Aging-related diseases and disorders affect public health, society, and economics worldwide. Adults 65 years and older are the fastest growing segment of the US population. Sarcopenia (the age-related loss of muscle mass and function) is associated with a high risk of morbidity-disability, decreased quality of life, increased burden of treatment and caregiving, and increased mortality. No medication is currently available to treat sarcopenia. Therefore, there is a substantial unmet clinical need for effective treatments of sarcopenia. The dysfunction of the neuromuscular junction (NMJ) plays a crucial role in the development of sarcopenia, which is characterized by: (i) decreased acetylcholine (ACh) content and muscarinic ACh receptors (mAChRs) at the NMJ, (ii) decreased activation of AMP kinase and the consequent decrease in mitochondrial biogenesis, (iii) increased inflammation, (iv) decreased number and activation of satellite cells, and (v) decreased capillary density. Chromogranin A (CgA) derived peptide catestatin (CST: hCgA352-372) decreases inflammation, increases AMPK phosphorylation, increases capillary density, increases muscle ACh content, and increases grip strength in old WT and CST knockout (CST-KO) mice. Therefore, we hypothesize that CST and CST mimetic pharmacophore TKO-10-18 will ameliorate sarcopenia by reversing sarcopenic phenotypes. We have developed 3 Specific Aims to test and validate our hypotheses: Aim I: Evaluation of in vivo plasma pharmacokinetics of oral CST and TKO-10-18. This aim will determine standard non-compartmental pharmacokinetic parameters such as AUC, CL, Vss, T1/2, Cmax, Tmax, Clast, and Tlast. Aim II: CST promotes healthy rehabilitation by improving muscle strength and function in aging WT mice. In Aim II, we will determine the following: (i) whole body grip strength after 4 months of treatment of 16-month-old mice with saline, oral CST, and intraperitoneal CST; (ii) sciatic nerve-induced contractility in situ in gastrocnemius muscle; (iii) ex vivo contraction of soleus and EDL muscles. Based on the existing literature and preliminary data, we expect CST and TKO-10-18 to increase grip strength in aging WT and CST-KO mice. Aim III. Mechanisms underlying CST regulation of functional independence or “active aging” in aging WT mice. In Aim III, we will determine the following: (i) assessment of inflammation by measuring cytokines/chemokines, (ii) muscle regeneration by determining expression of IL-33, Pax7, Myf5, MyoD1, Mef2, MyoG, Six1 and Six4 genes, (iii) AMPK phosphorylation by Western blotting, (iv) mitochondrial biogenesis and mitochondrial health by electron microscopy, (v) determination ACh by ELISA, (vi) capillary density; and (vi) muscle glycogen content. Based on the published and preliminary data, we expect that CST and TKO-10-18 will improve grip strength in aging mice by increasing ACh release, activating AMPK, stimulating mitochondrial biogenesis, activating muscle regeneration, and increasi...