Carnitine metabolism in relation to physical performance and cognition in aging

Chapter 1 provides background on the role of carnitine in energy regulation, on aging and frailty, on how carnitine may be related to frailty, on the role of carnitine in cognition and which tools are used to measure mild cognitive impairment.Chapter 2 describes a detailed phylogenetic analysis of the carnitine/choline acyltransferase family to better understand the origin, evolution and function of this physiologically important gene family. Although CPT1 and CPT2 must have co-evolved to establish carnitine shuttling, CPT1 and CPT2 are the most distantly related carnitine transferases. The genes encoding these enzymes split early in evolution, during which a switch occurred in the location of the encoded proteins. Furthermore, we found that choline acetyltransferase is closely related to carnitine acetyltransferase and shows lower evolutionary rates than long chain acyltransferases. The gene encoding CPT1 duplicated several times during evolution, resulting in the isoforms CPT1A, CPT1B and CPT1C. CPT1C is the brain specific isoform that resulted from positive and/or relaxed selection in the mammalian lineage.In Chapter 3 intramuscular (acyl)carnitine profiles were studied in fit and (pre-)frail males and females, with young males and females serving as healthy controls. We hypothesized that muscle acylcarnitine status is associated with (pre-)frailty, diminished physical performance and altered mitochondrial function. A cross-sectional study was performed in well age‑matched fit (n = 15) and (pre-)frail (n = 13) old males as well as in fit (n = 15) and (pre‑)frail (n = 11) old females, using healthy young males (n = 13) and females (n = 13) as controls. In the elderly, frailty was assessed according to the Fried criteria and physical performance was determined by a 400m walk test, short physical performance battery and handgrip strength. Liquid chromatography-tandem mass spectrometry was used to assess acylcarnitine status in muscle biopsies and blood plasma. In addition, mitochondrial gene expression was analysed by RNA sequencing. We found that intramuscular total carnitine levels and short chain acylcarnitine levels were lower in (pre-)frail old females compared to fit old females and young females, whereas we found no differences in males. The age of the fit and (pre-)frail subjects was highly matched, which excludes age as an explanatory variable. The intramuscular short chain acylcarnitine levels were associated with low physical function in females, even after correction for muscle mass (%), whereas in males no such association was found. The decline in short chain acylcarnitine levels in (pre‑)frail old females was accompanied by low expression of genes involved in mitochondrial energy production and mitochondrial functionality. We concluded that in (pre-)frail old females, intramuscular total carnitine levels and short chain acylcarnitine levels are decreased and this decrease is accompanied by reduced physical performance and low expression of a wide range of genes involved in mitochondrial function. The mitochondrial gene expression changes that were found suggest that the observed decrease in muscle short chain acylcarnitine status in (pre‑)frail females may be a consequence rather than a cause of mitochondrial dysfunction.Carnitine metabolism is also important for brain function. Therefore, we investigated in chapter 4 a newly developed cognitive test, the MemTrax test, and compared it to the Montreal Cognitive Assessment (MoCA) tool, which is a commonly used tool to screen for mild cognitive impairment. We evaluated the performance of a computerized memory test (MemTrax), which is an adaptation of a continuous recognition task. Two outcome measures are generated from the MemTrax test: MemTraxspeed and MemTraxcorrect. Subjects (≥ 75 years) were administered the MoCA and the MemTrax test. Based on the results of the MoCA, subjects were divided in two groups of cognitive status; normal cognition (n = 45) and mild cognitive impairment (n = 37). Mean MemTrax scores were significantly lower in the mild cognitive impairment than in the normal cognition group. All MemTrax outcome variables were positively associated with the MoCA. Two methods, computing the average MemTrax score and linear regression, were used to estimate the cutoff values of the MemTrax test to detect mild cognitive impairment. These methods showed that for the outcome MemTraxspeed a score below the range of 0.87 – 91 s-1 is an indication of mild cognitive impairment, and for the outcome MemTraxcorrect a score below the range of 85 – 90% is an indication for mild cognitive impairment. For future research we suggest to study the MemTrax test in a larger and more clearly defined population to establish MemTrax as screening tool for mild cognitive impairment. Subsequently, in Chapter 5, we studied whether cognitive impairment is an early feature in the development of frailty. In addition, we studied whether carnitine metabolism may also provide a possible predictive role in the frailty associated cognitive decline. We included 15 fit and 13 pre-frail old males and 15 fit and 11 pre-frail old females for the analysis. Cognitive function was assessed by using both the cognitive tests MoCA and MemTrax. We used (acyl)carnitine data from blood plasma. Besides we measured inflammatory markers in blood. We found that cognitive function was modestly declined in pre-frail males and females. Physical function was positively correlated with cognitive function in males, but not in females. The medium chain acylcarnitines C8 and C10 were lower in pre-frail males compared to fit males. In females, free carnitine levels were higher in pre‑frail females compared to fit females. No correlations were found between plasma acylcarnitines or inflammatory markers and cognitive function. We concluded that pre-frail males and females have a modest cognitive decline. In males, physical function was positively associated with cognitive decline, but no associations were found with acylcarnitines suggesting that carnitine has no direct determining role in cognitive decline.In chapter 6 the main findings of this thesis are discussed and the conclusions presented. Furthermore, some topics were explored more deeply; the brain isoform CPT1C, sex dependent differences in aging research, mitochondria in aging and MemTrax as a cognitive test for clinical research. In addition, it has been studied if peripheral blood mononuclear cells can be used as a biomarker for intramuscular carnitine status and the design of a follow-up carnitine supplementation study is presented.

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