FIGURE 4.

Timeline of the discovery of representative sirtuin‐activating compounds and their preclinical and clinical effects. (a) The effects of different sirtuin‐activating compounds on bone mass were determined using animal studies. (b) The chart shows the distribution and percentage of indications for clinical studies of sirtuin‐activating compounds registered on ClinicalTrials.gov, which were started between January 2004 and July 2020. We excluded studies with suspension, termination, and withdrawal statuses and those without FDA‐defined phases. Other diseases included Friedreich ataxia, pseudoachondroplasia, lymphangioleiomyomatosis, endometriosis, common cold, knee osteoarthritis, infertility, renal dysfunction, COVID‐19, cancer, allogeneic hematopoietic cell transplantation, and ataxia–telangiectasia. (c) The graph shows the number of studies of each sirtuin‐activating compound posted on ClinicalTrials.gov each year between 2004 and 2020, based on the start date. We excluded studies with suspension, termination, and withdrawal statuses. FDA, food and drug administration; COVID‐19, coronavirus disease 2019. ¹(Howitz et al., 2003), ²(Bieganowski & Brenner, 2004), ³(Milne et al., 2007), ⁴(Hoffmann et al., 2013), ⁵(Libri et al., 2012), ⁶(Hubbard & Sinclair, 2014), ⁷(Pillai et al., 2015), ⁸(Rahnasto‐Rilla et al., 2018), ⁹(Pearson et al., 2008), ¹⁰(Feng et al., 2014), ¹¹(H. Zhang, Ryu, et al., 2016), ¹²(Fang et al., 2016), ¹³(Zainabadi, Liu, Caldwell, et al., 2017), ¹⁴(Stegen et al., 2018), ¹⁵(Mercken et al., 2014), ¹⁶(Artsi et al., 2014), and ¹⁷(Cheng et al., 2018)