Benefits of Caloric Restriction on Brain Aging and Related Pathological States: Understanding Mechanisms to Devise Novel Therapies

Department of Biology, University of Bologna, Italy.
Current Medicinal Chemistry (Impact Factor: 3.85). 02/2009; 16(3):350-61. DOI: 10.2174/092986709787002637
Source: PubMed


Long term caloric restriction is known to counteract aging and extend lifespan in several organisms from yeasts to mammals. Recent research has provided solid ground to the concept that limiting calorie intake slows down brain aging and protects from age-related neurodegenerative diseases. The present review summarizes the most relevant among these data and highlights some genetic and molecular mechanisms responsible for caloric restriction-related neuroprotection. To understand these mechanisms is important because this information makes them potential targets for therapeutic intervention aimed at reproducing the metabolic, genetic and molecular features responsible for the beneficial effect of caloric restriction. Most promising among these targets are neurotrophins, such as BDNF, transcription factors, such as FoxO and PPAR, anti-aging proteins, such as sirtuins, and caloric restriction mimetics acting on oxidative stress and energy metabolism. Notwithstanding the complexity of any therapeutic strategy aimed at reproducing the beneficial effects of caloric restriction, due to multiplicity of the cellular pathways involved in the responses, a great expansion of medicinal chemistry research in this field is expected in the next future.

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    • "As an example , T-maze and object recognition performance were improved in aged rats by KD administration, suggesting a potential functional benefit in cognition (Xu et al., 2010). Finally, it should be noted that because of its similarities to calorie restriction (as noted above), the KD is likely to involve other neuroprotective mechanisms that could ameliorate pathological aging – especially when occurring in the context of neurodegeneration (Contestabile, 2009). "
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    ABSTRACT: Dietary and metabolic therapies have been attempted in a wide variety of neurological diseases, including epilepsy, headache, neurotrauma, Alzheimer disease, Parkinson disease, sleep disorders, brain cancer, autism, pain, and multiple sclerosis. The impetus for using various diets to treat - or at least ameliorate symptoms of - these disorders stems from both a lack of effectiveness of pharmacological therapies, and also the intrinsic appeal of implementing a more "natural" treatment. The enormous spectrum of pathophysiological mechanisms underlying the aforementioned diseases would suggest a degree of complexity that cannot be impacted universally by any single dietary treatment. Yet, it is conceivable that alterations in certain dietary constituents could affect the course and impact the outcome of these brain disorders. Further, it is possible that a final common neurometabolic pathway might be influenced by a variety of dietary interventions. The most notable example of a dietary treatment with proven efficacy against a neurological condition is the high-fat, low-carbohydrate ketogenic diet (KD) used in patients with medically intractable epilepsy. While the mechanisms through which the KD works remain unclear, there is now compelling evidence that its efficacy is likely related to the normalization of aberrant energy metabolism. The concept that many neurological conditions are linked pathophysiologically to energy dysregulation could well provide a common research and experimental therapeutics platform, from which the course of several neurological diseases could be favorably influenced by dietary means. Here we provide an overview of studies using the KD in a wide panoply of neurologic disorders in which neuroprotection is an essential component.
    Frontiers in Pharmacology 04/2012; 3:59. DOI:10.3389/fphar.2012.00059 · 3.80 Impact Factor
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    • "It is interesting to note that calorie restriction (i.e. negative energy balance) increases plasma ghrelin and calorie restriction has profound beneficial effects on lifespan, neuroprotection, cognition and mood [43] [44] [45] [46] [47] [48] [49] [50] [51]. Cultured cells treated with serum from calorie-restricted rats display mitochondrial biogenesis, enhanced bioenergetic capacity and reduced ROS production [52]. "

    Advanced Understanding of Neurodegenerative Diseases, 12/2011; , ISBN: 978-953-307-529-7
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    • "Indeed, it has been shown that despite ad libitum access to food, humans (Mady et al., 2003; VanItallie et al., 2005) and animals (Van der Auwera et al., 2005; Kennedy et al., 2007; Appelberg et al., 2009) under ketogenic regimens lose weight, thus a fasting/CR condition is mimicked. Moreover, it is well known that therapeutic fasting or CR can enhance metabolic efficiency leading to antiepileptic (Greene et al., 2001; Mantis et al., 2004; Wheless, 2008) and neuroprotective (reviewed in Contestabile, 2009) effects. It has been hypothesized that a key role in seizure control is played by seric glucose level reduction, not always obtained by not-restricted KDs (Greene et al., 2003). "
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    ABSTRACT: Ketogenic diets (KDs), successfully used in the therapy of paediatric epilepsy for nearly a century, have recently shown beneficial effects also in cancer, obesity, diabetes, GLUT 1 deficiencies, hypoxia-ischemia, traumatic brain injuries, and neurodegeneration. The latter achievement designates aged individuals as optimal recipients, but concerns derive from possible age-dependent differences in KDs effectiveness. Indeed, the main factors influencing ketone bodies utilization by the brain (blood levels, transport mechanisms, catabolic enzymes) undergo developmental changes, although several reports indicate that KDs maintain some efficacy during adulthood and even during advanced aging. Encouraging results obtained in patients affected by age-related neurodegenerative diseases have prompted new interest on KDs' effect on the aging brain, also considering the poor efficacy of therapies currently used. However, recent morphological evidence in synapses of late-adult rats indicates that KDs consequences may be even opposite in different brain regions, likely depending on neuronal vulnerability to age. Thus, further studies are needed to design KDs specifically indicated for single neurodegenerative diseases, and to ameliorate the balance between beneficial and adverse effects in aged subjects. Here we review clinical and experimental data on KDs treatments, focusing on their possible use during pathological aging. Proposed mechanisms of action are also reported and discussed.
    Ageing research reviews 02/2010; 9(3):273-9. DOI:10.1016/j.arr.2010.02.003 · 4.94 Impact Factor
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