X-Message-Number: 30968
Date: Thu, 21 Aug 2008 09:28:48 -0700 (PDT)
From: 
Subject: autophagy dramatically slows aging in mouse liver II

[Could DHA upregulate CMA?]

J Neurosci. 2005 Mar 23;25(12):3032-40.
A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces
amyloid burden in an aged Alzheimer mouse model.
    Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr,
Frautschy SA, Cole GM. Department of Medicine, University of California Los
Angeles, Los Angeles, California 90095, USA.
    Epidemiological studies suggest that increased intake of the omega-3
(n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is
associated with reduced risk of Alzheimer's disease (AD). DHA levels are
lower in serum and brains of AD patients, which could result from low
dietary intake and/or PUFA oxidation. Because effects of DHA on Alzheimer
pathogenesis, particularly on amyloidosis, are unknown, we used the APPsw
(Tg2576) transgenic mouse model to evaluate the impact of dietary DHA on
amyloid precursor protein (APP) processing and amyloid burden. Aged animals
(17-19 months old) were placed in one of three groups until 22.5 months of
age: control (0.09% DHA), low-DHA (0%), or high-DHA (0.6%) chow.
beta-Amyloid (Abeta) ELISA of the detergent-insoluble extract of cortical
homogenates showed that DHA-enriched diets significantly reduced total Abeta
by >70% when compared with low-DHA or control chow diets. Dietary DHA also
decreased Abeta42 levels below those seen with control chow. Image analysis
of brain sections with an antibody against Abeta (amino acids 1-13) revealed
that overall plaque burden was significantly reduced by 40.3%, with the
largest reductions (40-50%) in the hippocampus and parietal cortex. DHA
modulated APP processing by decreasing both alpha- and beta-APP C-terminal
fragment products and full-length APP. BACE1 (beta-secretase activity of the
beta-site APP-cleaving enzyme), ApoE (apolipoprotein E), and transthyretin
gene expression were unchanged with the high-DHA diet. Together, these
results suggest that dietary DHA could be protective against beta-amyloid
production, accumulation, and potential downstream toxicity.
PMID: 15788759

[However medium chain triglycerides are not without the risk of toxicity.]

Rejuvenation Res. 2008 Jun;11(3):631-40.
Ketogenic diets cause opposing changes in synaptic morphology in CA1
hippocampus and dentate gyrus of late-adult rats.
    Balietti M, Giorgetti B, Fattoretti P, Grossi Y, Di Stefano G, Casoli T,
Platano D, Solazzi M, Orlando F, Aicardi G, Bertoni-Freddari C. Neurobiology
of Aging Laboratory, INRCA Research Department, Ancona, Italy.

    Ketogenic diets (KDs) have beneficial effects on several diseases, such
as epilepsy, mitochondriopathies, cancer, and neurodegeneration. However,
little is known about their effects on aging individuals. In the present
study, late-adult (19-month-old) rats were fed for 8 weeks with two medium
chain triglycerides (MCT)-KDs, and the following morphologic parameters
reflecting synaptic plasticity were evaluated in stratum moleculare of
hippocampal CA1 region (SM CA1) and outer molecular layer of hippocampal
dentate gyrus (OML DG): average area (S), numeric density (Nv(s)), and
surface density (Sv) of synapses, and average volume (V), numeric density
(Nv(m)), and volume density (Vv) of synaptic mitochondria. In SM CA1,
MCT-KDs induced the early appearance of the morphologic patterns typical of
old animals (higher S and V, and lower Nv(s) and Nv(m)). On the contrary, in
OML DG, Sv and Vv of MCT-KDs-fed rats were higher (as a result of higher
Nv(s) and Nv(m)) versus controls; these modifications are known to improve
synaptic function and metabolic supply. The opposite effects of MCT-KDs
might reflect the different susceptibility to aging processes: OML DG is
less vulnerable than SM CA1, and the reactivation of ketone bodies uptake
and catabolism might occur more efficiently in this region, allowing the
exploitation of their peculiar metabolic properties. Present findings
provide the first evidence that MCT-KDs may cause opposite morphologic
modifications, being potentially harmful for SM CA1 and potentially
advantageous for OML DG. This implies risks but also promising
potentialities for their therapeutic use during aging.
PMID: 18593281

Acta Med Scand. 1972 Sep;192(3):201-12.
Coagulation defects and atherosclerosis induced in rabbits by a diet
containing medium chain triglyceries (MCT).Malmros H, Nilsson IM, Sternby
NH, Arvidson G, Kockum I.
PMID: 5055266

J Environ Pathol Toxicol Oncol. 1986 Mar-Apr;6(3-4):115-21.
Medium chain triglycerides (MCT) in aging and arteriosclerosis. Kaunitz H.
    Some of the nutritional work with triglycerides consisting mainly of C8
and C10 fatty acids (MCT) lends itself to speculations about their influence
on arteriosclerosis. Arteriosclerosis is thought to be part of the normal
aging process which is due to age associated molecular biological changes.
The lipid theory of arteriosclerosis is rejected. Pertinent studies with MCT
include these observations. Feeding of MCT to rats resulted in animals of
low body weight, small fat deposits and excellent survival rate. This
deserves emphasis because of the beneficial influence of low body weight on
aging and arteriosclerosis. MCT feeding was associated with low linoleate
and low tocopherol requirements in rats. This may lead to reduced formation
of those linoleate derived prostaglandins which favor thrombosis formation.
Lower linoleate requirements may also lead to the presence of fewer
uncontrolled free radicals in the cells. MCT feeding is associated with low
levels of serum and liver cholesterol involving speculations that tissue
conditions are such that an adaptive increase of cholesterol is unnecessary.
The Demographic Yearbook of the United Nations (1978) reported that Sri
Lanka has the lowest death rate from ischemic heart disease. Sri Lanka is
the only of the countries giving reliable data where coconut oil (containing
over 50% medium chain fatty acids) is the main dietary fat.
PMID: 3519928

J Neural Transm. 2008 Jul;115(7):1011-7. Epub 2008 May 14.
Ketogenic diet prevents cardiac arrest-induced cerebral ischemic
neurodegeneration.
    Tai KK, Nguyen N, Pham L, Truong DD. The Parkinson's and Movement
Disorder Research Laboratory, Long Beach Memorial Medical Center, 2625
Pasadena Ave., Long Beach, CA, USA,
    Ketogenic diet (KD) is an effective treatment for intractable
epilepsies. We recently found that KD can prevent seizure and myoclonic jerk
in a rat model of post-hypoxic myoclonus. In the present study, we tested
the hypothesis that KD can prevent the cerebral ischemic neurodegeneration
in this animal model. Rats fed a standard diet or KD for 25 days were being
subjected to mechanically induced cardiac arrest brain ischemia for 8 min 30
s. Nine days after cardiac arrest, frozen rat brains were sectioned for
evaluation of ischemia-induced neurodegeneration using fluoro-jade (FJ)
staining. The FJ positive degenerating neurons were counted manually.
Cardiac arrest-induced cerebral ischemia in rats fed the standard diet
exhibited extensive neurodegeneration in the CA1 region of the hippocampus,
the number of FJ positive neurons was 822 +/- 80 (n = 4). They also showed
signs of neurodegeneration in the Purkinje cells of the cerebellum and in
the thalamic reticular nucleus, the number of FJ positive neurons in the
cerebellum was 55 +/- 27 (n = 4), the number of FJ positive neurons in the
thalamic reticular nucleus was 22 +/- 5 (n = 4). In contrast, rats fed KD
showed no evidence of neurodegeneration, the number of FJ positive neurons
in these areas were zero. The results demonstrate that KD can prevent
cardiac arrest-induced cerebral ischemic neurodegeneration in selected brain
regions.
PMID: 18478178

[Could an unsaturated fat enriched ketogenic diet prove to be a safer means
for upregulating CMA?]

J Clin Endocrinol Metab. 2004 Apr;89(4):1641-5.
Differential metabolic effects of saturated versus polyunsaturated fats in
ketogenic diets.
    Fuehrlein BS, Rutenberg MS, Silver JN, Warren MW, Theriaque DW, Duncan
GE, Stacpoole PW, Brantly ML. Department of Medicine, College of Medicine,
University of Florida, Gainesville, Florida 32610, USA.
    Ketogenic diets (KDs) are used for treatment of refractory epilepsy and
metabolic disorders. The classic saturated fatty acid-enriched (SAT) KD has
a fat:carbohydrate plus protein ratio of 4:1, in which the predominant fats
are saturated. We hypothesized that a polyunsaturated fat-enriched (POLY) KD
would induce a similar degree of ketosis with less detrimental effects on
carbohydrate and lipid metabolism. Twenty healthy adults were randomized to
two different weight-maintaining KDs for 5 d. Diets were 70% fat, 15%
carbohydrate, and 15% protein. The fat contents were 60 or 15% saturated, 15
or 60% polyunsaturated, and 25% monounsaturated for SAT and POLY,
respectively. Changes in serum beta-hydroxybutyrate, insulin sensitivity
(S(I)), and lipid profiles were measured. Mean circulating
beta-hydroxybutyrate levels increased 8.4 mg/dl in the POLY group (P =
0.0004), compared with 3.1 mg/dl in the SAT group (P = 0.07). S(I) increased
significantly in the POLY group (P = 0.02), whereas total and low-density
lipoprotein cholesterol increased significantly in the SAT group (both P =
0.002). These data demonstrate that a short-term POLY KD induces a greater
level of ketosis and improves S(I), without adversely affecting total and
low-density lipoprotein cholesterol, compared with a traditional SAT KD.
Thus, a POLY KD may be superior to a classical SAT KD for chronic
administration.
PMID: 15070924

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