A c c e p t e d A r t i c l e
This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process, which may lead todifferences between this version and the Version of Record. Please cite this article as doi:10.1111/acel.12049© 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of GreatBritain and Ireland
Accepted Date : 10-Jan-2013Article type : Original Paper
Protein restriction cycles reduce IGF-1 and phosphorylatedTau, and improve behavioral performance in an Alzheimer’sdisease mouse model
Edoardo Parrella
1
, Tom Maxim
1
, Francesca Maialetti
2
, Lu Zhang
1
, Junxiang Wan
1
, MinWei
1
, Pinchas Cohen
1
, Luigi Fontana
3,4,5
, Valter D. Longo
1, +
1
Andrus Gerontology Center and Dept. of Biological Sciences, University of Southern California,Los Angeles, USA
2
Division of Nutrition and Aging, Istituto Superiore di Sanità, Rome, Italy
3
Division of Geriatrics and Nutritional Science, Washington University in St. Louis, Missouri,USA
4
Department of Medicine, Salerno University School of Medicine, Salerno, Italy
5
CEINGE Biotecnologie Avanzate, Napoli, Italy
+
Corresponding author at: Andrus Gerontology Center, University of Southern California, 3715McClintock Avenue, Los Angeles, CA 90089-0191, USA. Tel.: +1-213-7406212. Fax: +1-213-8215714. E-mail address: vlongo@usc.edu (Valter D. Longo).
A c c e p t e d A r t i c l e
© 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of GreatBritain and Ireland
Running title:
Four months of protein restriction cycles (PRC) modulate circulating levels ofIGF-1 and IGFBPs, reduce tau hyperphosphorylation and alleviate cognitive deficits in 3xTg-ADmice. PRC is not associated with calorie restriction (CR).
Author Keywords:
tau, IGF-1, Alzheimer, protein restriction, aging, IGFBP-1.
Summary
In laboratory animals Calorie Restriction (CR) protects against aging, oxidative stress andneurodegenerative pathologies. Reduced levels of growth hormone and IGF-1, which mediatesome of the protective effects of CR, can also extend longevity and protect against age-relateddiseases in rodents and humans. However, severely restricted diets are difficult to maintain andare associated with chronically low weight and other major side effects. Here, we show that fourmonths of periodic protein restriction cycles (PRC) with supplementation of non-essential aminoacids in mice already displaying significant cognitive impairment and AD-like pathology reducedcirculating IGF-1 levels by 30-70% and caused an 8-fold increase in IGFBP-1. Whereas PRCdid not affect the levels of
β
amyloid (A
β
) they decreased tau phosphorylation in thehippocampus and alleviated the age-dependent impairment in cognitive performance. Theseresults indicate that periodic protein restriction cycles without CR can promote changes incirculating growth factors and tau phosphorylation associated with protection against age-related neuropathologies.
Introduction
Calorie Restriction (CR) without malnutrition is effective in protecting the brain against agingand oxidative stress (Martin
et al.
2006). Several studies support a beneficial role for this dietaryintervention in protecting against age dependent decay in cognitive performance in rodents
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© 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of GreatBritain and Ireland
(Fontan-Lozano
et al.
2008). In addition CR shows remarkable neuroprotective propertiesagainst neurodegenerative diseases including stroke, Parkinson’s disease (PD), Huntington’sdisease (HD) and Alzheimer’s Disease (AD) in several animal models (Mattson 2005; Patel
et al.
2005).Recent studies in different AD mouse models reported that reducing food intake can diminishAD-related neuropathologies and cognitive dysfunction. For example, CR reduces theprogression of
β
amyloid (A
β
) deposition in the hippocampus and cerebral cortex of AD micecarrying mutations for FAD (Wang
et al.
2005), APP (amyloid precursor protein) and APP + PS-1 (presenilin 1) (Patel
et al.
2005; Mouton
et al.
2009). CR ameliorates neurodegenerativephenotypes assessed by object recognition and contextual fear conditioning tests in cDKO(conditional double knockout) AD mice (Wu
et al.
2008). Mattson and coworkers have shownthat CR can also ameliorate age-related memory impairment and decrease A
β
andphosphorylated tau accumulation in a triple transgenic mouse (3xTg-AD) that overexpressmutations linked to AD (PS-1, APP) and frontotemporal dementia (tau) (Halagappa
et al.
2007).Also studies in human populations suggest that diet plays an important role in AD and reducedfood intake may protect against this pathology. For example, an epidemiological study byLuchsinger and colleagues provided evidence that individuals with a low calorie intake have areduced risk of developing AD (Luchsinger
et al.
2002).Among the large number of metabolic and physiological changes caused by CR, reduction ofgrowth hormone (GH)/insulin-like factor (IGF-1) signaling axis may be important for itsprotective effects (Fontana
et al.
2010). Circulating IGF-1 is a hormone produced primarily bythe liver that regulates energy metabolism, cell proliferation, cell differentiation, body size andlongevity. IGF-1 levels are regulated by calorie and/or protein availability and long-term CRdecreases serum IGF-1 concentration by approximately 30–40% in rodents (Thissen
et al.
1994) but not in humans unless protein intake is also reduced (Fontana
et al.
2008). Mutations
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