Neural mechanisms of age-related weakness

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ABSTRACT More than 40% of older adults (OAs) report limitations to performing tasks that are essential to maintain independence. Weakness is an important contributor to physical impairments; indeed, weakness predisposes OAs to a four-fold increase in physical limitations. Because strength is a vital factor for health and longevity, more comprehensive understanding of the causes of weakness is needed to develop targeted interventions to enhance strength and function in OAs. While age-related loss of muscle mass and quality are partly responsible for weakness, there is increasing evidence that deficits in neural activation are critically linked to age-related weakness. In particular, we and others have demonstrated that weakness associated with aging and other conditions (e.g., disuse, injury, sepsis) is due, in part, to neural hypoexcitability. In this application, we seek to fundamentally advance our understanding of the mechanisms of and treatment strategies for age-related weakness and mobility limitations through translational human (Aim 1) and pre-clinical rodent (Aim 2) experiments that, collectively, will provide strong data indicating a causal association between neural hypoexcitability and age-related weakness. The first aim will test the hypothesis that indices of neural hypoexcitability are associated with greater future (longitudinal) losses of strength in OAs. Here, we will leverage data from a prior R01 to conduct a longitudinal study in humans where we quantify indices of neural excitability, lean mass, strength, and mobility after ~ 8-years in older adults. These data will be used to determine the relative contribution of indices of neural excitability and thigh lean mass on future decline in muscle strength in older adults, with a robust design accounting for alternative mechanisms. By using a longitudinal design in humans, this aim will provide the strongest level of evidence for neural excitability being a key predictor of age-related strength loss, which is a paradigm shift away from the current consideration of primarily muscular factors (e.g., muscle mass). The second aim will consist of four experiments. Experiments 1-3 will use a 5-HT2c agonist (lorcaserin) with a well-known mechanism of action that increases persistent inward currents and motoneuron excitability. SA2.1 will test the hypothesis that there is an inverted U-shape relationship between 5-HT2c agonist dose and motor function response in old mice. SA2.2 will test the hypothesis that a 5-HT2c agonist will enhance motor function in aged mice by increasing neural excitation to demonstrate that the reduction in MN excitability is a significant contributor to motor dysfunction in old mice. SA2.3 will test chronic effects of lorcaserin treatment on motor unit number and function in aged mice. SA2.4 will test the impact of tamoxifen-inducible genetic deletion of 5-HT2c receptors in MNs using Cre-Lox system. In the long-term, this proof-of-concept, proof-of-mechanism work could serve as evidence for a neurotherapeutic agent to enhance motor function in older adults.