X-Message-Number: 29424
Date: Sat, 14 Apr 2007 16:17:33 -0700 (PDT)
From:
Subject: engineered negligible senescence Part III
[Glycotoxins are a powerful modulator of survival in rodents.]
Diabetes. 2003 Jun;52(6):1441-8.
Fetal or neonatal low-glycotoxin environment prevents autoimmune diabetes
in NOD mice.
Peppa M, He C, Hattori M, McEvoy R, Zheng F, Vlassara H. Division of
Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai
School of Medicine, Box 1640, New York, NY 10029, USA.
Advanced glycation end products (AGEs) are implicated in beta-cell
oxidant stress. Diet-derived AGE (dAGE) are shown to contribute to
end-organ toxicity attributed to diabetes. To assess the role of dAGE on
type 1 diabetes, NOD mice were exposed to a high-AGE diet (H-AGE) and to
a nutritionally similar diet with approximate fivefold-lower levels of
N(epsilon)-carboxymethyllysine (CML) and methylglyoxal-derivatives
(MG) (L-AGE). Suppression of serum CML and MG in L-AGE-fed mice was
marked by suppression of diabetes (H-AGE mice >94% vs. L-AGE mice 33% in
founder [F](0), 14% in F(1), and 13% in F(2) offspring, P < 0.006) and by
a delay in disease onset (4-month lag). Survival for L-AGE mice was 76
vs. 0% after 44 weeks of H-AGE mice. Reduced insulitis in L-AGE versus
H-AGE mice (P < 0.01) was marked by GAD- and insulin-unresponsive
pancreatic interleukin (IL)-4-positive CD4+ cells
compared with the GAD- and insulin-responsive interferon
(IFN)-gamma-positive T-cells from H-AGE mice (P < 0.005). Splenocytes
from L-AGE mice consisted of GAD- and insulin-responsive IL-10-positive
CD4+ cells compared with the IFN-gamma-positive T-cells from H-AGE mice
(P < 0.005). Therefore, high AGE intake may provide excess antigenic
stimulus for T-cell-mediated diabetes or direct beta-cell injury in NOD
mice; both processes are ameliorated by maternal or neonatal exposure to
L-AGE nutrition.
PMID: 12765955
[One of the reasons I agree with conservative gerontologists that ENS will
probably not be developed in this century, is due to the slow rate that
information filters through to the scientific community. The following
abstract is an excellent case in point, but unfortunately it is not the
only one. The antiaging benefits of feed restriction, that have been
usually (but not always) found, have been consistently, but erroneously
attributed to calorie restriction. The main benefit of feed restriction
in rodents appears to derive from of a reduction in glycotoxins, rather
than calories, as the following abstract shows. This information is
unknown to most researchers in CR, even to the present day. A
good example of this is an eight page review entitled "Calorie restriction
and Aging" in the March 14,2007 edition of Scientific American
Reports: Special Edition on diet and health, which makes no references
at all to glycotoxins. I'm not pointing fingers at any one scientist
here. Rather this is a global problem throughout the entire scientific
community, where it can take decades for advances in knowledge to be
recognized and built upon. The reason for the "slow" rate of scientific
advance, as a whole, derives in part from this same tardy transmission of
information within the scientific community. Why this delay occurs, and
what can be done about it is a large question, which I do not have a
comprehensive answer to. However this is the main reason why the hopes
of life-extensionists are almost certainly to be in vain. Older life
extensionists like Roy Walford (79) have been dieing pretty much on
schedule. I expect this to continue to be the case for some time to
come. If anybody has any idea for facilitating the transmission of new
(as well as old) findings to the gerontology community for consideration,
please speak up! For those who are willing to take a active part in this
proposed endevour, with an investment of their time, or money, please
email me privately.]
(Diabetes Abstract Book, 64th Scientific Session June 4 - June 8, 2004)
Diabetes June 2004 Volume 53 Supplement 2 A343 1426-P
Amelioration of Insulin Resistance, Weight Gain and Markers of Oxidant
Stress in Aging Mice by Dietary Glycotoxin Restriction: A Therapeutic
Alternative to Caloric Restriction?
Weijing Cai, John C. He, Min Lu, Li zhu, Melpomeni Peppa, Helen Vlassara,
New York, NY
Insulin Resistance (IR) and T2D are prevalent in older adults, and
preventable in animals by caloric restriction (CR), which is also known
to extend survival. Dietary AGE restriction prevents diabetic tissue
injury and recent data suggest that it may prevent IR in
db/db(+/+) mice. Herein we asked whether AGE restriction and CR have
similar effects on IR and OS in normal mice. In a 24-mo study, body
weight (BW), fasting glucose:insulin ratio (GIR), serum AGE (sAGE),
glutathone (GSH/GSSG), F8-isoprostanes (8-iso) and 2-ear survival were
assessed in C57BL/6 mice (age: 4 mos, n=20/group) kept on
different diets: Group A) regular ad lib (NIH-31, 323 AGE u/mg
protein); Group B) CR (60% of group A (NIA, 329 AGE u/mg); Group C) Low
in AGE, ad lib (NIH-31, L-AGE; 154 AGE u/mg) and Group D) CR (60% of
A) but high in AGE (H-AGE/CR: 928 AGE u/mg). At 24 mos, the following
data were obtained (Table 1):
Table 1
Groups BW fasting- sAGE 8-iso GSH/ 2y-
(g) GIR (u/ml)(pg/ml)GSSG survival
__________________________________________________________
H/CR D 29 11 60 226 90% 0/22
Regular/Ad-Lib A 38 12 42 103 100% 2/22
Regular/CR B 28 21 23 92 160% 5/22
L/Ad-Lib C 31 20 20 58 207% 9/22
Conclusions: 1. Long-term AGE restriction, like CR, prevents
age-related IR, weight gain, systemic OS and extends survival in mice,
but without compromising nutrient or energy content. 2. CR, without
restriction in glycoxidant content reduces BW, but fails to protect
against IR, AGE burden and OS, leading to reduced survival.
[The Age-Reader can noninvasively measure glycotoxin content of tissues
via skin autofluorescence. Readings have been validated as being
predictive of human mortality in a number of clinical trials. Price for
the Age-Reader is currently about 22,000 Euros. For further references see
http://www.diagnoptics.com/index.php?cat=products&page=publications]
J Am Soc Nephrol. 2005 Dec;16(12):3687-93. Epub 2005 Nov 9.
Skin autofluorescence, a measure of cumulative metabolic stress and
advanced glycation end products, predicts mortality in hemodialysis
patients.
Meerwaldt R, Hartog JW, Graaff R, Huisman RJ, Links TP, den Hollander NC,
Thorpe SR, Baynes JW, Navis G, Gans RO, Smit AJ. Department of Medicine,
University Medical Center Groningen, University of Groningen, Groningen,
The Netherlands.
Tissue advanced glycation end products (AGE) are a measure of
cumulative metabolic stress and trigger cytokines driven inflammatory
reactions. AGE are thought to contribute to the chronic complications of
diabetes and ESRD. Tissue autofluorescence is related to the accumulation
of AGE. Therefore, skin autofluorescence (AF) may provide prognostic
information on mortality in hemodialysis (HD) patients. Skin AF was
measured noninvasively with an AF reader at baseline in 109 HD
patients. Overall and cardiovascular mortality was monitored
prospectively during a period of 3 yr. The AF reader was validated against
AGE contents in skin biopsies from 29 dialysis patients. Forty-two of the
109 (38.5%) HD patients died. Cox regression analysis showed that AF was
an independent predictor of overall and cardiovascular mortality (for
overall mortality odds ratio [OR] 3.9), as were pre-existing
cardiovascular disease (CVD; OR 3.1), C-reactive protein (OR 1.1), and
serum albumin (OR 0.3). Multivariate analysis revealed that 65% of the
variance in AF could be attributed to the independent effects of age,
dialysis and renal failure duration, presence of diabetes, triglycerides
levels, and C-reactive protein. AF was also independently linked to the
presence of CVD at baseline (OR 8.8; P < 0.001). AF correlated with
collagen-linked fluorescence (r = 0.71, P < 0.001), pentosidine (r =
0.75, P < 0.001), and carboxy(m)ethyllysine (both r = 0.45, P <
0.01). Skin AF is a strong and independent predictor of mortality in
ESRD. This supports a role for AGE as a contributor to mortality and CVD
and warrants interventions specifically aimed at AGE accumulation.
PMID: 16280473
[Note that aminoguanidine has failed to extend rodent lifespan in a
number of trials. This is believed to be due to the toxicity of
aminoguanidine itself.]
Eur J Dermatol. 2007 Feb 27;17(1):12-20 [Epub ahead of print]
Collagen glycation triggers the formation of aged skin in vitro.Pageon H,
Bakala H, Monnier VM, Asselineau D.
L'Oreal, Life Sciences, Centre Charles Zviak, 90 rue du General Roguet,
92583 Clichy Cedex France.
Glycation products accumulate during the aging of many slowly renewing
tissues, including skin. We have developed an in vitro model of
chronologic aging of skin based on reconstructed skin modified by
artificially glycating the collagen used to prepare the dermal
compartment. The morphology of the modified skin is close to the
morphology usually observed except that the dermis is altered in its
fibrillar structure. Moreover, the analysis of skin markers revealed
several unexpected biological and morphological modifications, which
reflect in vivo aging and could be related to glycation per se.
These include the activation of fibroblasts, increase of matrix molecules
(collagen type III and collagen type IV) and metalloproteinase production
(MMP1, MMP2 and MMP9), thickening of the basement membrane zone, and more
strikingly, the modification of alpha6 and beta1 integrin patterns
especially in epidermis, in a way closely resembling aged skin in vivo. We
also found that these effects could be related to the production of
putative diffusible factors by the dermal fibroblasts activated by
glycation. Finally, we show that all these effects are likely to be
glycation specific since they could be inhibited by aminoguanidine, a
well-known glycation inhibitor. We conclude that the reconstructed skin
model modified by glycation of the collagen closely mimics chronologic
aging of skin in vivo. Taken together, these results strengthen the
importance of glycation reactions in skin aging.
PMID: 17324821
[Example of deaths in a small vitamin D trial: placebo 2/25, 200 IU 2/26,
400 IU 2/25, 600 IU 1/25, 800 IU 0/23.]
J Am Geriatr Soc. 2007 Feb;55(2):234-9.
A higher dose of vitamin d reduces the risk of falls in nursing home
residents: a randomized, multiple-dose study.Broe KE, Chen TC, Weinberg
J, Bischoff-Ferrari HA, Holick MF, Kiel DP. Institute for Aging Research,
Hebrew SeniorLife, Boston, Massachusetts.
OBJECTIVES: To determine the effect of four vitamin D supplement doses
on falls risk in elderly nursing home residents. DESIGN: Secondary data
analysis of a previously conducted randomized clinical
trial. SETTING: Seven hundred twenty-five-bed long-term care
facility. PARTICIPANTS: One hundred twenty-four nursing home residents
(average age 89). INTERVENTION: Participants were randomly assigned to
receive one of four vitamin D supplement doses (200 IU, 400 IU, 600 IU,
or 800 IU) or placebo daily for 5 months. MEASUREMENTS: Number of fallers
and number of falls assessed using facility incident tracking
database. RESULTS: Over the 5-month study period, the proportion of
participants with falls was 44% in the placebo group (11/25), 58%
(15/26) in the 200 IU group, 60% (15/25) in the 400 IU group, 60%
(15/25) in the 600 IU group, and 20% (5/23) in the 800 IU
group. Participants in the 800 IU group had a 72% lower adjusted-incidence
rate ratio of falls than those taking placebo over the 5 months (rate
ratio=0.28; 95% confidence interval=0.11-0.75). No significant
differences were observed for the adjusted fall rates compared to placebo
in any of the other supplement groups.
CONCLUSION: Nursing home residents in the highest vitamin D group (800
IU) had a lower number of fallers and a lower incidence rate of falls
over 5 months than those taking lower doses. Adequate vitamin D
supplementation in elderly nursing home residents could reduce the number
of falls experienced by this high falls risk group.
PMID: 17302660
Recent Results Cancer Res. 2007;174:225-34.
An estimate of cancer mortality rate reductions in Europe and the US with
1,000 IU of oral vitamin D per day.Grant WB, Garland CF, Gorham
ED. Sunlight, Nutrition and Health Research Center, San Francisco, CA
94109-2510, USA.
Solar ultraviolet B (UVB) irradiance and/or vitamin D have been found
inversely correlated with incidence, mortality, and/or survival rates for
breast, colorectal, ovarian, and prostate cancer and Hodgkin's and
non-Hodgkin's lymphoma. Evidence is emerging that more than 17 different
types of cancer are likely to be vitamin D-sensitive. A recent
meta-analysis concluded that 1,000 IU of oral vitamin D per day is
associated with a 50% reduction in colorectal cancer incidence. Using
this value, as well as the findings in a multifactorial ecologic study of
cancer mortality rates in the US, estimates for reductions in risk of
vitamin D-sensitive cancer mortality rates were made for 1,000
IU/day. These estimates, along with annual average serum
25-hydroxyvitamin D levels, were used to estimate the reduction in cancer
mortality rates in several Western European and North American
countries that would result from intake of 1,000 IU/day of vitamin D. It
was estimated that reductions could be 7% for males and 9% for females in
the US and 14% for males and 20% for females in Western European
countries below 59 degrees. It is proposed that increased fortification
of food and increased availability of supplements could help increase
vitamin D intake and could augment small increases in production of
vitamin D from solar UVB irradiance. Providing 1,000 IU of vitamin D per
day for all adult Americans would cost about $1 billion; the expected
benefits for cancer would be in the range of $16-25 billion in addition to
other health benefits of vitamin D.
PMID: 17302200
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