Elsevier

Neurobiology of Aging

Volume 29, Issue 9, September 2008, Pages 1404-1411
Neurobiology of Aging

Creatine improves health and survival of mice

https://doi.org/10.1016/j.neurobiolaging.2007.03.001Get rights and content

Abstract

The supplementation of creatine (Cr) has a marked neuroprotective effect in mouse models of neurodegenerative diseases. This has been assigned to the known bioenergetic, anti-apoptotic, anti-excitotoxic, and anti-oxidant properties of Cr. As aging and neurodegeneration share pathophysiological pathways, we investigated the effect of oral Cr supplementation on aging in 162 aged C57Bl/6J mice. Outcome variables included “healthy” life span, neurobehavioral phenotyping, as well as morphology, biochemistry, and expression profiling from brain. The median healthy life span of Cr-fed mice was 9% higher than in control mice, and they performed significantly better in neurobehavioral tests. In brains of Cr-treated mice, there was a trend towards a reduction of reactive oxygen species and significantly lower accumulation of the “aging pigment” lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data show that Cr improves health and longevity in mice. Cr may be a promising food supplement to promote healthy human aging.

Introduction

The mitochondrial theory of aging implies that reactive oxygen species, mitochondrial DNA (mtDNA) damage, and progressive respiratory chain dysfunction are mutually interacting links in a vicious circle (Harman, 1972, Bender et al., 2006). Although the overexpression of antioxidant enzymes increases life span in several organisms, this is not feasible in humans (Schriner et al., 2005). Food supplemented with various antioxidants on the other hand has so far failed to retard aging in mice (Lee et al., 2004). Creatine (Cr) is a natural ergogenic compound and is widely used by athletes as a food supplement to enhance muscular performance. It also has anti-apoptotic (O’Gorman et al., 1997), anti-excitotoxic (Xu et al., 1996), and directly anti-oxidative properties (Lawler et al., 2002), both in vitro and in vivo. Marked Cr-mediated neuroprotection was found in rodent models of neurodegenerative diseases, in particular Parkinson and Huntington disease (Matthews et al., 1999, Andreassen et al., 2001). Since aging and neurodegeneration share pathophysiological pathways (Beal, 2005), we hypothesized that Cr may also exert an anti-aging effect in wild-type mice. To test this hypothesis, “healthy” life span, neurobehavioral functioning, and aging-associated changes of biomarkers were examined in 162 female wild-type C57BL/6J mice fed a standard rodent diet ad libitum with (n = 81) or without (n = 81) 1% Cr beginning at age of 365 ± 2 days.

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Mice and animal welfare

Inbred C57BL/6J were bred and kept at the GSF animal facilities in isolated ventilated cages type II at a temperature of 20–24 °C, humidity of 50–60%, 20 air exchanges per hour and a 12/12-h light/dark cycle. They were tested for microorganisms in 12-week intervals according to the FELASA Guidelines to the level required for rederived mice (Nicklas et al., 2002). Mice were provided with a standardized mouse diet (1314, Altromin, Germany) and drinking water ad libitum until the age of 12 months.

Cr increases health and lifespan

Cr levels in serum increased in the Cr-fed group after 3 (245.5 ± 184.5 versus 73.5 ± 14.4 μmol/l in Cr- and control mice, respectively; p = 0.003) and after 6 months (385.6 ± 237 versus 84.2 ± 19.1 μmol/l; p = 0.0001) of supplementation as a proof of actual gastrointestinal Cr ingestion and resorption. Mean “healthy” life span (i.e. age at which mice were classified as suffering from disease) was higher in Cr-fed mice (613 ± 84 days) than in their littermates (563 ± 95 days), corresponding to a 9% increase (p < 

Discussion

We have chosen a long-term model of dietary supplementation to examine changes in longevity, neurological function, biomarkers of aging, and gene expression promoted by the common “lifestyle” supplement Cr. Unlike most other life span studies, we have introduced healthy life span as main outcome variable as there is general consent that a gain of healthy lifetime is what is desirable in human aging. Cr increased healthy life span in mice by 9%. This seems rather modest compared to the increased

Acknowledgement

Creatine was kindly provided by SKW Trostberg, Germany. This project was supported by grants 01GR0434, 01GR0430 and 01GS0476 from Germany's National Genome Research Network (Nationales Genom-Forschungs-Netz, NGFN) and by Eumorphia grant No. EU QLG2-CT-2002-00930. Disclosure statement: The authors declare that they have no conflicts of interest relating to this manuscript. Mice husbandry and all animal procedures were in accordance with the Animal Care and Use Regulations of the GSF and with

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