Aging of multicellular organisms typically involves progressive decline in the body's ability to maintain homeostatic cell replacement and to regenerate tissues and organs after injury. Skeletal muscle, in particular, regenerates robustly through most of adult life but fails to do so in old age. Age-acquired defects in muscle function profoundly impact the health of older individuals, resulting in a high incidence of age-associated muscle deterioration (sarcopenia) and inefficient or incomplete recovery from injury in the elderly. Precisely how aging causes deterioration of muscle function is poorly understood, but several lines of evidence, including preliminary data from my lab, suggest that loss or functional impairment of skeletal muscle stem cells directly contributes to age-dependent failures in tissue repair. In light of these data, the primary focus of this application is to identify age-regulated genes and pathways that can be manipulated in aging muscle to reverse the detrimental effects of age on muscle stem cell number and improve muscle stem cell function. To this end, we have generated extensive preliminary data that strongly suggest that the age-related impairment of muscle stem cell function may be mediated by increased exposure to a pro-inflammatory environment. In particular, we have found that aging of muscle stem cells is accompanied by induced expression of multiple inflammation-associated genes. In addition, we have found that restoration of myogenic function, which can be induced by heterochronic parabiosis, is accompanied by normalization of expression of at least some of these age-regulated, pro-inflammatory targets. Thus, the experiments described in this application are designed to (1) better understand the systemically regulated induction of inflammatory genes that occurs in aged skeletal muscle stem cells, (2) examine whether inhibition of inflammation can prevent or reverse age-associated suppression of muscle stem cell proliferation and muscle regenerative function, and (3) identify the physiological mechanism(s) that ultimately result in enhanced, chronic inflammation in aged muscle. These studies will use well-established mouse models already available to us and cell isolation strategies pioneered by my lab, and will provide a solid basis for clinical extension into novel treatments for human age-associated muscle disease.

Public Health Relevance

Our data in mice suggest that progressive loss of muscle stem cells and dysregulation of their function is an important underlying cause of muscle deterioration in old age. Therefore, in these studies, we will use genetic and biochemical approaches to identify the mediators of age-associated dysfunction of muscle stem cells, as well as factors that can restore their youthful function. This work holds tremendous promise for halting and potentially reversing age-related defects in muscle regenerative function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033053-05
Application #
8309970
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Williams, John
Project Start
2009-08-15
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$327,728
Indirect Cost
$132,652
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Painter, Michio W; Brosius Lutz, Amanda; Cheng, Yung-Chih et al. (2014) Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration. Neuron 83:331-43
Sinha, Indranil; Sinha-Hikim, Amiya P; Wagers, Amy J et al. (2014) Testosterone is essential for skeletal muscle growth in aged mice in a heterochronic parabiosis model. Cell Tissue Res 357:815-21
Sinha, Manisha; Jang, Young C; Oh, Juhyun et al. (2014) Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344:649-52
Katsimpardi, Lida; Litterman, Nadia K; Schein, Pamela A et al. (2014) Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344:630-4
Oh, Juhyun; Lee, Yang David; Wagers, Amy J (2014) Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med 20:870-80
Loffredo, Francesco S; Steinhauser, Matthew L; Jay, Steven M et al. (2013) Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153:828-39
Shadrach, Jennifer L; Wagers, Amy J (2011) Stem cells for skeletal muscle repair. Philos Trans R Soc Lond B Biol Sci 366:2297-306
Woo, Melissa; Isganaitis, Elvira; Cerletti, Massimiliano et al. (2011) Early life nutrition modulates muscle stem cell number: implications for muscle mass and repair. Stem Cells Dev 20:1763-9