Genetic associations with longevity are on average stronger in females than in males

Yi Zeng; Huashuai Chen; Xiaomin Liu; Zijun Song; Yao Yao; Xiaoyan Lei; Xiaozhen Lv; Lingguo Cheng; Zhihua Chen; Chen Bai; Zhaoxue Yin; Yuebin Lv; Jiehua Lu; Jianxin Li; Kenneth C Land; Anatoliy Yashin; Angela M O'Rand; Liang Sun; Ze Yang; Wei Tao; Jun Gu; William Gottschalk; Qihua Tan; Kaare Christensen; Therese Hesketh; Xiao-Li Tian; Huanming Yang; Viviana Egidi; Graziella Caselli; Jean-Marie Robine; Huali Wang; Xiaoming Shi; James W Vaupel; Michael W Lutz; Chao Nie; Junxia Min

doi:10.1016/j.heliyon.2023.e23691

Genetic associations with longevity are on average stronger in females than in males

Heliyon. 2023 Dec 14;10(1):e23691. doi: 10.1016/j.heliyon.2023.e23691. eCollection 2024 Jan 15.

Authors

Yi Zeng^{1

2}, Huashuai Chen^{3

1}, Xiaomin Liu⁴, Zijun Song⁵, Yao Yao², Xiaoyan Lei², Xiaozhen Lv⁶, Lingguo Cheng⁷, Zhihua Chen⁴, Chen Bai², Zhaoxue Yin⁸, Yuebin Lv⁹, Jiehua Lu¹⁰, Jianxin Li¹⁰, Kenneth C Land¹¹, Anatoliy Yashin¹¹, Angela M O'Rand¹¹, Liang Sun¹², Ze Yang¹², Wei Tao¹³, Jun Gu¹³, William Gottschalk¹⁴, Qihua Tan¹⁵, Kaare Christensen¹⁵, Therese Hesketh^{16

17}, Xiao-Li Tian¹⁸, Huanming Yang^{4

19}, Viviana Egidi²⁰, Graziella Caselli²⁰, Jean-Marie Robine⁶, Huali Wang²¹, Xiaoming Shi⁹, James W Vaupel¹⁵, Michael W Lutz¹⁴, Chao Nie^{4

22}, Junxia Min⁵

Affiliations

¹ Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing, 100871, China.
² Center for the Study of Aging and Human Development, Medical School of Duke University, Durham, NC, USA, 27710.
³ Business School of Xiangtan University, Xiangtan, 411105, China.
⁴ BGI-Shenzhen, Shenzhen, 518083, China.
⁵ The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
⁶ French National Institute of Health and Medical Research (INSERM) and Ecole Pratique des Hautes Etudes (EPHE) FR, Italy.
⁷ School of Business, Nanjing University, Nanjing, 210093, China.
⁸ Division of Non-Communicable Disease Control and Community Health, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
⁹ National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, 100021, China.
¹⁰ Department of Sociology, Peking University, Beijing, 100871, China.
¹¹ Duke Population Research Institute's Center for Population Health and Aging, Duke University, Durham, NC, USA, 27710.
¹² The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
¹³ School of Life Sciences, Peking University, Beijing, 100871, China.
¹⁴ Department of Neurology, Medical Center, Duke University, Durham, NC, USA, 27710.
¹⁵ University of Southern Denmark, Odense, DK-5000, Denmark.
¹⁶ Institute for Global Health, University College London, London, UK.
¹⁷ Institute for Global Health, School of Public Health, Zhejiang University, Hangzhou, 310058, China.
¹⁸ Human Aging Research Institute and School of Life Science, Nanchang University, Jiangxi, 330031, China.
¹⁹ James D. Watson Institute of Genome Sciences, Hangzhou 310008, China310058.
²⁰ Department of Statistical Sciences, University of Rome La Sapienza, Roma, 00161, Italy.
²¹ The Third Affiliated Hospital of Health Science Center, Peking University, Italy.
²² BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, 518083, China.

Abstract

It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians. The present study's findings may partially explain the well-known male-female health-survival paradox and suggest that genetic variants may be associated with different reactions between males and females to the same vaccine, drug treatment and/or nutritional intervention. Thus, our findings provide evidence to steer away from traditional view that "one-size-fits-all" for clinical interventions, and to consider sex differences for improving healthcare efficiency. We suggest future investigations focusing on effects of interactions between sex-specific genetic variants and environment on longevity as well as biological function.

Keywords: Centenarians; Longevity; Male-female health-survival paradox; Polygenic risk score analysis; Precise healthcare for males and females; sex differences.