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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/or 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 4 months of periodic protein restriction cycles (PRCs) with supplementation of nonessential amino acids in mice already displaying significant cognitive impairment and Alzheimer's disease (AD)-like pathology reduced circulating IGF-1 levels by 30-70% and caused an 8-fold increase in IGFBP-1. Whereas PRCs 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.)

Mutations that reduce glucose or insulin/insulin-like growth factor-I (IGF-I) signaling increase longevity in organisms ranging from yeast to mammals. Over the past 10 years, several studies confirmed this conserved molecular strategy of longevity regulation, and many more have been added to the complex mosaic that links stress resistance and aging. In this review, we will analyze the similarities that have emerged over the last decade between longevity regulatory pathways in organisms ranging from yeast, nematodes, and fruit flies to mice. We will focus on the role of yeast signal transduction proteins Ras, Tor, Sch9, Sir2, their homologs in higher organisms, and their association to oxidative stress and protective systems. We will discuss how the "molecular strategy" responsible for life span extension in response to dietary and genetic manipulations appears to be remarkably conserved in various organisms and cells, including neuronal cells in different organisms. Taken together, these studies indicate that simple model systems will contribute to our comprehension of aging of the mammalian nervous system and will stimulate novel neurotherapeutic strategies in humans.

Saccharomyces cerevisiae has played an important role as a model system to understand the biochemistry and molecular biology of mammalian cells. The genetic tools available and the short life span have also made S. cerevisiae a powerful system to study aging. The yeast chronological life span (CLS) is a measure of the survival of a non-dividing population of cells, and thus can model aging of mammalian non-dividing cells but also of higher eukaryotic organisms. The parallel description of the pro-aging role of homologs of Akt, S6 kinase, adenylate cyclase, and Tor in yeast and in higher eukaryotes, suggests that findings in the S. cerevisiae will be valuable to understand human aging and diseases. Moreover, the similarities between mitochondria and age-dependent mitochondrial damage in yeast and mammalian cells indicate that S. cerevisiae is a valuable model to study mitochondrial dysfunction and diseases that involve this organelle. Here, we describe the use of S. cerevisiae CLS in combination with three methods to quantify age-dependent mitochondrial damage and the accumulation of mitochondrial DNA mutations.