Abstract
Author SummaryThe simple manipulation of dietary restriction (DR) (reduction of caloric intake by about 30% in rodents) produces robust increases in lifespan and slows the development of almost all age-related diseases, including cancer and neurological diseases. This relationship between dietary restriction and longevity is observed in most models in which the effect of DR has been tested. Thus, understanding how DR produces its protective mechanisms would have potentially profound implications for the treatment of age-related diseases, including possibly the development of a “magic bullet” for these diseases. In the present study we have discovered that DR induces a transcription factor, CBP, and additional factors that work with CBP to control the expression of other genes involved in determination of lifespan. When we blocked the DR-mediated increase in CBP and associated factors, we blocked all the protective effects of DR on lifespan extension, on the slowed rate of aging, and on protection against pathology in a model of Alzheimer's disease. Further, in mice expression of CBP and a CBP-interacting factor positively predicted lifespan, and expression of both factors decreased with age and in diabetes. Finally, pharmacological manipulations that mimicked enhanced CBP activity increased lifespan and reduced pathology in a model of Alzheimer's disease.
Highlights
Elucidation of mechanisms mediating lifespan extension and reduction of disease burden, including cancer and neurodegenerative diseases, by dietary restriction (DR) is a major goal of aging research [1]
Since hypothalamic neurons mediate physiological responses to nutritional deprivation, we hypothesized that hypothalamic gene expression may play a role in mediating lifespan extension by DR [10], a hypothesis supported by the observation that two neurons mediate protective effects of DR in C. elegans [3]
Hypothesizing that expression of genes mediating lifespan extension by DR may predict lifespan under ad lib fed conditions, we screened over 40 genes, including CREB-binding protein (CBP) and genes otherwise implicated in lifespan extension, to detect genes whose hypothalamic expression predicts lifespan across five strains of mice (BALB/cByJ, A/J, C3H/HeJ, DBA/2J, and C57Bl/6J) in order of increasing lifespan, based on published lifespan data [12,13]
Summary
Elucidation of mechanisms mediating lifespan extension and reduction of disease burden, including cancer and neurodegenerative diseases, by DR is a major goal of aging research [1]. Recent studies have implicated sirtuins [2], SKN-1 [3], SMK-1 and PHA-4/Foxa [4], AMPK [5], RHEB-1 [6], daf-16/Fox1a [5], and HSF-1 [7] in mediating lifespan extension by some, but not all [8,9], protocols of DR in Caenorhabditis elegans. The purpose of the present studies was to discover genes whose expression predicts lifespan and whose expression decreases with age and disease in mammals, whose expression is induced by DR, and whose inhibition attenuates life extension by several distinct protocols of DR. We report that among genes implicated in lifespan extension by DR or the insulin-like signaling pathway, only CBP meets these criteria
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