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Aging (Albany NY). 2018 Aug 8;10(8):1947-1963. doi: 10.18632/aging.101515.

Impact of demography and population dynamics on the genetic architecture of human longevity.

Author information

1
Department of Biological, Geological, and Environmental Sciences (BiGeA), Laboratory of Molecular Anthropology and Centre for Genome Biology, University of Bologna, Bologna, Italy.
2
School of Anthropology and Museum Ethnography, University of Oxford, Oxford, UK.
3
Interdepartmental Center "L. Galvani," (CIG), University of Bologna, Bologna, Italy.
4
IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy.
5
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
6
Applied Biomedical Research Center (CRBA), S. Orsola-Malpighi Polyclinic, Bologna, Italy.
7
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA.
8
Istituto Auxologico Italiano IRCCS, Cusano Milanino, Milan, Italy.
9
Department of Biology, Ecology and Earth Sciences, University of Calabria, Rende, Italy.
10
Geriatric Unit, Department of Medical Sciences and Community Health, Milan, Italy.
11
Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
12
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
13
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
14
IRCCS Don Gnocchi, Florence, Italy.
15
Azienda Ospedaliera-IRCCS, Reggio Emilia, Italy.
16
Department of Surgical, Medical, Dental and Morphological Sciences with Interest Transplant, Oncological and Regenerative Medicine, , Italy.
17
Department for the Cultural Heritage (DBC), University of Bologna, Ravenna, Italy.
18
Co-senior authors.
19
Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, S-141 86 Stockholm, Sweden.
20
CNR Institute of Molecular Genetics, Unit of Bologna, Bologna, Italy.
21
Rizzoli Orthopaedic Institute, Laboratory of Cell Biology, Bologna, Italy.
#
Contributed equally

Abstract

The study of the genetics of longevity has been mainly addressed by GWASs that considered subjects from different populations to reach higher statistical power. The "price to pay" is that population-specific evolutionary histories and trade-offs were neglected in the investigation of gene-environment interactions. We propose a new "diachronic" approach that considers processes occurred at both evolutionary and lifespan timescales. We focused on a well-characterized population in terms of evolutionary history (i.e. Italians) and we generated genome-wide data for 333 centenarians from the peninsula and 773 geographically-matched healthy individuals. Obtained results showed that: (i) centenarian genomes are enriched for an ancestral component likely shaped by pre-Neolithic migrations; (ii) centenarians born in Northern Italy unexpectedly clustered with controls from Central/Southern Italy suggesting that Neolithic and Bronze Age gene flow did not favor longevity in this population; (iii) local past adaptive events in response to pathogens and targeting arachidonic acid metabolism became favorable for longevity; (iv) lifelong changes in the frequency of several alleles revealed pleiotropy and trade-off mechanisms crucial for longevity. Therefore, we propose that demographic history and ancient/recent population dynamics need to be properly considered to identify genes involved in longevity, which can differ in different temporal/spatial settings.

KEYWORDS:

centenarians; human genetics; longevity; population dynamics

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