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Glycine supplementation extends lifespan of male and female mice

methionine glycine lifespan

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#1 Engadin

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Posted 31 March 2019 - 10:14 PM


Abstract

Diets low in methionine extend lifespan of rodents, though through unknown mechanisms. Glycine can mitigate methionine toxicity, and a small prior study has suggested that supplemental glycine could extend lifespan of Fischer 344 rats. We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program. Elevated glycine led to a small (4%–6%) but statistically significant lifespan increase, as well as an increase in maximum lifespan, in both males (p = 0.002) and females (p < 0.001). Pooling across sex, glycine increased lifespan at each of the three independent sites, with significance at p = 0.01, 0.053, and 0.03, respectively. Glycine‐supplemented females were lighter than controls, but there was no effect on weight in males. End‐of‐life necropsies suggested that glycine‐treated mice were less likely than controls to die of pulmonary adenocarcinoma (p = 0.03). Of the 40 varieties of incidental pathology evaluated in these mice, none were increased to a significant degree by the glycine‐supplemented diet. In parallel analyses of the same cohort, we found no benefits from TM5441 (an inhibitor of PAI‐1, the primary inhibitor of tissue and urokinase plasminogen activators), inulin (a source of soluble fiber), or aspirin at either of two doses. Our glycine results strengthen the idea that modulation of dietary amino acid levels can increase healthy lifespan in mice, and provide a foundation for further investigation of dietary effects on aging and late‐life diseases.

 
INTRODUCTION

 

Experiments to find drugs or nutritional supplements that can extend healthy lifespan in mice have four main goals. First, they provide new models for testing the idea that interventions can retard multiple aspects of age‐dependent decline, including lethal illnesses and changes that impair health but seldom lead to death. Second, they give specific biochemical and physiological clues as to the nature of processes that regulate the pace of age‐dependent decline in multiple systems. Lifespan extension and health preservation in rapamycin‐treated mice, for example, have prompted valuable studies into the role of mTOR, the target of rapamycin, in normal mice and in mice with unusual susceptibility to organ‐specific illnesses (Harrison et al., 2009; Miller et al., 2014; Wilkinson et al., 2012). Third, they help guide the search for additional interventions with potential beneficial effects. Beneficial effects of acarbose, which inhibits postprandial glucose spikes, can, for example, motivate new studies of drugs that also modulate glucose transients. Lastly, data on longevity and health outcomes in mice can serve to guide and inspire parallel searches for interventions that might, hypothetically, postpone multiple aspects of age‐related decline in humans.

 

The NIA Interventions Testing Program (ITP) has to date reported on four drugs with consistent major effects on mouse lifespan in one or both sexes and found evidence for significant but less dramatic effect of four other drugs. Rapamycin, started at 9 months of age, was found to increase median lifespan by as much as 26% in females and 23% in males, and to retard many aspects of age‐related pathological change (Harrison et al., 2009; Miller et al., 2014). Surprisingly, similarly strong lifespan effects were seen even in mice not given rapamycin until 20 months of age (Harrison et al., 2009). Acarbose can lead to an increase of 22% in median lifespan in male mice, and to a significant, but smaller, 5% increase in female mice (Harrison, 2014; Strong, 2016). Both rapamycin and acarbose improve longevity in the oldest age‐groups, as indicated by a statistical test that compares the proportion of control and drug‐treated mice surviving to the 90th percentile age of the joint distribution, the Wang/Allison test (Wang, Li, Redden, Weindruch, & Allison, 2004). Acarbose produces significant longevity increases, including survival to the 90th percentile, in both sexes, when started as late as 16 months of age (Strong, 2016). A third drug, 17‐α‐estradiol (17aE2), a nonfeminizing congener of the well‐known estrogen 17‐β‐estradiol, increases lifespan of male mice by 19% (Harrison, 2014; Strong, 2016) and has a significant effect on survival to the 90th percentile age, but has no significant effect on female mice. Male mice given 17aE2 live significantly longer than female mice whether or not the females have been exposed to 17aE2. Lastly, NDGA (nordihydroguaiaretic acid) has been shown to increase lifespan of male mice only, with an increase of 12% in median in two independent experimental groups (Strong, 2016; Strong et al., 2008), without a significant effect in female mice. Nordihydroguaiaretic acid, at the doses used, did not lead to significant changes in survival to the 90th percentile age.

 

Of the other agents tested so far by the ITP, four (methylene blue, aspirin, Protandim, and green tea extract [GTE]) provided some evidence for possible health benefits. Methylene blue (Harrison, 2014) led to a significant (p = 0.004) increase in maximum lifespan that was limited to females and was not accompanied by alteration in median. Aspirin produced an 8% increase in median lifespan (p = 0.01) that was seen only in male mice, with no significant change in maximal lifespan by the Wang/Allison test (Strong et al., 2008). Protandim, an inducer of the stress‐resistance factor Nrf2, led to a 7% increase in median lifespan in male mice (Strong, 2016), but there was no effect in females, no effect on maximum lifespan in either sex, and a dramatic site‐to‐site variance, with strong lifespan effects seen only at the University of Texas Health Science Center at San Antonio (UT) but not at the Jackson Laboratory (TJL) or University of Michigan (UM) sites. Green tea extract (Strong et al., 2013) did not show a significant effect by our standard analyses in either sex, but may have conferred some benefit, in females, against early and mid‐life deaths (p = 0.03 by Wilcoxon–Breslow test, which gives greater weight to early than to later deaths).

 

Diets low in the amino acid methionine have been shown to extend median and maximum lifespan in rats (Orentreich, 1993; Richie et al., 1994; Zimmerman, 2003) and in mice (Brown‐Borg et al., 2014; Miller et al., 2005; Sun, 2009), although it is not yet clearly established if diets deficient in other single amino acids might also lead to similar benefits. As a practical matter, interventions that involve supplementation of specific nutrients would be easier to test, in humans or mice, than diets that require depletion of specific compounds. Glycine plays a special role in methionine metabolism, serving as the only acceptor for methyl groups, through action of glycine‐N‐methyl transferase (GNMT), the key enzyme in the only pathway for methionine clearance in mammals (Luka, Mudd, & Wagner, 2009). Methionine toxicity can be blocked by dietary glycine (Luka et al., 2009), consistent with the notion that GNMT is the principal effector of methionine clearance, at least at toxic levels. These data suggest that excess dietary glycine might depress methionine levels and thus mimic some of the benefits of a low methionine diet. Glycine‐supplemented diets have been reported to produce anticancer and anti‐inflammatory effects in rodents (Alarcon‐Aguilar, 2008; Wang et al., 2013; Zhong et al., 2003) and to provide benefits in humans with type II diabetes during a 3‐month trial (Cruz, 2008). A small study using glycine supplementation in Fisher 344 rats showed significant lifespan extension at levels of 8%, 12%, and 20% (Brind, 2011), although the higher glycine levels led to weight loss compared to control rats. Maximum lifespan, evaluated by the Wang/Allison method, was significantly increased (p = 0.03) only at the 8% supplementation level. In this earlier experiment, glycine treatment did not elevate plasma methionine levels, suggesting that the effect was not due to minimizing methionine toxicity, but to some other, unknown, mechanism.

 

We have now conducted a lifespan trial of glycine supplementation in a large group of genetically heterogeneous male and female mice, and report here that 8% glycine leads to significant increases in longevity in both sexes and at each of three independent test sites. In the same annual cohort, we found no alteration of lifespan in mice treated with aspirin (60 or 200 ppm), inulin (600 ppm), or TM5441 (an inhibitor of plasminogen activator inhibitor 1; used at 60 ppm.).

 

 

Finish your reading here: https://onlinelibrar...1111/acel.12953

 


Edited by Engadin, 31 March 2019 - 10:16 PM.

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