X-Message-Number: 28711 Date: Sun, 3 Dec 2006 12:06:18 -0800 (PST) From: Subject: glycotoxin restriction extends rodent lifespan [Feed restriction has extended lifespan in a wide variety of short lived animal species. It had been assumed that the toxic effect of ad-libitum feed consumption was due to excess calories. In the last several years this assumption has been proven to be false. In nematodes, the benefit of feed restriction is now ascribed to the restriction of coenzyme Q. In drosophila, the benefit of feed restriction has been ascribed to protein restriction. In mice, the benefit of feed restriction has been ascribed to glycotoxin restriction. Over the years there have been a number of failures in CR studies, where lifespan was not extended. These can be explained, in the case of rodents, by a failure to control for glycotoxin intake.] [Glycotoxin content of rodent chow can be increased by roasting it at high temperatures during sterilization. Rodents are adapted to consuming only raw food in the wild, and they may be more vulnerable than humans to the deletarious effects of Advanced Glycation End-products. Below serum AGE levels closely predicted two year survival. Calorie intake by itself was without effect. Note that glycotoxins are believed themselves to affect body weight by influencing water retention.] 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? 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. [Coenzyme Q10 is nontoxic in nematodes. It is dietary coenzyme Q8 which reduces their lifespan.] Science. 2002 Jan 4;295(5552):120-3. Extension of life-span in Caenorhabditis elegans by a diet lacking coenzyme Q. The isoprenylated benzoquinone coenzyme Q is a redox-active lipid essential for electron transport in aerobic respiration. Here, we show that withdrawal of coenzyme Q (Q) from the diet of wild-type nematodes extends adult life-span by approximately 60%. The longevity of clk-1, daf-2, daf-12, and daf-16 mutants is also extended by a Q-less diet. These results establish the importance of Q in life-span determination. The findings suggest that Q and the daf-2 pathway intersect at the mitochondria and imply that a concerted production coupled with enhanced scavenging of reactive oxygen species contributes to the substantial life-span extension. Mech Ageing Dev. 2006 Jul;127(7):643-6. Epub 2006 Apr 17. Restriction of amino acids extends lifespan in Drosophila melanogaster. Dietary restriction extends adult Drosophila melanogaster life span when the concentration of dietary yeast is diluted in a media with abundant carbohydrates. Here we vary the concentration of casein as a source of amino acids in adult diet to uncover a quality of nutrient yeast responsible for longevity control. Longevity is maximized upon diet with intermediary levels of casein. Differences in survival are not caused by elevated age-independent mortality; the longevity maximum at intermediate casein does not arise because casein is non-specifically harmful at higher concentrations. Furthermore, fecundity increases when the level of dietary casein is elevated. The demographic phenotypes of adult Drosophila maintained on intermediate levels of casein resemble their response to limited dietary yeast. Dietary restriction through dilution of yeast may extend longevity because this limits the intake of amino acids. [Here's are some examples of failures in a CR experiments.] Aging (Milano). 1995 Apr;7(2):136-9. Is late-life caloric restriction beneficial? Caloric restriction initiated in young mice and rats results in increases in mean and median life span. When caloric restriction is implemented in older animals, an increase in life span is still observed; however, the magnitude of the increase is not as great as that observed in animals calorie restricted since they were young. Here we report the results of a pilot study in which caloric restriction was initiated in mature, older rats. Survival rates and terminal pathology were characterized and compared between a cohort of 17 continually ad libitum fed Long Evans rats and a cohort of 18 Long Evans rats, which were gradually introduced to 33% restriction in diet consumption at 18 months of age. No difference in the median life span was observed between the two groups. The data suggest there may be a level of maturity, or a stage in the aging process, after which caloric restriction no longer increases longevity. Exp Gerontol. 1980;15(4):237-58. Survival and disease patterns in C57BL/6J mice subjected to undernutrition. Cheney KE, Liu RK, Smith GS, Leung RE, Mickey MR, Walford RL. [One can avoid excessive AGEs in food by avoiding food that has been processed at high temperatures. Example: Boiled oatmeal is low in AGEs, while "Fiber 1" bran cereal is high in AGEs since "Fiber 1" is extruded at a higher temperature. In general, steam, or boil instead of fry, or broil. However it must be added that humans are not rodents, and may not benefit much from dietary AGE reduction.] [Can one reduce serum AGEs by means other than diet? Yes, activated carbon can absorb AGEs, and this has increased lifespan in rodents. In Japan a prescription activated carbon product has been used for years in the treatment of kidney failure patients. However the primary dietary toxin specific for humans which is scavenged by this product may have another source.] Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=28711