Whole-genome sequencing analysis of semi-supercentenarians.

Paolo Garagnani,Vincenzo Iannuzzi,Luca Bertamini,Claudia Sala,Nicola Martinelli,Gastone Castellani,Sebastiano Collino,Benedetta Nacmias,Sandro Sorbi,Daniela Mari,Julien Marquis,Davide Pettener,Giuseppe Passarino,Martina Casati,Katarzyna Malgorzata Kwiatkowska,Alberto Ferrarini,Cristina Giuliani,Chiara Pirazzini,Beatrice Arosio,Donata Luiselli,Luciano Xumerle,Patrick Descombes,Claudio Franceschi,Daniela Monti,Oliviero Olivieri,Elena Marasco,Maria Giulia Bacalini,Massimo Delledonne,Evelyn Ferri,Francesco De Rango,Armand Valsesia,Domenico Girelli,Frédéric Raymond ,Patrizia D’aquila ,Jérôme Carayol

doi:10.7554/elife.57849

Abstract

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.

Highlights

The study of healthy aging is of increasing importance since the phenomenon of human aging is inevitably linked to cumulative burden of age-associated diseases – such as cardiovascular disease (CVDs), stroke, type 2 diabetes, hypertension, different type of cancer, or dementia (Christensen et al, 2009; Franceschi and Bonafe, 2003)
We used the data produced by whole genome sequencing (WGS) in 105+/110+ as discovery data (Cohort 1) to have information about all the variants, and to maximize the probability to identify significant genetic association according to biological models
To validate the results obtained in Cohort 1, we used Cohort 2 that is characterized by a high number of samples (333 centenarians and 358 controls)

Summary

Introduction

The study of healthy aging is of increasing importance since the phenomenon of human aging is inevitably linked to cumulative burden of age-associated diseases – such as cardiovascular disease (CVDs), stroke, type 2 diabetes, hypertension, different type of cancer, or dementia (Christensen et al, 2009; Franceschi and Bonafe, 2003). Sebastiani et al, 2016 showed that, considering individuals surviving to age 105 years, the relative risk of sibling surviving to 105 years is 35 times the chance of living to age 105 of the control population. These data suggest a more potent genetic contributions if samples are recruited in the last percentile of survival in accord with Tan et al, 2008 who reported that the power to detect association with longevity is greater for centenarians versus nonagenarians samples of the same birth cohort. Healthy aging and exceptional longevity (people who live more than 100 years) are deeply related (Christensen and McGue, 2016)

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Conclusion