Sarcopenia is the decline in muscle mass and muscle strength that inevitably accompanies human aging. Loss initiates at middle age (even in healthy individuals) and progresses such that virtually everyone can expect to experience significant decline in muscle strength over time (approximately 50% strength loss by age 90). Unfortunately, this universal phenomenon is often sufficiently incapacitating such that assistance in basic life activities, such as walking and lifting, becomes necessary. Despite the substantial toll taken by sarcopenia, relatively little is understood about how and why sarcopenia occurs, especially at the molecular level. To date, genetic models have not been exploited to investigate molecular mechanisms of sarcopenia. We have found that C. elegans aging features age-related muscle decline that shares striking similarities to human sarcopenia. Moreover, we have identified one gene that plays a critical role in the process--AGE-1 PI3 kinase (known to act in the DAF-2 insulin-like signalling pathway that influences longevity). That downregulation of a single gene activity can markedly delay the onset of sarcopenia is highly encouraging. The overall goal of our research is to identify the genetic influences on C. elegans sarcopenia and to define molecular strategies that """"""""youthenize"""""""" muscle. We will pursue 3 aims: I) The molecular characterization of the effects of insulin-like signalling on C. elegans sarcopenia; II) The evaluation of the impacts of oxidative damage and caloric restriction on muscle healthspan; III) The execution of a genome-wide, non-biased RNAi screen to identify novel genes that influence sarcopenia. At the completion of the study we propose, we expect to provide a detailed molecular description of how nematode insulins and components of the canonical DAF-2 insulin signalling pathway influence nematode sarcopenia. We will also define how oxidative stress and caloric restriction protocols influence cellular aspects of muscle decline. Furthermore, we expect to identify novel genetic factors with major impacts on muscle aging. The end result should be a significant advance in the level of molecular and mechanistic detail with which we understand sarcopenia in the C. elegans model. Our hope is that the novel insight we anticipate will stimulate the search for conserved processes in mammals, and that data we generate may influence design of new therapeutic intervention strategies for combating human sarcopenia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024882-04
Application #
7246559
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (02))
Program Officer
Williams, John
Project Start
2004-09-15
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$324,621
Indirect Cost
Name
Rutgers University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Toth, Marton Lorant; Melentijevic, Ilija; Shah, Leena et al. (2012) Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system. J Neurosci 32:8778-90
Ruck, Alexander; Attonito, John; Garces, Kelly T et al. (2011) The Atg6/Vps30/Beclin 1 ortholog BEC-1 mediates endocytic retrograde transport in addition to autophagy in C. elegans. Autophagy 7:386-400
Yu, Simon; Driscoll, Monica (2011) EGF signaling comes of age: promotion of healthy aging in C. elegans. Exp Gerontol 46:129-34
Onken, Brian; Driscoll, Monica (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS One 5:e8758
Iwasa, Hiroaki; Yu, Simon; Xue, Jian et al. (2010) Novel EGF pathway regulators modulate C. elegans healthspan and lifespan via EGF receptor, PLC-gamma, and IP3R activation. Aging Cell 9:490-505
Hansen, Malene; Chandra, Abha; Mitic, Laura L et al. (2008) A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4:e24
Ibanez-Ventoso, Carolina; Vora, Mehul; Driscoll, Monica (2008) Sequence relationships among C. elegans, D. melanogaster and human microRNAs highlight the extensive conservation of microRNAs in biology. PLoS One 3:e2818
Tsechpenakis, Gabriel; Bianchi, Laura; Metaxas, Dimitris et al. (2008) A novel computational approach for simultaneous tracking and feature extraction of C. elegans populations in fluid environments. IEEE Trans Biomed Eng 55:1539-49
Melendez, Alicia; Hall, David H; Hansen, Malene (2008) Monitoring the role of autophagy in C. elegans aging. Methods Enzymol 451:493-520
Gerstbrein, Beate; Stamatas, Georgios; Kollias, Nikiforos et al. (2005) In vivo spectrofluorimetry reveals endogenous biomarkers that report healthspan and dietary restriction in Caenorhabditis elegans. Aging Cell 4:127-37