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

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