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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 75, NO. 8, 2020

2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

The Contextualized Genetics of Human Longevity JACC Focus Seminar Claudio Franceschi, MD,a,b,* Paolo Garagnani, PHD,a,* Fabiola Olivieri, PHD,c,d Stefano Salvioli, PHD,a,y Cristina Giuliani, PHDe,y ABSTRACT The genetics of human longevity has long been studied, and in this regard, centenarians represent a very informative model. Centenarians are characterized by 2 main features: 1) the capability to avoid or postpone the major age-related diseases; and 2) a high level of heterogeneity of their phenotype. The rst suggests that longevity and resistance to diseases are mediated by shared mechanisms, the latter that many strategies can be used to become long lived, likely as a result of variable genome-environment interactions. The authors suggest that the complexity of genome-environment interactions must be considered within an evolutionary and ecological perspective and that the concept of risk allele is highly context dependent, changing with age, time, and geography. Genes involved in both longevity and cardiovascular diseases, taken as a paradigmatic example of age-related diseases, as well as other emerging topics in genetics of longevity, such as microribonucleic acid (miRNA) genetics, polygenic risk scores, environmental pollutants, and somatic mutations are discussed. (J Am Coll Cardiol 2020;75:96879) 2020 by the American College of Cardiology Foundation.

I

n recent decades the brand-new phenomenon

considered, compared with large genome-wide as-

of worldwide longevity is emerging, boosting

sociation studies (GWAS), and starting from 2 of

the

to

their peculiar features: 1) the heterogeneity of cen-

longevity. However, the results of this research

tenarians phenotype; and 2) the fact that they

have

avoid

study

been

of

the

sometimes

genetic extremely

contribution

heterogeneous

and often contradictory, possibly at least in part

or

postpone

major

age-related

diseases

(ARDs).

because of the denition of long-lived people that

Starting from this viewpoint, we will try to illus-

applies. In this regard, centenarians (age $100

trate some informative examples of genetic de-

years), semi-supercentenarians (age $105 years),

terminants of longevity, showing that: 1) genetics is

and supercentenarians (age $110 years) are people

context dependent; 2) the genetics environment

who are not only indisputably long lived but also

equation has multiple solutions, accounting for the

those

heterogeneity of the phenotype in centenarians;

who

better

exploited

the

potential

lifespan of Homo sapiens as a species. In fact, no

and

one has been reported so far to live more than

diseases such as cardiovascular ones are highly

about 120 years. We thus focus this review on the

interconnected, suggesting that they may be consid-

results

ered 2 sides of the same coin.

of

studies in

which

centenarians were

3)

genetic

determinants

of

longevity

and

From the aDepartment of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; bDepartment of Listen to this manuscripts

Applied Mathematics, Institute of Information Technology, Mathematics and Mechanics, Lobachevsky State University of Nizhny

audio summary by

NovgorodNational Research University, Nizhny Novgorod, Russia; cLaboratory of Experimental Pathology, Department of

Editor-in-Chief

Clinical and Molecular Sciences, Universit Politecnica delle Marche, Ancona, Italy; dCenter of Clinical Pathology and Regenerative

Dr. Valentin Fuster on

Therapy, IRCCS INRCA, Ancona, Italy; and the eLaboratory of Molecular Anthropology and Centre for Genome Biology, Depart-

JACC.org.

ment of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy. *Dr. Franceschi and Dr. Garagnani contributed equally to this work. yDr. Salvioli and Dr. Giuliani are co-senior authors. This study was supported by a grant from the Ministry of Education and Science of the Russian Federation Agreement (075-15-2019-871) and by ALMA IDEA-2017 project from the University of Bologna to Dr. Giuliani. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received November 14, 2019; revised manuscript received December 13, 2019, accepted December 17, 2019.

ISSN 0735-1097/$36.00

https://doi.org/10.1016/j.jacc.2019.12.032

Franceschi et al.

JACC VOL. 75, NO. 8, 2020 MARCH 3, 2020:96879

However,

HIGHLIGHTS

The effect of nuclear DNA variants (single or combinations) on longevity is context dependent. The genetics of longevity is informative to identify GxE interactions that protect against ARDs.

have

mixed

extreme limits of human life thanks to their capability to successfully adapt to a variety of stressors and to remodel better and more harmoniously (1). The prevalence of centenarians in a population can be assumed as an ecological indicator of optimization of the anthropological environment (2). The peculiar characteristics of centenarians are reported in Table 1. As a whole, centenarians maximized the product of their personal gene environment (GxE) equation, which is dynamic and dependent on a variety of historical and ecological factors (such as individual and population genetics, demography, sex, family and and

geographic environment, cultural and anthropological environment, social networks, and socioeconomic status) that we term ecological space, according to the evolutionary and anthropological concept of niche construction (3). This concept may help in understanding why only a few longevity variants and genes shared among different populations have been identied in GWAS, as recently reviewed consequence

of

this

concept

is

that

longevity variants are strongly context dependent. The following evidence supports this idea. First, it is known that longevity runs within families, as demonstrated by many studies, including those conducted on Sardinian people (3). Assortative mating (based on behavioral and cultural traits), favoring an excess of homozygosity, may play a role in the genetics of longevity in some populations (6) but not in others (such as in Utah and among the Dutch), as suggested by spouse data (7,8). On the whole, these data support the importance of context.

example, the European project GEHA (Genetics of Healthy Ageing) considered 2,118 nonagenarian sibling pairs enrolled at 15

ABBREVIATIONS AND ACRONYMS ARD = age-related disease CVD = cardiovascular disease DNA = deoxyribonucleic acid GxE = gene 3 environment

centers from 11 European countries. The re-

GWAS = genome-wide

sults highlighted the importance of APOE and

association studies

TOMM40, as well as the possibility to identify

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