There has been a progressive increase in lifespan over the past century. At the turn/end of the 20th century， the average lifespan was 48 years for men and 51 years for women. More than 100 years of progress has led to a life expectancy of 76 years for men and 81 years for women as of 2017 (Xu, Murphy et al. 2020). Prima facie, these data are encouraging, as almost everyone wishes to live longer. However, an extended lifespan carries with it the burden of concomitant debilitating diseases and accompanying morbidity, which limit ambulation and enjoyment of life.
It is important to recognize that most of these diseases are mediated, in part, by increased oxidative stress (Beck 2000, Cervantes Gracia, Llanas-Cornejo et al. 2017, Guzik and Touyz 2017, Butterfield and Halliwell 2019, Goncalves and Romeiro 2019, Hosseinabadi and Khanjani 2019, Katerji, Filippova et al. 2019, Gyuraszova, Gurecka et al. 2020, Zhang, Li et al. 2020). Oxidative stress is thought to be a major mechanism limiting longevity in general(Finkel and Holbrook 2000, Yoon, Yun et al. 2002), and limiting healthful longevity, in particular, which has not been examined in depth.
Ribosomal Protein S6 Kinase β-1 (S6K1) KO Mice：Median Age of Survival, of S6K1 KO is Increased by 19% in Females Compared to WT Median Age of Survival of 28 Months S6K1 is the principal kinase effector downstream of mammalian target of rapamycin complex 1 (mTORC1), which lowers mitochondrial ROS levels(Binsch, Jelenik et al. 2017). Longevity as measured by median lifespan was enhanced in female S6K1 KO mice by 19%, but no such difference was observed in males (Selman, Tullet et al. 2009). These gender differences could be due to estrogen regulation of S6K1 activation (Jaffer, Shynlova et al. 2009).
Young male S6K1 KO mice, due to a marked increase in metabolic rate and lipolysis, exhibit lower body weight and have improved glucose tolerance and insulin sensitivity compared to WT in response to either normal diet (Um, Frigerio et al. 2004) or high fat diet (Um, Frigerio et al. 2004, Binsch, Jelenik et al. 2017). In addition, improved glucose tolerance and insulin sensitivity were also observed in 20 month old female S6K1 KO compared to WT mice in response to high fat diet, though this protective feature was not observed in young female S6K1 KO mice (Selman, Tullet et al. 2009). S6K1 KO with high fat diet also exhibited greater running distance, longer running times, and reduced triglyceride contents in liver and skeletal muscle after 4 weeks of exercise training compared to WT mice (Binsch, Jelenik et al. 2017). Two mechanisms mediate increased oxidative stress by S6K1: 1) mitochondrial superoxide production is directly increased. 2) S6K1 activation mediates uncoupling of eNOS, decreasing antioxidant capacity (Rajapakse, Yepuri et al. 2011). In addition, S6K1 KO mice exhibit less mitochondrial ROS production (Binsch, Jelenik et al. 2017). In vitro, overexpression of S6K1 results in increased superoxide and decreased NO production (Rajapakse, Yepuri et al. 2011). S6K1 levels are elevated in breast cancer, a result that is mediated by estrogen receptors, whereas S6K1 also regulates ligand independent estrogen receptor activity. Together the two form a feed-forward loop, promoting breast cancer cell proliferation (Maruani, Spiegel et al. 2012). In addition, S6K1 inhibitors induce autophagy and apoptosis in cervical cancer cells (Nam, Yi et al. 2019) and BT474 breast cancer cells (Park, Jin et al. 2015) in vitro. Cardioprotection, and the role of β-adrenergic signaling have not been examined in this model.
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