Protein restriction cycles reduce IGF-1 and phosphorylated Tau, and improve behavioral performance in an Alzheimer's disease mouse model

Andrus Gerontology Center and Dept. of Biological Sciences, University of Southern California, Los Angeles, USA.
Aging cell (Impact Factor: 6.34). 01/2013; 12(2). DOI: 10.1111/acel.12049
Source: PubMed


In laboratory animals Calorie Restriction (CR) protects against aging, oxidative stress and neurodegenerative pathologies. Reduced levels of growth hormone and IGF-1, which mediate some of the protective effects of CR, can also extend longevity and protect against age-related diseases in rodents and humans. However, severely restricted diets are difficult to maintain and are associated with chronically low weight and other major side effects. Here, we show that four months of periodic protein restriction cycles (PRC) with supplementation of non-essential amino acids in mice already displaying significant cognitive impairment and AD-like pathology reduced circulating IGF-1 levels by 30-70% and caused an 8-fold increase in IGFBP-1. Whereas PRC did not affect the levels of β amyloid (Aβ) they decreased tau phosphorylation in the hippocampus and alleviated the age-dependent impairment in cognitive performance. These results indicate that periodic protein restriction cycles without CR can promote changes in circulating growth factors and tau phosphorylation associated with protection against age-related neuropathologies. © 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

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Available from: Junxiang Wan, Oct 01, 2014
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    • "Benefits of short-term protein deprivation also include protection from intimal hyperplasia (Mauro et al., 2014). Similarly, cycles of protein deprivation lasting 1 week, followed by a week of ad libitum access to a complete diet, protect against Tau phosphorylation in a mouse model of Alzheimer's disease (Parrella et al., 2013). Finally, protein restriction has beneficial effects on metabolism, activating a fasting-like response that requires both GCN2 and PPAR-alpha (peroxisome proliferator-activated receptor-alpha), and that causes an increase in the fasting hormone FGF21 (Laeger et al., 2014). "
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    ABSTRACT: The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR-S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging Cell 04/2015; 14(4). DOI:10.1111/acel.12338 · 5.71 Impact Factor
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    • "Vascular aging is accelerated in rats fed a high methionine (2%) or high-protein (50%) diet (Fau et al., 1988). Alzheimer mice that undergo protein restriction cycles (a diet lacking essential amino acids is provided every other week), reduce IGF-1 levels, slow down the deposition of tau protein in the brain, and score higher on behavioral performance tests (Parrella et al., 2013). How can we use these insights in the context of human diets? "
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    ABSTRACT: Many diets and nutritional advice are circulating, often based on short- or medium-term clinical trials and primary outcomes, like changes in LDL cholesterol or weight. It remains difficult to assess which dietary interventions can be effective in the long term to reduce the risk of aging-related disease and increase the (healthy) lifespan. At the same time, the scientific discipline that studies the aging process has identified some important nutrient-sensing pathways that modulate the aging process, such as the mTOR and the insulin/insulin-like growth factor signaling pathway. A thorough understanding of the aging process can help assessing the efficacy of dietary interventions aimed at reducing the risk of aging-related diseases. To come to these insights, a synthesis of biogerontological, nutritional, and medical knowledge is needed, which can be framed in a new discipline called 'nutrigerontology'. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 12/2014; 14(1). DOI:10.1111/acel.12284 · 6.34 Impact Factor
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    • "Mouse has been useful also as Alzheimer's disease model. A study conducted at the Los Angeles Longevity Institute shows that periodic protein restriction cycles, without CR, in mice already displaying significant cognitive impairment and Alzheimer's disease (AD)-like pathology can promote changes in circulating growth factors (reduction of IGF-1 and increase of IGFBP-1) as well as decrease of tau phosphorylation in the hippocampus with a consequent reduction of the age-dependent impairment in cognitive performance [82]. "
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    ABSTRACT: Calorie restriction (CR), which usually refers to a 20-40% reduction in calorie intake, can effectively prolong lifespan preventing most age-associated diseases in several species. However, recent data from both human and nonhumans point to the ratio of macronutrients rather than the caloric intake as a major regulator of both lifespan and health-span. In addition, specific components of the diet have recently been identified as regulators of some age-associated intracellular signaling pathways in simple model systems. The comprehension of the mechanisms underpinning these findings is crucial since it may increase the beneficial effects of calorie restriction making it accessible to a broader population as well.
    BioMed Research International 05/2014; 2014:308690. DOI:10.1155/2014/308690 · 3.17 Impact Factor
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