X-Message-Number: 24162 From: "michaelprice" <> References: <> Subject: Re: Mitochondrial theory of ageing on test Date: Sat, 29 May 2004 01:37:17 +0100 Hi Simon, there are things we can do to slow mitochrondrial decline: Mitochondrial Dysfunction Our cells have two centres of DNA, the nucleus and the mitochondria. Mitochondrial DNA may be more important to aging than nuclear DNA[46, 123e] Mitochondria are sub-cellular organelles possessed by all nucleated cells. The mitochondria multiply independently of their host cell and possess their own DNA. Once upon a time, perhaps a billion or so years ago, the mitochondrial ancestors were independent free-swimming organisms that evolved the unique ability to process oxygen to generate bio-energy, which we call respiration. Some of them formed a productive symbiotic relationship with other cellular life, where, today, the mitochondria act as powerhouses to their hosts. The extra energy available to these symbiotics enabled them to go on to form all the complex multicellular organisms, such as animals, plants and fungi. (The ancestor of all plants subsequently acquired chloroplasts for photosynthesis, in a similar fashion.) Unfortunately respiration with oxygen also produces free-radicals (or, in this context, reactive oxygen species or ROS), which are harmful. As we age our mitochondrial DNA degrades, presumably due to ROS-induced damage, and the efficiency of the mitochondria decline. Experiments with fruitflies have shown that longevity is transmitted by the mitochondrial DNA (which is inherited maternally) and correlates negatively with ROS production[46]. Transport of the respiratory substrates into the mitochondria requires the enzymes carnitine acyltransferase I & II, and co-enzyme A from B5 (pantothenate)). Feeding old rats with diets rich in carnitine and/or alpha-lipoic acid (both enzymic cofactor pre-cursors) reversed many aspects of age-related mitochondrial decline[37a, 37b, 37e], including lowering ROS production[37c]; early lifespan results are encouraging [37e]. The benefits of carnitine may synergise with biotin[37d]. The reduced form for alpha lipoic acid, DHLA, is a cofactor for MSRA, which has extended lifespan in fruit flies. Mitochondrial DNA shares with nuclear DNA the same base excision repair (BER) pathways.123 If mitochondrial DNA BER has the same dependency on PARP and NAD as the nuclear DNA BER then B3 (nicotinamide) should help protect mitochondrial DNA in a similar fashion to nuclear DNA. This might explain why feeding fruitflies B3 (nicotinamide) lowered ROS production and extended their lifespans4 and, in humans, has lowered long-term mortality.[27g] Dietary B4 (choline), supplied as lecithin (phosphatidylcholine), to rats, protects some mitochondrial DNA from age-related degradation.[125] Many other coenzymes are involved in mitochondrial metabolism. Summary: Carnitine, vitamins B3 (niacin), B4 (choline), B5 (pantothenate) and alpha-lipoic acid are effective at maintaining or even rejuvenating mitochondrial function. Terms: NAD+/NADP+/NADH/NADPH - the active coenzyme forms of vitamin B3, derived from dietary niacin. Niacin - Can mean any of the forms of vitamin B3 , such as niacinamide, NAD+, NADP+, nicotinic acid. Its carboxylic acid analogue is nicotinic acid, which is its usual dietary supplemented form. Niacinamide - also known as nicotinamide. Converted into the co-enzyme forms, NAD+ etc via nicotinic acid. PARP - poly(ADP-ribose) polymerase. An enzyme involved in the generalised excision-repair pathway, critical for repairing DNA damage. References: [27a] Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Lin SJ, Defossez PA, Guarente L in Science 2000 Sep 22;289(5487):2126-2128 PMID: 11000115 [27b] Manipulation of a Nuclear NAD+ Salvage Pathway Delays Aging without Altering Steady-state NAD+ Levels. Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Cohen H, Lin SS, Manchester JK, Gordon JI, Sinclair DA in J Biol Chem 2002 May 24;277(21):18881-90. PMID: 11884393 [27c] Oral Niacin Prevents Photocarcinogenesis and Photoimmunosuppression in mice. Gensler HL, Williams T, Huang AC, Jacobson EL in Nutrition and Cancer 34(1) (1999), pg 36-41. PMID: 10453439 The relationship between dietary intake of niacin and tissue NAD elevation is detailed in the main body of the article. The UV-irradiated mice on a diet with 0.003%, 0.1%, 0.5% & 1.0% niacin had a 0.72, 0.60, 0.48 & 0.40 tumours/mouse, respectively; a 44% reduction. The authors hypothesize that the cancer-protective effect is mediated by NAD-induced PARP activity. [27d] Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis. Jacobson EL, Shieh WM, Huang AC in Mol Cell Biochem 1999 Mar;193(1-2):69-74 PMID: 10331640 NAD is elevated by niacin in many human tissues. [27e] Evaluating the role of niacin in human carcinogenesis. Jacobson EL, Dame AJ, Pyrek JS, Jacobson MK. Biochimie 1995;77(5):394-8 PMID: 8527495 "NAD content varies by as much as 12-fold within a [human] population and can be modulated readily by supplementation [with niacin]" [27f] Protective effect of nicotinamide on bracken fern induced carcinogenicity in rats. Pamukcu AM, Milli U, Bryan GT in Nutr Cancer 1981;3(2):86-93 PMID: 6213941 0.5% nicotinamide in diet cut the induced cancer rate by 40% [27g] Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W in J Am Coll Cardiol 1986 Dec;8(6):1245-55 PMID: 3782631 "With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004)." [27h] Pharmacological intakes of niacin increase bone marrow poly(ADP-ribose) and the latency of ethylnitrosourea-induced carcinogenesis in rats. Boyonoski AC, Spronck JC, Jacobs RM, Shah GM, Poirier GG, Kirkland JB in J Nutr 2002 Jan;132(1):115-20 PMID: 11773517 "This study was designed to test the effects of supplementing an already high quality diet with pharmacologic levels of niacin. [...] Supplementation with NA or Nam at 4.0 g/kg diet (combined analysis) increased the latency of the ENU-induced morbidity curve, relative to niacin-adequate controls. Morbidity could be attributed in almost all cases to some form of neoplasm, with leukemias the predominant form. In short-term studies, supplementation with either NA or Nam caused dramatic increases in bone marrow NAD(+) (1- to 1.5-fold), basal poly(ADP-ribose) (3- to 5-fold) and ENU-induced poly(ADP-ribose) levels (1.5-fold). These data show that supplementation of a niacin-adequate, high quality diet with pharmacologic levels of nicotinic acid or nicotinamide increases NAD(+) and poly(ADP-ribose) levels in bone marrow and may be protective against DNA damage." [37a] Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L- carnitine and/or R-alpha -lipoic acid. Liu J, Killilea DW, Ames BN in Proc Natl Acad Sci U S A 2002 Feb 19;99(4):1876-81 PMID: 11854488 [37b] Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN in Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2356-61. PMID: 11854529 "Dietary administration of ALCAR and/or LA significantly reduced the extent of oxidized RNA, the combination being the most effective. Electron microscopic studies in the hippocampus showed that ALCAR and/or LA reversed age-associated mitochondrial structural decay." [37c] Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN in Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1870-5. PMID: 11854487 "Feeding ALCAR in combination with LA increased metabolism and lowered oxidative stress more than either compound alone." [37d] Acylcarnitine profile in tissues and body fluids of biotin-deficient rats with and without L-carnitine supplementation. Shigematsu Y, Bykov IL, Liu YY, Nakai A, Kikawa Y, Sudo M, Fujioka M in J Inherit Metab Dis 1994;17(6):678-90 PMID: 7707691 [37e] Acetyl-1-carnitine. 1: Effects on mortality, pathology and sensory-motor performance in aging rats. Markowska AL, Ingram DK, Barnes CA, Spangler EL, Lemken VJ, Kametani H, Yee W, Olton DS in Neurobiol Aging 1990 Sep-Oct;11(5):491-8 PMID: 2234279 "AC decreased mortality, and had no reliable effect on body weight, fluid intake, or the general health of the rats. These data indicate that a chronic dose of AC does not interfere with food and water intake, and may increase longevity." [46] Cytoplasmic genomes that confer additional longevity in Drosophila melanogaster. Driver C, Tawadros N in Biogerontology 2000;1(3):255-60 PMID: 11707902 [123a] Mitochondrial DNA repair of oxidative damage in mammalian cells. Bohr VA, Stevnsner T, de Souza-Pinto NC in Gene 2002 Mar 6;286(1):127-34 PMID: 11943468 "Most of these small base modifications are repaired by the base excision repair (BER) pathway. Despite the initial concept that mitochondria lack DNA repair, experimental evidences now show that mitochondria are very proficient in BER of oxidative DNA damage, and proteins necessary for this pathway have been isolated from mammalian mitochondria. Here, we examine the BER pathway with an emphasis on mtDNA repair." [123b] Mitochondrial DNA repair pathways. Bohr VA, Anson RM in J Bioenerg Biomembr 1999 Aug;31(4):391-8 PMID: 10665528 "Mitochondrial DNA does not code for any DNA repair proteins, but it has been observed that a number of repair factors can be found in mitochondrial extracts. Most of these participate in the base excision DNA repair pathway which is responsible for the removal of simple lesions in DNA. Recent work has shown that there is efficient base excision repair in mammalian mitochondria and there are also indications of the presence of more complex repair processes." [123c] Age-dependent decline of DNA repair activity for oxidative lesions in rat brain mitochondria. Chen D, Cao G, Hastings T, Feng Y, Pei W, O'Horo C, Chen J in J Neurochem 2002 Jun;81(6):1273-84 PMID: 12068075 "Mitochondrial BER activity showed marked age-dependent[80%] declines in the brain. [.] These results strongly suggest that the decline in BER activity may be an important mechanism contributing to the age-dependent accumulation of oxidative DNA lesions in brain mitochondria." [123d] Base excision repair in nuclear and mitochondrial DNA. Dianov GL, Souza-Pinto N, Nyaga SG, Thybo T, Stevnsner T, Bohr VA in Prog Nucleic Acid Res Mol Biol 2001;68:285-97 PMID: 11554304 [123e] Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells(1,2). Bohr VA in Free Radic Biol Med 2002 May 1;32(9):804-12 PMID: 11978482 "Exposure to exogenous and endogenous sources cause oxidative damage to cellular macromolecules, including DNA. This results in gradual accumulation of oxidative DNA base lesions, and in order to maintain genomic stability we must have effective systems to repair this kind of damage. The accumulation of lesions is most dramatic in the mitochondrial DNA, and this may cause dysfunction and loss of cellular energy production. Base excision DNA repair (BER) is the major pathway that removes oxidative DNA base lesions, and while we know much about its mechanism in the nuclear DNA, little is yet known about this pathway in mitochondria. While nuclear BER decreases with age, the mitochondrial DNA repair may increase with age. This increase is not enough to prevent the gradual accumulation of lesions in the mitochondrial DNA with age. Accumulation of DNA lesions with age may be the underlying cause for age-associated diseases including cancer." [125] Influence of lecithin on mitochondrial DNA and age-related hearing loss. Seidman MD, Khan MJ, Tang WX, Quirk WS in Otolaryngol Head Neck Surg 2002 Sep;127(3):138-44 PMID: 12297801 "Lecithin is a polyunsaturated phosphatidylcholine (PPC), which are high energy functional and structural elements of all biologic membranes. PPC play a rate-limiting role in the activation of numerous membrane-located enzymes, [..]Flow cytometry revealed significantly higher mitochondrial membrane potentials in the treated subjects, suggesting preserved mitochondrial function. Finally, the common aging mitochondrial DNA deletion (mtDNA(4834)) were amplified from brain and cochlear tissue including stria vascularis and auditory nerve. This specific deletion was found significantly less frequent in all tissues in the treated group compared with the controls. CONCLUSION: These experiments support our hypothesis and provide evidence that lecithin may preserve cochlear mitochondrial function and protect hearing loss associated with aging." for context see http://mcp.longevity-report.com Cheers, Michael C Price http://mcp.longevity-report.com http://www.hedweb.com/manworld.htm Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=24162