Recipient Organization
TENNESSEE STATE UNIVERSITY
3500 JOHN A. MERRITT BLVD
NASHVILLE,TN 37209
Performing Department
Family and Consumer Sciences
Non Technical Summary
The number of Americans aged 65 or older is quickly growing. This will place unprecedented burdens on health care costs. Approximately 45% of older adults in the United States are affected by sarcopenia. This a number will continue to increase as the population ages. The economic burden of related healthcare expenditures for sarcopenia in the United States was estimated to be $18.5 billion annually (or $900 per person per year) in 2004 and it continuing to grow. It is estimated that a reduction of sarcopenia of just 10% would save $1.1 billion in healthcare costs. Therefore, developing strategies to promote health and skeletal muscle (SkM) functional independence are very important for helping older Americans to stay healthy, live longer, and incur fewer health-related costs. A search for novel, cost-effective, and health-improving agents for the prevention of multiple organs' dysfunction and prolonging healthy lifespan is of major importance.In our recent study, we observed that dietary intake of epicatechin, a major bioactive compound of cocoa, significantly increased survival rate to 69.7% from 39.4% in control group in aged C57B6 mice fed a standard diet. Notably, we contend that anti-aging effects of epicatechin may be partly due to the improvement of SkM function because epicatechin intake improved physical activities and reversed aging-reduced SkM actin protein expression compared to the control group. These findings suggest that epicatechin may be a novel anti-aging and anti-sarcopenia compound. It is particularly a breakthrough of anti-aging natural compounds research because most potential natural agents including resveratrol, green tea extract and curcumin failed in extending the lifespan of mice at the National Institute on Aging Interventions Testing Program [1]. However, from our current studies, we used only one dosage (0.25% drinking) of epicatechin. Further pathological, biochemical and molecular analysis from collected animal tissues were not done because of lack of funding support. A more comprehensive aging study with different dosages of epicatechin and whole cocoa extracts to select the optimum dosage and define the physiological and transcriptional mechanisms is needed to confirm whether and how dietary epicatechin and cocoa extracts extend the lifespan and protect SkM dysfunction in aging mice fed a standard diet.In the present proposal, we will explore whether epicatechin acts as an anti-aging agent via improving muscle function suing large numbers of mice for long periods. Results of these studies could potentially lead to the development of strategies using cost-effective, naturally available compound to promote health and extend lifespan in humans. In addition, completion of this project will strengthen our capacities in molecular nutrition and chronic diseases research as well as support minority graduate students at Tennessee State University.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Goals / Objectives
Objective 1. Determine whether dietary supplementation of epicatechin and whole cocoa extracts extend the lifespan in aged C57BL/6 mice fed a standard diet.Objective 2. Determine whether and how dietary supplementation of epicatechin and whole cocoa extracts reverse the aging-induced SkM dysfunction in aged C57BL/6 mice
Project Methods
Objective 1. Determine whether dietary supplementation of epicatechin and whole cocoa extracts extend lifespan in aged C57BL/6 mice fed a standard diet.Our preliminary results showed that dietary epicatechin intake significantly promoted survival of diabetic mice, aged normal mice as well as Drosophila fed standard diets. Epicatechin intake also improved physical activity, inflammatory markers and antioxidant status, supporting that epicatechin may be a novel anti-aging compound. However, it is hard to conclude that epicatechin definitely extends lifespan in normal aged mice now because of the limitations of our preliminary studies including only one single dosage of pure epicatechin and the mice were terminated when control group had 12 mice. Therefore, this comprehensive aging study with large number of animals will verify whether dietary epicatechin and whole cocoa extract extend lifespan in aging mice fed a standard diet. We will 1) extend our preliminary study (one dose 0.25%) to establish a dose-dependent effect of epicatechin (0.05%, 0.15%, 0.25%) on extending lifespan since 0.25% epicatechin used in the preliminary studies is relatively high and it is very hard to achieve by consuming cocoa products; 2) We will add cocoa polyphenolic extract (0.25%) group because there is no report that cocoa polyphenolic extract increased lifespan in mice although it extended lifespan in aged rats (9 rats/group only) [1]; 3) The mice number of each group will be 42 since we only have 12-33 mice/group in our preliminary studies and had 9 rats/group in the previous study [1]; 4) the experiment will be ended after last mouse dies for all groups to generate complete Kaplan-Meier survival curves; 5) physical activity (Voluntary wheel running) and metabolic measurements will be conducted at relevant times.Objective 2. Determine whether and how dietary supplementation of epicatechin and whole cocoa extracts reverse aging-induced SkM dysfunction in aged C57BL/6 mice.Aging-induced SkM dysfunction results in the reduced endurance capacity, increased muscle fatigability, and decreased muscle force in older persons [15, 5]. Aging-induced high level of ROS damages proteins, DNA and other molecules, particularly in mitochondrion [3]. The biological process to remove these accumulated damaged proteins and DNA leads to chronic increased levels of pro-inflammatory markers IL-1, IL-6 and TNF-α [11]. This ROS-apoptosis-chronic inflammation cycle drives the onset and the reduction of mitochondrial biogenesis, ATP production and myocytes turnover and therefore increases SkM loss of mass and dysfunction [6, 1, 4, 6, 2]. Our preliminary studies showed that dietary intake of epicatechin improved SkM function in diabetic mice, reduced inflammatory markers in aging mice while extending lifespan in these animals. Therefore, it is reasonable to speculate that the anti-aging effect of epicatechin may be mediated by improving SkM function via regulating oxidative stress, chronic inflammation as well as apoptosis. Because of the limitations of our preliminary studies, in the present study, we will 1) conduct SkM functional experiments using 1.1) voluntary wheel running test and uphill treadmill assay in conscious mice to test the SkM function, the traditional approaches in evaluating muscle force changes [6]; and 1.2) isolate the intact extensor digitorum longus (EDL) to conduct EDL contractility ex vivo, a classic approach in evaluating SkM force changes [6]; 2) We will conducting following Mechanism experiments to determine how epicatechin and cocoa extract improving SkM function: 2.1) Identification of genes and metabolic pathways that underline the molecular mechanisms by which dietary epicatechin improves SkM function in aged mice 2.2) SkM satellite cells studies both in cultured satellite cells and SkM tissues; 2.3) Evaluation of mitochondrial biogenesis ; 2.4) Measurements of oxidative stress; 2.5) Apoptotic assays: 2.6) Analysis of plasma inflammatory markers and 2.7) SkM pathological analysis.