Exercise is arguably the most potent approach we can take to defer physical decline associated with aging and to protect against late onset diseases such as diabetes, cancer, and Alzheimer's disease. Molecular understanding of how exercise benefits translate into healthy aging is thus of definitive medical interest. We study fundamental processes relevant to healthy aging in the 959-celled nematode C. elegans. Recently we made a fascinating discovery-C. elegans can exercise (swim) to exhibit training benefits, and appear to gain benefits by molecular pathways conserved in humans. Our initial model development opens up a new research area for understanding how tissue-specific and organism-wide health benefits are induced by exercise, and creates a novel paradigm for identifying exercise mimetic drugs that might promote healthy aging. To really harvest the potential of this model, we need to measure the strength of the tiny C. elegans. We collaborated to develop a strength test in which trained animals thread through a matrix of deformable pillars, and the extent of pillar deflection is used to calculate force. Our NemaFlex force detection device is the quantitative foundation with which we expect to break new ground in understanding exercise impact on healthy aging. Here we propose required development to enhance assay throughput and pursue applications that will not only anchor this technology as an essential component of C. elegans exercise evaluation but also accelerate studies on exercise biology and healthy aging in this powerful model.
Aim 1 is to develop a novel high throughput tool for direct strength evaluation in C. elegans.
This aim will generate an essential tool for analysis of C. elegans strength at multiple life stages, define the exercise regimen that will become the anchor protocol in the field, and reveal features of training in this model.
Aim 2 is to use NemaFlex to evaluate exercise mimetic drugs & to facilitate focused pilot genetic screens.
This aim will establish critical proof-of-principle for genetic and drug discovery using the NemaFlex.
Aim 3 is to initiate dissection of the functional and molecular relationship between exercise and healthy aging, grounded in NemaFlex force measures of training benefits. To begin, we will test how optimized strength training tracks with a broad spectrum of healthspan indicators that decline with age, we will investigate impact of cessation of training on aging quality, and we will ask if exercise mimetic drugs extend healthspan in the absence of training. Our goals will create novel technology that for the first time permits facile quantitativ analysis of exercise adaptations in the powerful C. elegans genetic model. Accomplishment of our tractable aims will anchor a new subfield of genetic investigation of exercise and healthy aging that may influence design of interventions that broadly promote health and defer aging.
Exercise has a profound positive impact on health of the aging population in that it protects against age-associated diseases including cancer, diabetes, and cardiovascular disease, at the same time it maintains muscle, immune system, and nervous system function in aging. We are developing the first exercise model in the simple animal C. elegans, in which training benefits appear mediated by conserved mechanisms and exercise promotes healthy aging. We will optimize a novel tool for direct strength measurement of these tiny 959-celled animals and show how our device can facilitate searches for exercise mimetic drugs and genes that are associated with training adaptations, and can also help define exercise impact on a broad range of healthy aging measures. The experimental advantages of C. elegans may yield unexpected insights that inspire development of novel interventions that protect against age-associated disease and age-associated decline.
| Bilbao, Alejandro; Patel, Amar K; Rahman, Mizanur et al. (2018) Roll maneuvers are essential for active reorientation of Caenorhabditis elegans in 3D media. Proc Natl Acad Sci U S A 115:E3616-E3625 |
| Hartman, Jessica H; Smith, Latasha L; Gordon, Kacy L et al. (2018) Swimming Exercise and Transient Food Deprivation in Caenorhabditis elegans Promote Mitochondrial Maintenance and Protect Against Chemical-Induced Mitotoxicity. Sci Rep 8:8359 |
| Rahman, Mizanur; Hewitt, Jennifer E; Van-Bussel, Frank et al. (2018) NemaFlex: a microfluidics-based technology for standardized measurement of muscular strength of C. elegans. Lab Chip 18:2187-2201 |
| Laranjeiro, Ricardo; Harinath, Girish; Burke, Daniel et al. (2017) Single swim sessions in C. elegans induce key features of mammalian exercise. BMC Biol 15:30 |
