  Citation: Guan, Y.; Yan, Z. Molecular Mechanisms of Exercise and Healthspan. Cells 2022, 11, 872. https://doi.org/10.3390/ cells11050872 Academic Editor: Michael Deschenes Received: 28 December 2021 Accepted: 26 February 2022 Published: 3 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cells Review Molecular Mechanisms of Exercise and Healthspan Yuntian Guan 1,2 and Zhen Yan 1,2,3,4, * 1 Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA; yg6ju@virginia.edu 2 Center for Skeletal Muscle Research at the Robert M. Berne Cardiovascular Research Center, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA 3 Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA 4 Department of Molecular Physiology and Biological Biophysics, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA * Correspondence: zhen.yan@virginia.edu; Tel.: +1-434-982-4477; Fax: +1-434-982-3139 Abstract: Healthspan is the period of our life without major debilitating diseases. In the modern world where unhealthy lifestyle choices and chronic diseases taper the healthspan, which lead to an enormous economic burden, finding ways to promote healthspan becomes a pressing goal of the scientific community. Exercise, one of humanity’s most ancient and effective lifestyle interven- tions, appears to be at the center of the solution since it can both treat and prevent the occurrence of many chronic diseases. Here, we will review the current evidence and opinions about regu- lar exercise promoting healthspan through enhancing the functionality of our organ systems and preventing diseases. Keywords: healthspan; exercise; chronic diseases; adaptations 1. Introduction Two thousand and two hundred years have passed since the first Chinese emperor, Qin Shi Huang, ordered a nationwide hunt for the elixir for eternal life. Proven to be futile, his effort gave rise to the creation of a glorious terracotta army of 8000 that was buried alongside with him to embargo the pursuit for longevity [1]. Throughout the history of modern medicine, much like the emperor’s dream, scientists have never halted the search for ways to extend our lifespan. In the past 50 years, extensive research and development with tremendous amount of investment have led to an increase of lifespan in the U.S. by 10 years [2]. In 2019, there were over 703 million of the world population aged 65 or more; this number is projected to be over 1.5 billion by 2050 [3]. However, healthspan, the period of our life without major debilitating diseases, has not been prolonged [2]. Because aging remains the most important risk factor for nearly all chronic diseases [4,5], this creates a conundrum that the extended lifespan without improvement of healthspan leads to significant aging of the society and unsustainable economy. Evidence and theories from research in the recent decades have shown that human life expectancy may have reached or come close to a limit set primarily by natural causes (chronic diseases) and genetics [6,7]. The concept of “healthy aging”, that is, to maximally expand the expectancy of healthy living before a person suffers from permanent aging- associated disabilities and chronic diseases, has emerged in the past two decades and gained significant popularity [8–10]. In the 21st century, there is a dire need of research on extending our healthspan [11–13]. Up to date, over 2100 active clinical trials in the United States are focusing on therapies that improve the quality of life (QOL) under the conditions of chronic diseases. Much like lifespan, healthspan can be influenced by numerous factors, namely genetics, environmental factors, social-economic status, lifestyle choices including dietary intake, physical activities, etc. Cells 2022, 11, 872. https://doi.org/10.3390/cells11050872 https://www.mdpi.com/journal/cells