The use of n-3 fatty acids (n-3 FA) from fish oil as dietary supplements to protect against inflammatory disorders is recently on the rise by the general public in US. Further, 40% calorie restriction (CR) is also known to prolong lifespan of rodents by decreasing the expression of various pro-inflammatory genes, cytokines and insulin resistance. We recently reported that combination of n-3 FA + CR significantly extend lifespan of autoimmune-disease prone mice when compared to mice fed n-3 FA ad-libitum (AL) or mice fed corn oil (n-6 FA) with CR. We hypothesize that n-3 FA+CR increases activity of antioxidant enzymes and decreases pro-inflammatory cytokines leading to increased lifespan. We now further hypothesize that a similar mechanism may operate in prolonging significantly the lifespan of long-lived C57BL/6 (B6) mice when fed a diet with n-3 FA+CR than when fed n-6 FA+CR. In addition, n-3 FA may also decrease insulin resistance and age-related bone loss. Based on strong preliminary data, we propose to undertake new studies by feeding concentrated n-3 FA as well as by including transgenic mice carrying the fat-1 gene which endogenously synthesizes n-3 fatty acids and lowers pro-inflammatory n-6 FA in all tissues. We will use both B6 mice fed n-3 FA, AL or CR and fat-1+ x B6 mice fed AL or CR and compare with mice fed n-6 FA, AL or CR to further establish the protection induced by exogenous or endogenous n-3 fatty acids with and without CR on mean and maximal lifespan.
The specific aims are:
Aim 1 : Effect of feeding n-3 fatty acids, AL or CR (40%), from 4 mo and 20% CR 15 mo onwards to measure changes in the survival of B6 mice and to compare with fat-1+ x B6 F1 and fat-1- x B6 F1 mice fed AL or CR (40%).
Aim 2 : Measure changes in anti- and pro- inflammatory cytokines and expression of longevity SIRT I gene with age.
Aim 3 : Measure changes in fat and lean body mass as well as adipokines and bone mineral density during aging with or without n-3 FA or fat-1 gene in AL and CR. Since n-3 FA are found to be anti-inflammatory, the proposed studies are likely to establish the protective role of n-3 FA + CR in down-regulating oxidative stress and inflammatory gene expression thereby prolonging lifespan, much longer than n-6 FA + CR fed mice. In summary, favorable outcome of this study is likely to reinforce the intake of n-3 FA with CR to induce several health benefits in elderly, particularly against inflammation and musculoskeletal loss during aging.

Public Health Relevance

This grant proposal is directed closely to study the effect of commonly consumed n-6 (corn oil) fatty acids vs. n-3 (fish oil) fatty acids containing diets fed to mice ad-libitum and 40% or 20% calorie restriction to measure optimal lifespan, anti-inflammatory cytokines and bone mass, in long-lived C57BL/6 and fat-1 tg mice.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDA-C (02))
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Finkelstein, David B
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University of Texas Health Science Center San Antonio
Internal Medicine/Medicine
Schools of Medicine
San Antonio
United States
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Halade, Ganesh V; El Jamali, Amina; Williams, Paul J et al. (2011) Obesity-mediated inflammatory microenvironment stimulates osteoclastogenesis and bone loss in mice. Exp Gerontol 46:43-52
Halade, Ganesh V; Williams, Paul J; Lindsey, Merry L et al. (2011) Fish oil decreases inflammation and reduces cardiac remodeling in rosiglitazone treated aging mice. Pharmacol Res 63:300-7
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