by 180 minutes of exercise). A IL-6/PI3K/Akt/NFkB cascade may drive hTERT mRNA transcription [PDF ref].
HIF-1Directly upregulates hTERT transcription, upregulated by exercise 2.4-fold, hypoxia, ginkgo biloba, or diosgenin from fenugreek seeds or wild yam. Upregulates telomerase activity in every cell. HIF-1 levels may be sustained with leucine or its metabolite beta-hydroxy-beta-methylbutyrate.
EpiregulinTelomerase activator, EGF family, probably upregulates c-Myc. Epiregulin is upregulated 3.5-fold by exercise. Further upregulated by sodium butyrate [Images], up to 90 times. Epiregulin is a ligand of the EGF receptor. Cells expressing EGFR: EGF Receptor Expression in Human Tissues includes epidermal and glandular tissue.
AmphiregulinTelomerase activator, EGF family. Amphiregulin is upregulated 3.4-fold by 30 minutes of exercise in human neutrophils. Amphiregulin is a ligand of the EGF receptor.
Testosterone [Index]Androgenic telomerase activator, converted by aromatases into estrogen. Testosterone may be further upregulated with DHEA, Forskolin, Tribulus, Fenugreek, Longjack (Tongcat Ali), boron citrate, 6-OXO, exercise, and other testosterone boosters [Images, Papers] or supplements. L-carnitine L-tartrate [Images] can be used to boost the number of androgen receptors.
Estrogen [Index]Telomerase activator, obtainable direct or from testosterone by aromatases. See also estriol skin creams. Strong estrogen bioactivity substances include:
(10.1) Estrogen [Links, Supplements, Images] (10),
(10.2) Fo-Ti (He Shou Wu) [Links, Supplements, Images] (168),
(10.3) Soy [Links, Supplements, Images] (169),
(10.4) Clover [Links, Supplements, Images] (170),
(10.5) Licorice [Links, Supplements, Images] (171) and
(10.6) Hops [Links, Supplements, Images] (172),
HSP90 [Index]Accelerates telomerase synthesis by improving protein folding. Upregulated by Alpha Lipoic Acid, exercise, and stress.
TGF-alpha [List]Candidate telomerase activator upregulated by exercise and found in colostrum. TGF-alpha is a ligand of the Epidermal Growth Factor Receptor. EGF Receptor Expression in Human Tissues includes epidermal and glandular tissue.
IL-2 [Index]A telomerase activator for T-cell lymphocytes. Phosphorylates hTERT via PI3K/AKT1. Exercise upregulated IL-2 1.43-fold in Frank Zaldivar, Jessica Wang-Rodriguez, Dan Nemet, Christina Schwindt, Pietro Galassetti, Paul J. Mills, Lori D. Wilson and Dan M. Cooper (2006), Constitutive pro- and anti-inflammatory cytokine and growth factor response to exercise in leukocytes, Journal of Applied Physiology 100:1124-1133, 2006.
TNF-alpha [Index]An inflammatory cytokine with telomerase activation effect. TNF-alpha is upregulated by exercise and is contained in colostrum.
Nitric Oxide [Index]Nitric oxide is upregulated by exercise and telomerase-activating supplements such as L-arginine, L-citrulline, and whey protein, and by telomerase-inhibiting supplements including cocoa and pomegranate. Gamma Tocopherol is used to control lipid peroxidation from NO.
VEGFVEGF is upregulated 1.36 times by 30 minutes of exercise and may be supplemented with colostrum [List]. VEGF is also used in some growth factor skin creams. VEGF and FGF-2 (FGF/FGF-2, or bFGF) upregulate survivin, which can reverse cellular senescence.
Exercise can bring P16INK4A expression down by 2 binary orders of magnitude (factor of 4). Other factors that can decrease P16INK4a expression (P16INK4a makes recovery from cellular senescence difficult) include retinol from carrots, retinoic acid from beta-carotene, resveratrol, and ID-1 transcription factor from nerve growth factor.
I note that carnosine, the abundance of which in tissue is a longevity biomarker between species, is found in fast-twitch ("white meat") muscle fibers. On the other hand, red meat increases the incidence of colon cancer, so reach for the turkey breast at Thanksgiving. Also, "blood levels of high density lipoprotein cholesterol (HDL-C) are inversely related to the risk of developing coronary heart disease (the higher the HDL-C, the lower the risk), and exercise raises HDL-C." Exercise [Index] has also been shown to reduce the risk of colon cancer. About 250,000 deaths USA deaths per year result from a lack of exercise. According to Dr. Timothy J. Smith, exercise results in "increased levels of anti-aging hormones (HGH and IGF-1), increased production of endogenous antioxidants (SOD, catalase, glutathione), and higher levels of endorphins, cytokines and enzymes. HGH activates transcription from the hTERT gene before being converted to IGF-1 in the liver. IGF-1 phosphorylates hTERT protein (the catalytic component of telomerase) in the cytoplasm for import into the nucleus, where it combines with other factors to produce the telomerase holoenzyme used to lengthen telomeres. Thirty minutes of exercise upregulates PDGF (1.55-fold), and also HIF-1 (hypoxia-inducible factor-I) (2.40-fold) in blood mononuclear cells. Both are telomerase activators. Epiregulin is also upregulated by 30 minutes of exercise (3.50-fold). Epiregulin is a candidate telomerase activator from the EGF family of growth factors. See Peter H. Connolly, Vincent J. Caiozzo, Frank Zaldivar, Dan Nemet, Jennifer Larson, She-pin Hung, J. Denis Heck, G. Wesley Hatfield and Dan M. Cooper (2004), Effects of exercise on gene expression in human peripheral blood mononuclear cells, Journal of Applied Physiology, October 2004, vol. 97 no. 4 1461-1469. Exercise also enhances glutamine production, which protects the aging immune system [Images, Papers, Patents, Books]." Exercise also conveys "cardiovascular benefits, improved insulin response and bone strengthening... Less widely appreciated benefits include heightened immunity, cancer protection and slower neuromuscular aging." According to Ben Best, "Aging results in greater loss of fast-twitch than slow-twitch muscle. Muscle fibers are replaced by fat and connective-tissue. Mitochondria die [Images, Papers, Patents, Books]. Exercise can slow this deterioration because fast-twitch fibers atrophy due to loss of the nerves that innervate them (a loss possibly due to disuse). " - from Mechanisms of Aging. Also, moderate exercise may generate enough Nitric Oxide (NO) to promote mitochondrial biogenesis [112] and activate telomerase [Vasa, et.al, 2000, Hayashi, et.al, 2006]. It has been shown that patients with physically active liesure time have telomere lengths about 200 bp longer than controls [Lynn F. Cherkas, et.al, 2008]. NO can be supplemented from arginine by the action of nitric oxide synthase [Links], as is done in bodybuilding supplementation of Nitric Oxide for anabolic growth [Links]. The synthesis of nitric oxide can also be increased with pomegranate [Links], or by 5 grams of L-arginine per day with 250-1000 mg per day of L-citrulline (with antioxidants such as alpha lipoic acid), as recommended by Nobelist Dr. Louise B. Ignarro in his book NO More Heart Disease. Furthermore, resveratrol stimulates the production of NO, as does genistein [Links] and broccoli sprouts [Links]. "What does not kill us, makes us stronger." - Research suggests that exercise provides a controlled oxidative stress exciting a beneficial anti-aging reaction if the stress is not too intense. Muscle strength is more associated with life extension than is muscle mass. Power training improves elderly balance, protecting from falls. The oxygen-handling capacity of tissue is superior for aging athletes, but may fall to normal levels if exercise is not maintained, so keep pumping up. See books on exercise physiology, exercise and aging, hormesis and aging. I note that extreme exercise may suppress functions of the immune system, making matters worse rather than better. If you feel you would benefit more from recovery time than from more exercise, by all means get that rest. Extreme exercise, for example 10 hours per day for 30 days, may expose one's mtDNA to increased oxidative damage, worsening health instead of improving it. (Arking, p.232) Twenty men exercised 10 hours/day for 30 days showed a 33% increase of oxidative DNA damage products in their urine (Poulsen, et.al, 1996). Note that human cells cannot repair oxidative damage done in mitochondria by extreme oxidative stress. (Yakes and Van Houten 1997, cited in Arking.)
It may be that the maintenance of mitochondria in mass by maintaining bodybuilder quality muscle mass, plus the stimulation of mitochondrial biogenesis by NO from exercise and arginine-based NO supplements or broccoli will be generally beneficial and figure more importantly in the mitochondrial theory of aging than we have seen in the past. (See B. Chabi and V. Ljubicic, (2007) Mitochondrial function and apoptotic susceptibility in aging skeletal muscle for mitochondrial and muscle failure mechanisms in aging animals.) Note that the branched-chain amino acids leucine, isoleucine, and valine not only stimulate muscle growth, but also support mitochondrial biogenesis. Thus whey protein formulations such as Mus-L Blast with extra branched-chain amino acids support mitochondrial biogenesis and are useful for aging specimens if suitable caloric restriction can be maintained.
Jack LaLanne, mentally vigorous, bouncy, well-defined, exercising with weights 1 1/2 hours a day, and muscularly massive to 96, was fairly convincing evidence that bodybuilding technology and the relevant sports medicine involving whey protein, creatine, and HGH-enhancing amino stacks applied during, just before, and just after workouts, could be very important for longevity applications. ("I cannot afford to die, it will ruin my image.") I get the impression that the primary danger here for old people is attempting heavy single repetitions, especially without adequate safeguards, or in the presence of hardening of the arteries (arteriosclerosis), which might cause a subclavian aneurysm. Squats and so forth should be done a rack, so that if one collapses, one's back is not broken, for instance. It should be difficult for movements to get out of spec, so perhaps machines that guarantee this should be used, and perhaps 5-12 reps per set would be ideal, with the objective of pumping up a specific muscle or muscle group using a number of sets in each workout using a 3 to 4 day split routine to cover the body. This gets the cortisol level down, rather than up, like stress at work sometimes can, and promotes healthy levels of cortisol antagonists like DHEA and HGH, which it pays to supplement in aging specimens. I note that males over 90 are very much more likely to be independently functional than women the same age. Studies show that exercise protects elderly specimens against dementia [Links, Papers, Books]. Sarcopenia [Index], or muscle-wasting, starts in the 4th decade of life and accelerates after 75, being due to inactivity, reduced protein synthesis, reduced protein intake, reduced blood supply to tissues, and reduced number and size of mitochondria in muscle [ Physiological Basis of Aging and Geriatrics, 4th edition, 2007, p.384-385]. Sarcopenia is also associated with atrophy and loss of associated motor neurons and frequently with osteoporosis [Index]. Resistance training has been observed to increase elderly muscle protein synthesis by up to 50%, increase insulin sensitivity and glucose tolerance, reduce blood pressure, normalize blood lipid levels by reducing triglycerides, and increase HDL cholesterol, preventing "cardiovascular diseases, diabetes, osteoporosis, obesity-related diseases, colon cancer, and, possibly, pancreatic cancer." See Hamburg NM, McMackin CJ, Huang AL, et al. (2007), Physical inactivity rapidly induces insulin resistance and microvascular dysfunction in healthy volunteers, Arterioscler Thromb Vasc Biol, 2007 Dec;27(12):2650-6.

Cyclic AMP from Exercise and Forskolin inhibits caveolin-1 and Restores Senescent Cells
Cyclic AMP from exercise or forskolin represses the expression of caveolin-1, allowing recovery from cellular senescence. Check cyclic AMP (Refs9/cAMP), cyclic AMP signal, adenyl cyclase, cyclic AMP in bodybuilding cyclic AMP from exercise, and plasma levels of cyclic AMP from exercise. "The effect of one bout of intense swimming caused significant increases in the cyclic AMP content of fast-twitch white skeletal muscle, liver, and heart. Further investigation of the exercise-induced increase in myocardial cyclic AMP indicates that the nucleotide content remained elevated long after (24 h) termination of exercise. This increase in cyclic AMP was time dependent, with the level increasing gradually throughout the work bout. The increase in cardiac cyclic AMP seemed to be independent of work intensity, provided that work time was of sufficient duration (greater than or equal to 30 min)." - After Palmer WK (1988), Effect of exercise on cardiac cyclic AMP, Med Sci Sports Exerc 1988 Dec;20(6):525-30. Also see Yamamoto M., Okumura S., Oka N., Schwencke C., Ishikawa Y. (1999), Downregulation of caveolin expression by cAMP signal, Life Sciences, 1999;64:13491357 and Cho KA, Ryu SJ, Park JS, Jang IS, Ahn JS, Kim KT, Park SC (2003), Senescent phenotype can be reversed by reduction of caveolin status [Papers, Patents], Journal of Biological Chemistry, 2003 Jul 25;278(30):27789-95.

Muscle Regeneration [Links, Images, Papers, Patents, Books, LifeExtension].
Telomolecular Nanotechnologies (now defunct) [SEC info] licensed a Notch 1 Stanford University technology [Links, Papers, Patents, Books] to regenerate musculature, heart tissue, and neuronal tissue. (See notch signaling in muscle regeneration [Images, Papers, Patents, Books, Muscle Stem Cell Activation in Aging].) Aging is associated with human musculature having diminished regenerative potential. "The mechanism of this decline is now known. Analysis of injured muscle revealed that, with age, resident precursor muscle (satellite cells [Books]) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. Sufficient up-regulation of a special receptor ligand results in muscle, neuronal, and heart tissue regeneration in old musculature." See also Notch Signaling Pathway Microarrays, [Links/Notch signaling ligand Delta, Images, Papers, Patents, Books; Links/Notch ligand factor Delta activators, Papers, Patents, Books]. Recently, young serum [Links, Images, Papers, Patents, Books] has been shown to help with muscle stem cell regeneration via notch signaling mechanisms. See Irina M. Conboy et al. (2005), Methods and compositions for regeneration of aged skeletal muscle tissues, US Patent 7,837,993 B2. (Perhaps it is useful to orally consume young horse serum or the blood of a calf. Check.) Muscle tissue heals faster in the presence of young blood serum [article], which activates muscle satellite stem cells [Links, Papers, Patents, Books]. Similar regenerative effects of young serum [Images, Papers, Patents, Books] have been observed in liver tissue. Old muscle satellite stem cells bathed in young serum increase their level of Delta production and begin dividing. It may be possible to produce young serum by persistent treatment with small molecule telomerase activators such as TA-65 or the astragalosides including Astragaloside IV and Cycloastragenol. [81s]. Also, specific proteins PCG-1Q and CaMK have been found which aid muscle regeneration in aging specimens. PCG-1Q regulates energy metabolism in mitochondria [Links, Papers, Patents Books], stimulates mitochondrial biogenesis, and is interferred with in Huntington's Disease. See also CaMK [Links/CaMK in muscle regeneration, Images, Papers, Patents, Books]. The Wnt signalling pathway [Links, Images, Papers, Patents, Books] activating CD45+ stem cells [Links, Books] in muscle is also a target for muscle regeneration [article].

Heat-Shock Proteins and Hormesis [Index/Heat Shock Proteins, Index/Hormesis, Wikipedia/Heat shock protein, Links/heat shock proteins, Images, Video, Papers, Patents, Books, LifeExtension; Links/heat shock proteins and hormesis, Images, Papers, Patents, Books, LifeExtension]. Exercise is associated with hormesis [Links, LifeExtension], an adaptation to a regularly imposed moderate stress that improves the strength of organism to a class of stress, such as radiation stress or exercise stress. Mitochondrial hormesis or mitohormesis [Links] induces life-extending endogenous free radical response to exercise. Another kind of hormesis is associated with the elevation of heat-shock protein [LifeExtension, Books] levels, which has been observed to be associated with life extension in experimental animals and humans. Perhaps workouts in sweat clothes and regular sauna heat-treatments would beneficially elevate our heat-shock protein levels [LifeExtension, Books]. "Our studies have shown that repeated mild heat stress (RMHS) has antiaging effects on growth and various other cellular and biochemical characteristics of normal human skin fibroblasts undergoing aging in vitro. RMHS at 41C, for 1 h twice a week (105.8 degrees F)..." (Suresh I. S. Rattan and Rehab E. Ali, 2007, Index/Hormesis). See heat shock protein enhancing supplements [Images, Papers, Patents, Books]. Heat shock protein levels are activated by temperature, rather than by exercise alone, and by cellular stress. Blueberry supplements cause brain tissue to respond with heat shock proteins to an inflammatory stimulus [LifeExtension]. See also heat-shock protein therapies [Links, Papers, Patents, Books, LifeExtension]. Certain drugs can be used to elevate heat-shock protein levels, such as alpha lipoic acid or tricostatin A (TSA), a histone deacetylase inhibitor used as a small-molecule telomerase activator for lengthening telomeres which is also known to elevate heat-shock protein levels in Drosophila. Glutamine, the most abundant amino acid in the body, also stimulates heat shock protein expression [LifeExtension], and researchers speculate that curcumin promotes heat shock protein expression in the brain [LifeExtension]. HSP90 [Wikipedia, Links, Images, Video, Papers, Books] binds endothelial nitric oxide synthase [Wikipedia], which in the presence of arginine produces Nitric Oxide (NO) to activate telomerase in endothelial cells [Vasa, et.al., 2000; Hayashi, et.al, 2006]. HSP90 [Index] can be elevated by Interleukin 6 [Links] generated from exercise [Links]. HSP90 and p23 are required for telomerase activity.

Damage from Exercise in the presence of Arterioscleriosis
Hard exercise can contribute to an arterial aneurysm in the coronary arteries, especially if the exerciser is an aging specimen suffering from arteriosclerosis [Index]. One patient who contacted me tried hard exercise, but suspects he must have had too much ice cream, producing glycation hardening of the arteries due to sugar damage and a consequent painful subclavian aneurysm during bench pressing activity. Calcification of atherosclerotic plaque leading to arteriosclerotic hardening of the arteries is sometimes due to a lack of Vitamin K2 in the diet, which can be corrected with MK-7 supplements or Swiss cheese. Vitamin K2 can produce osteocalcin that guides calcium in the blood back into the bones, preventing the calcification of the arterial wall, hardening of the arteries, aortic sclerosis, and aortic stenosis. In fact, vitamin K2 can reverse arterial calcification, de-calcifying hardened arteries. Vitamin D3 helps in this process because it regulates bone mineralization of the calcium. Surprisingly, supplemental calcium may also be beneficial. The situation can be complicated if simultaneous atherosclerosis exists involving atherosclerotic plaque in the arterial system. This can become calcified. The condition is dangerous, and can lead to an arterial embolism, a piece of loose atherosclerotic plaque that can cause a stroke or a heart attack. Aging specimens usually benefit from lifting weights, but blood tests may be in order to check for indicators of inflamed atherosclerotic plaque, atherosclerotic plaque, and/or arteriosclerosis, and levels of vitamin K2 should be kept high enough to generate enough osteocalcin for the decalcification of arteries. See LifeExtension/vitamin K2, LifeExtension/Endothelial Defense, LifeExtension/Blood Tests, and NO More Heart Disease by Dr. Louis Ignarro. Vitamin C to support collagen synthesis for bone remineralization and telomerase activating drugs to prevent senescence of the vascular endothelium may be useful in preventing weakness of the arterial walls. Telomerase may be employed to close telomere t-loops in the vascular endothelium, relieving replicative senescence in the arterial wall tending to impact collagenase levels and other factors tending to reduce the strength of the arteries. Many telomerase activators such as nitric oxide strengthen endothelial progenitor cells in the bloodstream. Furthermore, the senescence of the vascular endothelium makes it more adhesive to monocytes, initiating the process of atherosclerotic plaque development. If statin drugs are used to promote telomere loop closure, extra CoQ10 must be taken, as statin drugs reduce CoQ10 levels. I note that TRF2 overexpression has been reported to degrade telomeres by Woodring E. Wright and Jerry W. Shay, so that perhaps t-loop closure had best be implemented wih telomerase activators if TRF2 levels are sufficient for normal closure. When telomere t-loops are opened by poly(ADP-ribo)sylation of TRF1 protein by tankyrase 1 (phosphorylated by insulin stimulation at insulin receptors on the cell membrane) in the presence of a NAD+ substrate, the loops are reclosed by further expression of TRF1 [Links, Images, Papers, Patents, Books].


(10) The DNA Repair Theory (Refs1c, Index, Links, Images, Papers, Patents, Books, Amazon, LifeExtension/DNA_repair and Aging, Wikipedia, Mechanisms of Aging/DNA, DNA Repair Adjuvants; Ben Best/DNA Damage and DNA Repair).

Introduction: DNA Repair and Species Life Span
Species-specific life spans are correlated to DNA repair capability [Hart & Setlow (1974), Links, Images, Papers, Patents, Books, LifeExtension]. Chromosomal abnormalities increase with aging [Images, Papers, Patents, Books] and may be reduced by improving DNA repair. [LifeExtension/improving DNA repair, Links, Images, Papers, Patents, Books]. The quality of DNA repair and DNA defense varies enourmously between species. [Links, Images, Papers, Patents, Books]. Among DNA microbes, the spontaneous mutation rate per base pair varies 100,000-fold. [Hisama, 2003]. Human DNA is much better repaired and defended than mouse or rat DNA, although the rodents have made a tremendous investment in huge telomeres. Recent research [86] suggests that interference with the nuclear membrane causes progeria, a premature aging disorder, so that more attention may be focused in the future on damage to the membrane of the cell nucleus preventing certain DNA repairs. We have already noted DNA damage to telomeres in (1) on the free radical theory of aging.

SIRT6 for DNA Repair
Fasting with cinnamon, exercise and sirtuin activators such as green tea, quercetin, and resveratrol is probably best for elevating SIRT6, which promotes DNA repair several different ways, improves double-strand DNA repair, rescues homologous DNA repair during cellular senescence, prevents telomere dysfunction, and deflects premature cellular senescence. In addition, SIRT6 has anti-inflammatory and anticancer effect. SIRT1 and SIRT6 should be elevated during anticancer telomerase inhibitition periods, as sirtuin activators tend to condense chromatin, discouraging transcription of protein mRNA and promoting gene silencing.

Also see the recent article Mechanisms of Aging by Ben Best. For still more fine points on theories of aging, see Why Do We Age? from Senescence Info. See Wikipedia on Senescence. Also see the PhD thesis of Joao Pedro de Magalhaes, Modeling human ageing: role of telomeres in stress-induced premature senescence and design of anti-ageing strategies, and his papers.

"Yet in vivo cell senescence can be found without telomere shortening (Melk et al., 2003), suggesting that RS [Replicative Senescence] may not be the prevailing mechanism in vivo."

"...results suggested that telomere capping, not just telomere length, is crucial in avoiding telomere dysfunction and preventing apoptosis and death."

"Telomere shortening in vivo has been reported in liver cells (Aikata et al., 2000), lymphocytes (Mariani et al., 2003), skin cells (Lindsey et al., 1991), blood (Iwama et al., 1998), and colon mucosa (Hastie et al., 1990)."

"Finally, long telomeres have been found in cells from centenarians (Franceschi et al., 1999)."

"DNA damage induces cellular senescence through complementary pathways."

"If chromatin changes play a role in aging... then anti-aging therapies may involve chromatin remodeling factors [Images, Papers, Patents, Books]. One study showed that feeding sodium 4-phenylbutyrate (PBA) [Index, Links, Images, Papers, Patents, Books, 87] to Drosophila extends longevity by about 40% (Kang et al., 2002)."

Sodium 4-Phenylbutyrate [Index, Images] increased drosophila lifespan 30% to 52% depending on the sex and the genetic background, with the largest effect on life span being found when the drug was applied in the middle and late life phases. (Arking, p.285.) I note that Butyrate [Links] is a histone deacetylase inhibitor (HDAC inhibitor) that dissociates DNA from histone protein cores prior to transcription activity with RNA polymerase. Sodium butyrate [Index, Images] is available as a supplement in pill form. Since it expands chromatin for transcription, it may be useful in improving hTERT transcription rates when using telomerase activators [Index, List, (7)]. However, this must be tested. Expansion of chromatin may be why the histone deacetylase inhibitor Tricostatin A works to increase hTERT mRNA transcription activity, and garlic allicin metabolites diallyl disulfide and allyl mercaptan are thought to do likewise.

"Perhaps upregulating oxidative defenses might be a more promising approach."
"...a recent study found a correlation between telomere length and mortality in people over 60 years of age (Cawthon et al., 2003)"
"...results suggest that telomerase activity promotes tumerogenesis independently of telomere elongation....we argue that telomerase is unlikely to become a source of anti-aging therapies."

In yeast, mother cells spin off extra copies of rDNA forming eccDNA rings (Extra Chromosomal Circular DNA) after a few cell divisions, such that mother cells accumulate an increasing number of the rings with subsequent divisions until the mother cell dies. Adding an extra copy of the SIR2 gene extends the life of such mother cells 30%, and similar effects can be obtained with resveratrol (and to a lesser degree with quercetin), which stimulates SIR2 (or SIRT1 in mammals). So resveratrol may be used to avoid death by DNA clogging in the nucleus due to the generation of eccDNA, a process which also somewhat applies to mammals. [14s].

Finally, the maximum life span of 13 species is directly correlated to the activity of poly (ADP-ribose) polymerase (PARP, Links, Images, Papers, Patents, Books) in mononuclear leukocytes [59s]. ADP-ribosylation of proteins [Links, Images, Papers, Patents, Books] is involved in chromatin maintenance, DNA repair [Books, Books/with ADP-Ribosylation], protein synthesis, cell differentiation, and cell transformation. "Normal cells replicate by dividing DNA into two strands and copying each strand. (Pol II polymerase is used, requiring magnesium as a cofactor.) Before replication, damage in the DNA is usually repaired using a protein called PARP. If PARP is absent or inhibited then the cells use a second mechanism called recombination to fix the damage and continue to replicate." Note that tankyrase 1 is a telomeric PARP that may be phosphorylated with insulin to poly(ADP-ribo)sylate TRF1 in the presence of a NAD+ substrate, stripping it from the telomere to open the telomere t-loop and allow access by the telomerase holoenzyme for telomeric DNA repair and telomere re-extension. See Links/PARP, Books/PARP, and Links/PARP and life extension with the article L-Selegiline (Deprenyl) Potentiates the Cellular Poly(ADP-Ribosyl)ation Response to Ionizing Radiation. I note that niacin also plays a role in DNA repair, and that poor longevity due to problems with DNA repair may be due to a deficiency in niacin (niacinamide, nicotinamide, vitamin B3). The most useful form of niacin for life extension purposes is nicotinamide (niacinamide). Poly(ADP-Ribose) polymerase (PARP) is NAD+ dependent, and has NAD+ for a substrate. [Inotek, Wikipedia, Links]. The DNA repair polymerase PARP is enhanced by combined supplementation of nicotinamide, zinc, and carotenoids. [Nicoplex, Sheng Y, Pero RW, et al, 1998]. See also cofactors in human DNA repair [Links, Images, Papers, Patents, Books], which must include the magnesium ion for proper functioning of DNA and RNA polymerases and the 5 RecQ helicase genes that telomeres use. Also note that Suracell provides a DNA-repair enhancer CAE, an extract from the tropical rainforest botanical Uncaria Tomentosa, "Cat's Claw", described in The Anti-Aging Solution [80s] by Giampapa, Pero, and Zimmerman. [LifeExtension/Cat's Claw, Ray Sahelian; Links/Cat's Claw Extract for DNA repair, Images Papers, Patents, Books]. In addition to promoting single-strand and double-strand DNA repair and photochemical DNA damage repair in normal human cells, cat's claw extract (AC-11, formerly C-MED-100) fights cancer in cancer cells. It can be applied internally or topically. It is also an anti-inflammatory blocker of NF-kappaB that reduces Tumor Necrosis Factor alpha. Pero's AC-11 Cat's Claw Extract is prepared without oxindole alkaloids [Links, Papers, Patents, LifeExtension], relying on CAEs (carboxyl alkyl esters) for pharmaceutical effect. [LifeExtension, Papers, Patents, Sheng Y, Li L, Holmgren K, Pero RW, 2001]. Other DNA repair enhancing nutraceuticals and phytochemicals exist, including selenomethionine [LifeExtension, Links, Papers, Patents, Books] and T4 endonuclease V (Dimericine) [Links/Dimercine, Links/T4 endonuclease V, Papers, Patents, Books], a DNA repair enzyme produced in bacteria that is delivered in liposomes in the form of a topical cream. Perhaps it could also be delivered in a liposomal spray. "Indole-3-carbinol (from broccoli) and three other vege-compounds (resveratrol, curcumin, and ellagic acid) can actually enhance the body's DNA repair system". - LifeExtension. Sulforaphane (high in broccoli sprouts) "induces enzymes, including quinone reductase and the antioxidant glutathione S-transferase, that can detoxify carcinogens and prevent toxic electrophiles from damaging DNA." It turns out that DNA repair is linked to transcription, so that actively transcribed DNA is repaired at a higher rate (Arking, p.371.) than non-transcribed strands [Books]. Since telomeres are less actively transcribed, they are less well-repaired [Books], and therefore additional means of DNA repair such as Cat's Claw Extract may be very beneficial. DNA damage [Books, Books/in Aging] can induce cellular senescence [Links, Papers, Books], so defending against it also defends against genomic instability [Books] and cancer, and tends to promote youthful patterns of gene expression [Images, Papers, Patents, Books].
At this point I note that DNA melts at the strand separation temperature, which steadily increases with age due to links with proteins, or cross-linking with proteins. Complete deproteinization of DNA results in the disappearance of the phenomenon [Zs.Nagy, The Membrane Hypothesis of Aging, p15.]. Perhaps old-age damage to chromatin fibers yielding reduced transcription levels results primarily as a consequence of damage to DNA-management proteins and enzymes by free radicals, advanced glycation end products, and effectively by proteasomes clogged by isoketals from arachidonic acid that can no longer digest proteins for protein turnover (See Oleuropein).
The short one-day deamidation half-life of uracil DNA-glycosidase is suspected in the decline of DNA repair during aging. (Hipkiss, T. Zglinicki, Aging at the Molecular Level, pg. 155.) See a uracil DNA-glycosidase in cellular homolog from p.148 of the same book. 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.

Telomere Erosion, hTERT Activation improves DNA Repair, Chromosomal Instability, and Homocysteine
Chromosome tip-end telomere reconstruction via telomerase activation [81s] is another form of DNA repair via the telomerase reverse transcriptase, and is treated in (7), above. Chromosomal instability [Links, Papers, Patents, Books, Amazon] due to shortening telomeres is a primary cause of aging and of cancer. There are indications that, in addition to lengthening telomeres, hTERT protein expression enhanced by telomerase activators (7) leads to otherwise improved DNA repair and superior genomic stability. See Girdhar G Sharma, Arun Gupta, Huichen Wang, Harry Scherthan, Sonu Dhar, Varsha Gandhi, George Iliakis, Jerry W Shay, Charles S H Young and Tej K Pandita, (2003), hTERT associates with human telomeres and enhances genomic stability and DNA repair, Oncogene (2003) 22, 131146. Also see Ki-Hyuk Shin, Mo K. Kang, Erica Dicterow, Ayako Kameta, Marcel A. Baluda and No-Hee Park (2009), Introduction of Human Telomerase Reverse Transcriptase to Normal Human Fibroblasts Enhances DNA Repair Capacity, Clinical Cancer Research, December 1, 2009, 15 (23). Another source of chromosomal instability resulting in aneuploidy and an increasing number of micronuclei forming in aging cells [Links, Images, Papers, Books] at the final states of mitosis is homocysteine, which may be opposed using a homocysteine shield [Index, Links, Images] containing folic acid, vitamin B12, vitamin B6, and TMG (trimethylglycine). Studies show that chromosomal instabilities in aging cells resulting in the formation of a separate micronucleus may be reduced by reducing homocysteine (by eating less red meat, for instance, the usual source of excess methionine producing homocysteine), or by methylating homocysteine with folic acid, vitamin B12, vitamin B6, and TMG, or just with vitamin B12 and folic acid alone. Homocysteine associated with high homocysteine levels has also been shown to attack telomeres [Links, Papers, Patents, Books, Amazon], resulting in more severe telomere shortening per cell division.

Genomic Instability, DNA Helicases, and Magnesium as a Cofactor
There are 5 RecQ DNA helicase genes [Wikipedia/Helicases, Links/DNA helicases, Papers, Patents, Books; Links/RecQ DNA helicase genes, Papers, Patents, Books]. The RecQ DNA helicases are used to unwind DNA, some or all requiring Mg++ as a cofactor. [See 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 [Images] associated with Werner Syndrome, for instance, is localized to the telomere, and may malfunction if sufficient magnesium is not available as a cofactor. [Papers/WRN helicase with Mg cofactor; Links, Papers]. Consider magnesium as a supplement [Links, Images, Papers]. 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. Recently, it has been determined that the magnesium supplement magnesium L-threonate is more bioavailable to the brain than other magnesium supplements, and acts to prevent synapse loss and to restore neural synapses, working to prevent Alzheimer's disease.

Epigenetic Regulation and Undesirable DNA Demethylation in Aging
[Index/Epigenetic Regulation; Index/Methylation; Index/Demethylation of DNA; Links, Papers, Patents, Books, Amazon, LifeExtension; Links/Epigenetic Dysregulation in Aging, Papers, Patents, Books, Amazon; Links/DNA methylation, Books/DNA Demethylation, Links, Images, Papers, Patents, Books, Books/epigenetic regulation in senescent cells, Links/causes of DNA demethylation, LifeExtension/DNA demethylation]. Methylation of genes is used in the development of placental mammals to silence gene promoters after their developmental role is over, or to switch on genes controlled by an insulator in charge of an enhancer. Life Extension Magazine promotes SAMe [Links] as a cure for undesirable DNA demethylation, noting that "Cellular aging is partially caused by de-methylation".

Mitochondrial DNA Damage and Repair
In the human body, we observe about 2 x 10-7 mutations per gene per cell division [Fuki Hisama, 2003]. DNA sequence polymorphisms due to mutations are estimated to occur 17 times as rapidly in mtDNA as in nuclear DNA. [Neckelmann, et al., 1987; DC Wallace, et al., 1987]. Recently, mitochondrial DNA repair [Links, Papers, Patents, Books, LifeExtension, Amazon] has been addressed by applying mitofusins [Links, Papers, Patents Books], as explained by the now-defunct firm Telomolecular Nanotechnologies. See also Books/Mitochondrial DNA and Longevity, Books/Mitochondrial DNA and Life Extension, Books/Treating Mitochondrial Aging, Books/Mitochondrial Theory of Aging, and LifeExtension/mitochondrial theory of aging. Knockout of the MnSOD gene for mitochondrial SOD [Wiki/SOD2, Links, Papers, Patents, Books] fatally increases oxidative stress so that knockout mice die as neonates with mitochondrial DNA damage and membrane damage, unless MnSOD-mimetics [Links, Papers, Patents, Books, LifeExtension] are supplied, supporting the mitochondrial theory of aging devised by Australian scientist Anthony Linnane in 1989. Linnane began by observing that mutations accumulate in mitochondrial DNA with age and finished by showing that less than 5% of the mitochondrial DNA from the muscle tissue of a 90 year old subject [Images] was intact. Wolfberry, the legendary Goji berry of Shangri-La's eternal heaven, may be particularly useful in improving the relevant SOD levels [LifeExtension]. I note that lengthening telomeres using a cyclic treatment scheme with small molecule telomerase activators such as astragalus extract, astragaloside IV, or cycloastragenol also produces higher levels of endogenous antioxidants such as MnSOD (mitochondrial SOD) via the telomere position effect. It is interesting to note that mitochondria typically turn over every 14 days in cells, and that defective mitochondria are found primarily in postmitotic cells. "Permissive accumulation of defective mitochondria may the outcome of cell senescence." - Michael Fossel, Cells, Aging, and Human Disease, p. 69. The best known treatment to rejuvenate mitochondria is acetyl L-carnitine plus alpha lipoic acid. [Links, LifeExtension; Links/mitochondrial rejuvenation, Papers, Patents, Books, LifeExtension; LifeExtension/Alpha Lipoic Acid, Links]. Furthermore, supplements such as PQQ (found in cocoa), whey protein, and branced-chain amino acids (leucine, isoleucine, and valine) now exist for promoting mitochondrial biogenesis, supplying cells with fresh mitochondria to repair damage to mitochondrial DNA.

Deuterium Theory of Aging via Damage to DNA [article, Links, Papers, Patents, Books].
Deuterium in water is thought to contribute to DNA damage, and deuterium-depleted water [Links, Papers, Patents, Books], or Dd-water, may be taken to reduce damage to DNA from deuterium [Wikipedia]. Deuterium water is toxic, and the associated problems seem to stem from the effect of deuterium on the hydrogen bond. Deuterium bonds are stronger and shorter than normal hydrogen bonds, sometimes modifying the shape of an enzyme. Deuterium-depleted water has contributed to the survival time of breast cancer patients after metastases have been observed. Dd-water may be obtained from glaciers at high altitude, as for instance Hunza water [Links]. Hunza claims to have people who routinely live to 120-140 years, in good health with virtually no cancer, degenerative disease, dental caries or bone decay, who drink water from the Hunza glacier. Plants can be constructed to produce deuterium-depleted water on a large scale [article], and it is available in liter bottles like a soda beverage.

Preventing DNA Damage [Links, Images, Papers, Patents, Books, LifeExtension].
Antioxidant and antiglycating drugs prevent DNA damage due to free radicals or from ROS (Reactive Oxygen Species), and chlorophyllin is a potent nutrient protecting against environmentally induced damage to DNA. Daily grape juice consumption reduces oxidative DNA damage and plasma free radical levels [Mutation Research, 2003]. Antiglycating drugs also prevent direct damage to DNA from reactions with sugars, in addition to preventing elevated levels of free radicals stemming from the carbonylation of proteins or glycation of lipid membranes. Vitamin B1, vitamin B6, carnosine, and vitamin C are antiglycating. A low sugar diet and caloric restriction remove sources supporting glycation. I use cocoa powder in water as a powerful antioxidant to prevent DNA damage from free radicals, and also antioxidants such as alpha lipoic acid and CoQ10 or ubiquinol. The telomerase activators such as astragalus root extracts [Index] repair DNA damage to telomeres, causing senescent cells to recover their youthful phenotype, and defending cells against further telomere erosion that may lead to cancer via endpoint fusion of chromosomes, such as carcinomas in epithelial tissues as in breast cancer. Conversely, we may use telomerase inhibitors like garlic, silymarin, and resveratrol to freeze the cellular proliferation associated with cancer after cells have passed through the M2 crisis sometimes eventually following the M1 telomere shortening point at which shortening telomeres produce open t-loops and DNA damage signals associated with the senescent state of the cell. Consider DNA damage from carcinogens [Index]. DNA can be defended against damage by carcinogens such as benzopyrene from charcoal broiled meats and from polycyclic hydrocarbons in burned meat and burned foods by systematic avoidance of carcinogens and burnt foods. Also, eating beef fat may allow bacteria that produce carcinogens as secondary bile products to flourish, producing colon cancer.


(11) The Immunological Theory of Aging [Index, Refs1c/Immune Sys, Links, Images, Papers, Patents, Books, Amazon, LifeExtension, Mechanisms of Aging/Immune, [80s]; Links/Immunosenescence, Images, Papers, Patents, Books]. The immunological theory of aging is closest to the heart of the Theories of Aging (Books, Amazon, LifeExtension, IAS, Mechanisms of Aging/theories). I note that the thymus gland [Wikipedia, Links, Papers, Patents, Books] above the heart, which is associated with immune functions and the production of T-lymphocytes, withers after puberty, being modified by the sex hormones, and vanishes by the time we about 60 years old. It has been noted that castration tends to cause the thymus gland to recover and enlarge, which may have something to do with the mildly favorable impact of castration on longevity, usually described merely as heading off testicular cancer in old dogs, or preventing baldness due to dihydrotestosterone derived from testosterone. [See Links/Thymic Recovery, Images, Papers, Patents, Books; Books/Thymic theory of aging.] Castration reverses immunosenescence in mice. Thymic recovery and cellularity has also been promoted by IGF-1 and growth hormone HGH, both of which enhance telomerase activation. Arginine 3 grams/day [Links, Links/in protein powder] can restore blood thymic hormone levels to youthful values after several months [21s], and zinc has also been shown to be similarly useful. The thymus gland converts hemopoietic stem cells from the bone marrow into T-lymphocytes for the immune system, T-cell production peaking just prior to puberty. Recently thymic extracts [LifeExtension, Links, Images, Papers, Patents, Books] have been getting attention in anti-aging strategies for treating immunosenescence [Books, Amazon, LifeExtension]. "The thymus gland hormones can reduce autoimmune reactions, clinically and experimentally, such as occur in rheumatoid arthritis... Thymic hormones also stimulate non-specific phagocytic and cytotoxic cells to respond against foreign or "non-self" antigens." Thymomodulin? bovine thymus extract has been used to treat immune system disorders in HIV and other diseases. Immunosenescent diseases such as lupus and arthritis often have the characteristic that the body develops antibodies against its own tissues. See the article "Changes with aging of several leukocyte functions of male and female rats". Studies suggest that immunosenescence leads to greater vulnerability to cancer. One way to combat immunosenescence is via cord blood transplants (8). In fact, blood or serum transfusions from youthful characters may be helpful. "By and large, unlike the "average" elderly, the healthy very elderly (centenarians) are found to have well-preserved immune functions, similar but not identical to, the "young" immune system." Recently (2011) hyperimmune eggs, available as hyperimmune egg powder, have been used to attenuate immunosenescence, to lower lipid and cholesterol levels, and to improve athletic performance by lowering levels of proinflammatory cytokines. Studies suggest that moderate exercise attenuates immunosenescence. I note that aging world record holder Jeanne Calment took fencing lessons at 85 and rode a bicycle until she was 100 years old. Also, echinacea [105] has been shown to strengthen the immune system, as has garlic. Shark liver oil [108], which contains alkylglycerols, stimulates white blood cell production, modulates platelets, and boosts the immune system with anticancer effect. It is taken at up to 600 mg/day for no more than 30 days. Green tea [25b] is also thought to protect against aging by strengthening the immune system. Glycyrrhiza, the source of licorice, has been found to activate immune system cells [Links, Papers, Patents, Books, LifeExtension] as quantified by CD69 expression in manner similar to echinacea and astragalus membranaceus root. The lymphocytes of the adaptive immune system are mitotic, dividing cells subject to their shortening telomeres, which may be protected by agents like vitamin C [30], the other antioxidants (1), and by carnosine [69]. The St. Petersburg Institute for Biogregulation and Gerontology points out that thymalin [Links, Papers, Patents, Books] is geroprotective and useful for restoring immune functions. Telomere-lengthening strategies [81s] (7) strengthen T-lymphocytes and B-lymphocytes, extending their lifespan after extra clonal divisions to fight antigens, including treatments based on trichostatin A, IL-2, TA-65, astragalosides, astragaloside IV, cycloastragenol, astragalaus extract or Astragalus Membranaceus. Providing more cell divisions for B- and T-lymphocytes with small molecule telomerase activators such as TAT2 (cycloastragenol), astragaloside IV, or astragalus extract strengthens the immune system's ability to respond to challenges by rejuvenating immune system cells [Papers, Patents, Books].

Degradation of the Immune System by Environmental Challenges
Presentation of an antigen, for instance a hair dye antigen, to a lymph node [Links] can result in reactive lymphocytosis, in which case B-lymphocytes [Wikipedia/Lymphocyte, B-cell surface proteins & treatment] in the lymph node divide many times within their follicular membrane pockets. This produces a painlessly swollen lymph node (permanently enlarged) crammed full of senescence-accelerated B-lymphocytes which become chromosomally unstable before other cells of the body do, because they have divided many times to confront an antigen, but are still subject to the 50-times cell division ceiling or Hayflick limit. Such a lymph node may eventually exhibit neoplastic lymphocytosis [Images] associated with a full-blown case of initially indolent non-Hodgkins lymphoma [Wikipedia, Books, Amazon], and had probably best be surgically removed before neoplastic effects are observed along with classical lymphoma symptoms such as night sweats and weight loss. Astragalus Membranaceus, which contains small molecule telomerase activators, was the first medicine discovered to be effective against night sweats, probably because its telomerase activation cured senescence in problem B-lymphocytes more subject to genomic instabilities and cancer as senescent cells. Indolent lymphomas can start with a benign and painlessly swollen lymph node or asymptomatic "lymphadenopathy" [article] apparently harmless for years until it exhibits neoplastic, cancerous effects including metastasis to other parts of the body. Steve Reeves died of hair dye-generated lymphoma complications at 74. Non-Hodgkins lymphoma is 8 times as prevalent in the USA as Hodgkins lymphoma, which is characterized by the presence of cancerous Reed-Sternberg cells [Links, Images, Papers, Books] with multiple nuclei in the lymph nodes along with the B-lymphocytes. Non-Hodgkins lymphoma may begin with poisoning via hair dye or other chemicals. Temporary treatment with IL-2 (Interleukin-2), Trichostatin A, Geron TAT0001, Geron TAT0002 (cycloastragenol), TA-65 [Index], astragalus extracts, or perhaps amino stacks for elevating IGF-1 [sample, Links/IGF-1 supplements] may be applied for global, systemic treatment of prematurely senescent lymphocytes with telomerase activators [81s] to rejuvenate lymphocytes degraded by environmental challenge. This is most popular in the case of HIV infection, when small molecule telomerase activators such as cycloastragenol may be applied to lengthen T-lymphocyte telomeres (See Geron Corporation), perhaps in combination with a program of sugar restriction to frustrate the HIV virus, which uses a sugar coating to disguise itself to the immune system. Note that cancer feeds on sugar, a fact which is dramatically visible in PET scans when using radio-labeled glucose as a probe. Of course, cancer is more likely in patients with DNA damage due to glycation from excessive sugar consumption, which produces AGEs that raise Reactive Oxygen Species (ROS) levels to inflammatory heights. The same sort of inflammation can produce Alzheimer's Disease. Treatment of lymphoma in its neoplastic phase with monoclonal antibodies such as Rituxan may also be useful, but is considerably more harrowing. Observe than since mature adult telomeres have shrunken to allow just 20 cell divisions, the immune system can then only produce 220, or about 1 million clonally multiplied B-lymphocytes per original B-lymphocyte in a lymph node follicle, illustrating how the defensive capacity of the immune system goes down as we age. B-lymphocytes inside a painlessly swollen lymph node's lymphoreticular system follicles seem to exhibit clonal hyperplasia about 85% of the time [114, 115]. B-lymphocytes that have divided many times reacting to an antigen are closer to their Hayflick cell division limit than other cells in the body, and when they go bad before other cells due to senescent genomic instabilities, we then observe the symptoms of lymphoma in aging specimens with weakened immune systems. As we would expect from the telomere position effect, "in most cases B-cell non-Hodgkin lymphomas express telomerase..." (M.Fossel, p.110.). However, since the telomerase activator astralagus root extract can be used to stop lymphoma night sweats, it seems likely that a further increase in telomerase activation is required to halt the progress of lymphoma by ensuring relative genomic stability. "Telomerase is protective under certain circumstances, particularly early in the course toward malignancy when genetic stabilization is critical..." (M.Fossel, p.111.).
Patents on CoQ10 [Patents] have been applied to immunosenescence [Patents/immunosenescence control in humans].


(12) The Metallic Wastes Extension to The Mitochondrial Theory of Aging [Refs12, Index/Metal Ions, Books, Amazon, LifeExtension]. Deposits of copper and iron in hippocampal mitochondria [Images] eventually stop learning-crucial hippocampal cells, and the unchelated (pron: un-key-lated) metal ions also lead to Alzheimer's, Parkinson's disease, and age-related cognitive decline and dementia [89, 107]. This takes place independently of a caloric-restricted diet [89]. Copper comes primarily from beef (4/3 mg/oz) in the American diet, as does iron (1 mg/oz). Curcumin [Index, Turmeric] in curry powder chelates both iron and copper, as does carnosine [69], which can also chelate toxic heavy metals. R Alpha Lipoic Acid chelates divalent metal ions including iron and copper, and has been shown to reduce iron levels in cortical neurons, while increasing levels of glutathione-related antioxidants. Resveratrol chelates copper only. Quercetin [Index], a relative of resveratrol found in grapes, "neutralizes both iron and copper better than 10 other phytocompounds" [107]. Curcumin from tumeric or curry powder in the diet and the "holy cow" complex for avoiding beef results in reduced rates for Alzheimer's disease in India, and the Japanese preference for raw fish instead of beef has protected their brains from copper and iron, resulting in a lower incidence of dementia in Japanese elderly. Rat brains have been studied in cross section extensively, and exhibit hippocampal mitochondrial damage as a function of food intake of copper and iron independently of anti-aging restricted-calorie diets. Antioxidant protection for mitochondria may be defeated by unchelated metallic ions. Copper aids the spread of cancer [107]. Copper plus ascorbic acid tends to produce DNA damage and telomere shortening, so that it is particularly useful to chelate copper, say with Asp-Ala-His-Lys (DAHK) [Papers] or curcumin. The antioxidant Super Oxide Dismutase (SOD) [52] produced by mitochondrial DNA may be interfered with by lack of metal ion chelation leading to mitochondrial dysfunction. See neurobiological aging, dementia, cognitive decline, and brain deterioration. Otherwise, aluminum can cause neural tangles seen in Alzheimer's disease and the best way to defend against it has recently been identified. By 2009, I see that curcumin is useful in chelating aluminum (Jerry Brainum, Curcumin, Iron Man, Fall 2009, and Sharma, D., et al., (2009), Curcumin counteracts the aluminum-induced aging-related alterations in oxidative stress, Na+, K+, ATPase and Protein Kinase C in adult and old rat brain regions, Biogerontology, 10(4), pp. 489-502). See chelation of aluminum, slow poisons, carcinogens [71] and poisons and aging links.

Detoxification [Links, Images, Papers, Patents, Books, LifeExtension; Index/Metal Ion Chelation]. Detoxification of mercury, antimony, arsenic, and lead takes place via methylation processes that are deteriorated by aging [69s]. However, NAC (N-acetyl-cysteine) can be used to chelate mercury, arsenic, cadmium, and lead. Emergency detoxification is sometimes done with EDTA chelation. EDTA chelation therapy is also applied by anti-aging clinics to improve cell membrane and mitochondrial integrity, salvage heart muscle, to improve LDL cholesterol levels, to remove calcium from atherosclerotic plaque and soft tissues, and to improve bone formation.
Another way to decalcify tissues to oppose arteriosclerosis (hardening of the arteries) and the calcification of artheroscleroic plaque is via vitamin K2, also obtainable from vitamin K, which promotes the expression of osteocalcin that guides calcium from the blood back into the bones, where it belongs. Simultaneous application of Vitamin D3 can help by assisting with bone remineralization.

(13) The Membrane Theory of Aging by Imre Zs.-Nagy at the Verzar International Laboratory for Experimental Gerontology in Debrecen, Hungary, CRC Press, 1994. [Refs13, Links, Images, Papers, Patents, Books, LifeExtension, IAAS Zs.-Nagy articles].

The Membrane Theory of Aging (applies to a typical neuron).
Dr. Imre Zs.-Nagy [Links] developed a model for aging that explained a comprehensive range of aging effects based on a model for the impact of cross-linking processes on proteins in the cell membrane [Books, LifeExtension] that reduce the cell membrane lateral diffusion constant D [Books] as aging proceeds and gradually reduces the membrane permeability PK for potassium [Books], so that potassium levels for K+ inside the cell go up as the cell ages. The permeability of the cell membrane then modifies cellular homeostatic balance to produce aging effects, including cellular dehydration, increased cellular material density, reduced enzyme activity, reduced transcription from DNA, reduced turnover of proteins, and accumulation of protein wastes in the form of lipofuscin. "The MHA (Membrane Hypothesis of Aging) attributes the age-dependent dehydration of the intracellular mass to a life-long free radical-induced cross linking of the cell plasma membrane components, the consequence of which is a gradual decrease of the permeability for the cell membrane to potassium. This results in an increase of the intracellular potassium concentration, a condensation of cell colloids, and a loss of water content of the cells. Increasing intracellular density gradually inhibits all enzymatic processes, including the transcription, translation, and decomposition of damaged compounds, resulting ..." (p.131) in lipofuscin accumulation and other aging effects as shown in the diagram above from Nagy's book The Membrane Hypothesis of Aging. (p.44). Zs.-Nagy shows how to measure the membrane and cellular variables, and explores how OH. radicals cross-link proteins in the cell membrane to cause the decline in potassium permeability. He then shows how the cell membrane permeability to potassium can be restored by treatment with DMAE, Centrophenoxine, or BCE-001 to rejuvenate the cell membrane. BCE-001 works about twice as well as Centrophenoxine, which works somewhat better than DMAE (Dimethylaminoethanol). "The nootropic effects of centrophenoxine (CPH) can be interpreted on the basis of the OH. radical scavenger properties of DMAE incorporated into the phospholipid pool of neuronal membranes in the brain." The centrophenoxine molecule includes a molecule of DMAE. This model is perhaps applied to the aging of non-mitotic cells, in particular to neurons and hepatic liver cells. Zs.-Nagy goes on to show that caloric restriction improves membrane permeability to potassium. Basically, this model gives us an insightful model for cellular aging as a homeostatic feedback mechanism which includes new variables, the membrane permeabilities and lateral membrane diffusion constants, which become new factors to measure in the testing of anti-aging drugs and treatments. In muscle cells, the model is somewhat different, and the permeability to the chlorine ion becomes important. The theory seems to have been developed before the carbonylation of proteins due to glycation was understood in protein cross-linking, and before the role of Advanced Glycation End products was appreciated. It seems likely that Alagebrium (ALT 711 from Alteon), a cross-link breaker, may be important for membrane permeability restoration, as may PTB (N-Phenacyl Thiazolium Bromide), which breaks cross-links a little less effectively than Alagebrium. Perhaps membrane permeabilities are also impacted by glycation as well as by OH. radicals, and other factors such as ubiquinol CoQ10 concentrations may become important points in a more evolved future model for the Membrane Hypothesis of Aging, which provides sophisticated insights into the causal feedback connections between mechanisms in cellular aging, especially in non-mitotic cells not subject to replicative senescence.
The problem of immortalization or life-extension of non-mitotic cells [Links, Papers/immortalization of non-mitotic cells, Papers/life extension of non-mitotic cells, Links/life extension of non-mitotic cells], involving improved antioxidant defenses, better DNA repair, and cell membrane maintenance, is somewhat transverse to the problem of immortalization or life-extension of mitotic cells [Links, Papers, Patents, Books, Books/telomere maintenance], which must be attacked with telomerase activation (7) [81s] and cellular renewal via mitosis, though it involves many of the same problems.
"The most striking general physiochemical alteration of cells is the age-dependent increase of dry mass content, i.e., a decrease in intracellular water content of the cells." Newborns have 23% dry mass content, increasing to 40% in adults, and to 45% in old age. Between 20 and 99, intracellular water content decreased by 0.626% per year. Increases in intracellular ionic strength, especially in postmitotic cells like neurons, causes an age-dependent increase in chromatin and cytoplasm condensation in each cell type. The condensation of chromatin and cytoplasm may be automatically responsible for
1) Increased rate of free-radical induced damage of proteins and other cellular components.
2) Age-dependent decrease in the velocity of transcription and translation.
3) The slowing-down of the machinery of decomposition and replacement of damaged components.
PET studies show up to a 70% drop in glucose comsumption of various brain regions between 20 and 60, and oxygen consumption also drops. Crosslinking reactions between proteins in the cell membrane develops larger protein complexes imbedded in the membrane that lower the ion and water permeability of the cell membrane, which is indicated by the reduced lateral diffusion of cell membrane components in old age. The Zs-Nagy membrane hypothesis of aging was formulated in 1976-1977. Zs-Nagy noted that centrophenoxine for 60 days at 80-100 mg/kg) increases the potassium permeability of the neural membrane, decreases cellular potassium content, and rehydrates the cytoplasm of brain neurons, also increasing mRNA synthesis 80 to 90%. With BCE-001, only 3-5 weeks at 60 mg/kg was required to get the same results. DMAE acts in a similar manner. Zs-Nagy also noted that caloric restriction (CR) caused a 15% increase in the membrane lateral diffusion constant D in rodents.

Other cell membrane aging issues include the decline in phosphatidylcholine in aging cell membranes (from 90% to 10% of the cell membrane composition) and the utility of phosphatidylcholine (lecithin), alpha glycerlyphosphorylcholine (alpha GPC) and phosphatidylserine in restoring aging cell membrane functionality [Papers, Patents, Books].



(14) The Proteasome in Aging [Refs1c/Proteasome, Index/Proteasomes, Links, Images, Papers, Patents, Books, Amazon, Amazon/Proteasome, Wikipedia/Proteasome, LifeExtension/Proteasome, Protein Damage and Maintenance in Aging (Ben Best)]. The proteasome, which digests used-up, ubiquitinated proteins in implementing cellular protein turnover [Index], can be treated with oleuropein [Links, Papers, Patents, Books, Papers/Oleuropein & proteasome] from extra virgin olive oil or olive fruit. Carnosine [LifeExtension, Papers, Patents, Books] helps reverse proteasomal decline [Links, Books/proteasome treatment] and protects proteins from carbonylation that can jam proteasomes. Proteasomes can be clogged by a diet rich in arachidonic acid [Links, Papers, Patents, Books], and are better preserved by caloric restricted diets [Gaczynska M, Osmulski PA, Ward WF, 2001]. There are also indications that the proteasome can be fouled by advanced glycation end products. Carbonylated proteins can interfere with the proteasome. [R.Gonzalez-Dosal, MD Sorensen, B.F.C. Clark, S. Rattan, P. Kristensen, 2006]. "By inhibiting the proteasome, carbonylated proteins could interfere with cell cycle progression and control.... Protein carbonylation thus becomes a potentially terminal condition." - LifeExtension, 2001. Furthermore, there is evidence that the proteasome can be degraded by the lipid oxidation product 4-hydroxy-2-nonenal [B.Friguet, 2002], and degradation of proteasome performance by cell loading with ceroid (lipofuscin originating in alcholic wastes) or lipofuscin has also been demonstrated. It is also known that the glycooxidation product carboxymethyllysine inactivates the 26s proteasome. (See the formation of carboxymethyllysine.) Partial inhibition of proteasomes in young cells can lead to cellular senescence [N Chondrogianni, FLL Stratford, IP Trougakos, B Friguet, AJ Rivett, ES Gonos, 2003]. "We demonstrate that oleuropein, the major constituent of Olea europea leaf extract [Images], extra virgin olive oil and olives, enhances the proteasome activities in vitro stronger than other known chemical activators, possibly through conformational changes of the proteasome. Moreover,continuous treatment of early passage human embryonic fibroblasts with oleuropein decreases the intracellular levels of reactive oxygen species (ROS), reduces the amount of oxidized proteins through increased proteasome-mediated degradation rates and retains proteasome function during replicative senescence. Importantly, oleuropein-treated cultures exhibit a delay in the appearance of senescence morphology and their life span is extended by approximately 15%." - [M Katsiki, N Chondrogianni, I Chinou, AJ Rivett, ES Gonos, 2007]. Note that this partly explains the good results obtained by Jeanne Calment with olive oil as a skin rub and tends to promote extra virgin olive oil as a salad dressing component. [76]. Also see Olive Oil [Links, Books, Amazon, LifeExtension], health benefits, antioxidant hydroxytyrosol [Index, Books], squalene [Books], oleic acid [Books], [76]. See also Testing the garbage accumulation theory of ageing: mitotic activity protects cells from death induced by inhibition of autophagy by Yuri Stroikin, Helge Dalen, Ulf T. Brunk and Alexei Terman, 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 [Images] and garbage usually takes place via lysosomes, proteasomes, and cytosolic proteases, but this is inherently imperfect. Accumulation of lipofuscin [Images] and damaged mitochondria [Images] 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 [4s]. See also Enhancing proteasome activity [Papers, Books]. Note that defective proteasome function is viewed as a causal factor in the cellular degeneration occurring in neurodegenerative disorders [AL Bulteau, B Friguet, 2004], and amyloid beta has been shown to inhibit proteasome activity in Alzheimer's Disease [ S Ohb, HS Honga, E Hwanga, HJ Simb, W Leec, SJ Shina, I Mook-Jung, 2005]. Certainly resveratrol, which prevents accumulation of amyloid beta, could be useful in preserving proteasome function. Note that the failure of proteasomes results in the accumulation of damaged proteins into Lewis bodies [Index, Links, Papers, Patents, Books; Images/Lewy bodies, Wikipedia/Lewy body] often seen in Parkinson's disease, senile dementia, and some forms of Alzheimer's Disease. Lewis body formation (characteristic of Parkinson's Disease) is promoted by insoluble fibrils of alpha synuclein [Images, Papers, Patents, Books]. The expression of alpha synuclein can be blocked with NF-kB inhibitors such as black tea extract, grape seed extract, quercetin, and resveratrol, preventing Parkinson's Disease.



(15) Inflammation and Aging [Index, Links, Images, Papers, Patents, Books].
Inflammation, by raising ROS levels, can result in DNA damage to telomeres, resulting in shortened lifetimes. This can be combatted with anti-inflammatory nutraceuticals and antioxidants. Some inflammation, such as inflammation due to obesity giving rise to high levels of C-reactive protein, is chronic. Chronic inflammation may be associated with shorter lifetimes due to shorter telomeres, as well as with diseases of aging such as arthritis. Furthermore, the inflammatory cytokine and transcription factor NF-kB promotes genes associated with inflammation and coincidentally with cancer proliferation, invasion, angiogenesis, metastasis, and inhibition of apoptosis, so that treatment with NF-kB inhibitors is life-extending and anticancer. Note, however, that NF-kB is a telomerase activator, as is another inflammatory cytokine, TNF-alpha. Both NF-kB and TNF-alpha have reputations as tumor promoters. Both are involved in tissue remodeling and wound healing, TNF-alpha is elevated during exercise, with life-extending effect in short bursts. However, when chronically elevated it is associated, for instance, with Alzheimer's Disease. Old-age diseases featuring inflammation include:
Alzheimer's Disease [Index, Links, Images, Papers, Patents, Books, LEF, Amazon],
Atheroscelerosis [Index, Links, Images, Video, Papers, Patents, Books, LEF, Amazon],
Osteoporosis [Links, Images, Video, Papers, Patents, Books, LEF, Amazon],
Parkinson's Disease [Links, Images, Video, Papers, Patents, Books, LEF, Amazon],
Rheumatoid arthritis [Links, Images, Video, Papers, Patents, Books, LEF, Amazon], and
Ulcerative colitis [Links, Images, Video, Papers, Patents, Books, LEF, Amazon].


(16) Other mechanisms for aging [Refs15]
Racemization
Alternate aging mechanisms include racemization [Links, Links/in life span dating assay, Books/racemization assay, Papers], the spontaneous change from the L-form to the D-form of a molecule [Books], typically aspartic acid [Wikipedia/aspartic acid; Links/racemization and aging, Papers, Patents, Books]. Racemization is used to determine age from an examination of the dentine of teeth or other trapped fractions. For instance, it has been used to determine the life span of the bowhead whale by measurements on the nucleus of the eye. Racemization rates of trapped fractions typically vary between 8 x 10-4 and 2 x 10-3 parts per year between L- and D-symmetric chiral forms or enantiomers of amino acids. How impacting this may be to survival over very long life spans is presently unclear to me, as most living material of interest to life span potential is not in a trapped fraction and may be refreshed, say from stem cells or via a recycling mechanism converting proteins into amino acids such as proteolysis in proteasomes. Many molecules with inappropriate chiral symmetry are not trapped, but eliminated by the body, although some are toxic. [See Mendel Friedman, Chemistry, Nutrition, and Microbiology of D-Amino Acids, 1999; Links]. Note that D-amino acids changed by racemization from L-amino acids in DNA can be removed by DNA repair enzymes. [Links, Books; Papers/Repair of racemization in DNA, Links, Books].

Typical Impact of Smoking & Moderate Diet with Exercise [Index, Links, Images, Video, Papers, Books, LifeExtension; Index/Lung Cancer]. It has been shown [Toru Nyunoya, et.al, 2006] that cigarette smoke induces cellular senescence in lung fibroblasts, and is associated with cancer, heart attack, stroke, and chronic obstructive pulmonary disease (COPD), all major killers of the elderly. Smoking typically shortens life span 10 years. Smoking plus overeating typically lowers life span 13 years. Living a healthy life, by doing frequent exercise, not smoking, drinking in moderation and eating more fruit and vegetables, can increase life span by up to 14 years, according to a study done by Cambridge University. The Surgeon General proclaimed the lethal effects of cigarette smoking in 1964. Smoke is an example of an aerosol inflammogen with particles < 10 microns diameter, other examples of which include fossil fuel smoke, business combustion smoke, agricultural dust, and endotoxins from feces. In 1999, 20% of deaths from vascular disease [Index] were traceable to smoking, and second-hand smoke was also strongly associated with coronary disease [Index] and lung cancer. (Caleb E. Finch, p.126-127.) Smoking causes 80% to 90% of lung cancer cases, and is the primary causative factor in cancers of the oral cavity, pharynx, larynx, esophagus, and other sites in the body. Note that smoking, obesity, and stress all accelerate the rate of telomere shortening. (Maria A. Blasco, 2007).

Infections and the Cumulative Impact of Infections [Links, Images, Video, Papers, Patents, Books, LifeExtension; Links/Bacterial pathogens in human disease (Bacterial infections), Links/Viral pathogens in human disease (viral infections)]. Elimination of live bacteria from the diet increases life spans (excepting special bacteria designed to play the role of intestinal microflora), and cardiovascular mortality [Images] is 2-3 times higher in patients who have been infected with 4 or more pathogens including C. pneumonia, CMV, Epstein Barr Virus, H. Influenza, H.Pyroli, HSV-1, and HSV-2. (Caleb E. Finch, p.119 & 126). Note that infections can wear down the immune system by shrinking telomeres in cells with cell divisions that occur in response to infection, so that lymphocytes may become prematurely senescent and genomically unstable.

Wear and Tear - Dental
Some species, such as the horse, frequently die of hunger after wear and tear on the oral cavity that destroys their teeth. On the other hand, sharks continuously regenerate their teeth, and humans can continuously reconstruct theirs by artificial means, as described in our dental files. The normal wear rate for human dental enamel (the attrition) is less than 29 microns per year, typically about 8 microns/year. Intermittant engineered reconstruction of human teeth will obviously be required for extremely long life spans, so that our longevity strategy includes using a plaque-dissolving antiplaque mouthwash or antiplaque mouthwash prior to thorough brushing and flossing of all tooth surfaces using relatively abrasive anti-tartar Ultrabrite or perhaps Life Extension toothpaste, with another enamel-reconstructing or remineralizing mouthwash featuring sodium fluoride to be applied after the brushing. Remineralizing reconstructive tooth varnishes such as Enamel-Pro are also available. Human saliva [Wikipedia, Links] contains calcium and phosphate ions that remineralize teeth, in addition to enzymes that are antiplaque, antibacterial, and clear the teeth of cariogenic sugars, so at least brush with saliva. Dry mouth is often stated as a cause of dental caries.
Human teeth darken with age [Geriatric Dentistry Links, Images] as their dentin darkens and their enamel thins from attrition [Images]. The darkening is readily correctible with at-home or in-office dental bleaching systems, and is also sometimes corrected with direct resin composite veneers or porcelain veneers.

Solubility Changes in Proteins with Aging [Links, Images, Papers, Patents, Books]
The accumulation of certain proteins that become insoluble with aging may be a general feature of aging. Protein aggregation increases with age, and clumping together of certain cellular proteins is a common feature of a variety of diseases including neurodegenerative conditions such as Parkinson's, Alzheimer's, and Huntington's diseases. This may be due to protein glycation or other processes we have examined, such as lipid peroxidation or protein crosslinking with aging due to hydroxyl radicals. Most crosslinking behind age-related increases in protein aggregation is due to the binding of simple sugars such as glucose to protein in the presence of oxygen, which may be controlled with vitamin B1 and benfotiamine. Note that carnosine increases the unfolding and hydration of glycated protein and that acetyl L-carnitine decreases glycation of lens proteins. Protein crosslinking due to hydroxyl radicals can be treated with centrophenoxine. Glycation is inhibited by the vitamin B6 vitamers, which are converted in the intestine to the actived form PLP (pyridoxal-5'-phosphate), by carnosine, by vitamin C, by alpha lipoic acid, by benfotiamine (found in onions) and by aminoquanodine. See also AGE inhibitors inhibiting advanced glycation end-products. Note that AGEs such as pentosidine produce protein crosslinking.

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"I don't want to achieve immortality through my work... I want to achieve it through not dying." - Woody Allen
"I'm not in favor of aging for the same reason I'm not in favor of leprosy." - Aubrey de Grey (video, video2, video3)
"Apart from CR, exercise and the vital rubbing in of creams and oils, the mainstay of the modern rejuvenation method is: unscrew, shake, swallow, and screw, repeatedly. Thus one is recast in youthful condition." - Jim Green
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Music[2] || Email[2]: JimGreenHimself@gmail.com. Thanks for sending your pointers, insights, and remarks.