Centenarians as extreme phenotypes: An ecological perspective to get insight into the relationship between the genetics of longevity and age-associated diseases

Giuliani, Cristina; Pirazzini, Chiara; Delledonne, Massimo; Xumerle, Luciano; Descombes, Patrick; Marquis, Julien; Mengozzi, Giacomo; Monti, Daniela; Bellizzi, Dina; Passarino, Giuseppe; Luiselli, Donata; Franceschi, Claudio; Garagnani, Paolo

doi:10.1016/j.mad.2017.02.007

Cited by 37 publications

(20 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, the idea emerged that patients affected by age-related diseases could be an effective control group for the study of the genetics of longevity [39][40][41] , for two main reasons : 1) long living subjects such as centenarians and patients affected by age-related diseases constitute "extreme phenotypes", and the comparison between most divergent phenotypes can increase the probability to identify disease-specific genetic protective factors linked to longevity; 2) a group of individuals with a specific age-related disease help to disentangle the genetic heterogeneity of the control group that inevitably is composed of individuals most of whom will likely develop one or more age-related diseases that eventually reduce their chances to reach longevity ( Figure 2). The concept that aging and chronic pathologies share common mechanisms and constitute a continuum where centenarians and patients affected by age-related diseases represent the opposite side of the spectrum is at the basis of the inclusion of age-related patients in studies on the genetics of human longevity 41 .…”

Section: Controls As Individuals Affected By Age-related Diseasesmentioning

confidence: 99%

Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework

Giuliani

Garagnani

Franceschi

2018

Circulation Research

Self Cite

View full text Add to dashboard Cite

Genetics of human longevity within an eco-evolutionary nature-nurture framework. -Circulation Research 2018 ; 123(7) : 745-772.The final published version is available online at: https://www.ahajournals.org/ ABSTRACTHuman longevity is a complex trait, and to disentangle its basis has a great theoretical and practical consequence for biomedicine. The genetics of human longevity is still poorly understood, despite a number of investigations that used different strategies and protocols. Here we argue that such rather disappointing harvest is largely due to the extraordinary complexity of the longevity phenotype in humans. The capability to reach the extreme decades of human lifespan appears to be the result of an intriguing mixture of geneenvironment interactions. Accordingly, the genetics of human longevity is here described as a highly context-dependent phenomenon, within a new integrated, ecological and evolutionary perspective, and is presented as a dynamic process, both historically and individually. The available literature has been scrutinized within this perspective, paying particular attention to factors (sex, individual biography, family, population ancestry, social structure, economic status and education, among others) that have been relatively neglected. The strength and limitations of the most powerful and used tools, such as GWAS and whole-genome sequencing, have been discussed, focusing on prominently emerged genes and regions, such as APOE, FOXO3, IL-6, IGF-1, chromosome 9p21, 5q33.3 and somatic mutations among others. The major results of this approach suggest that: i) the genetics of longevity is highly population-specific; ii) small-effect alleles, pleiotropy and the "complex allele timing" likely play a major role; iii) genetic risk factors are age-specific and need to be integrated in the light of the geroscience perspective; iv) a close relationship between genetics of longevity and genetics of age-related diseases (especially cardiovascular diseases) do exist. Finally, the urgent need of a global approach to the largely unexplored interactions between the three genetics of human body, i.e. nuclear, mitochondrial and microbiomes, is stressed. We surmise that the comprehensive approach here presented will help in increasing the above-mentioned harvest.

show abstract

Section: Controls As Individuals Affected By Age-related Diseasesmentioning

confidence: 99%

Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework

Giuliani

Garagnani

Franceschi

2018

Circulation Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Longevity is also related to complex diseases with late age at onset [ 3 – 6 ], though this relationship may sometimes involve antagonistic pleiotropy or trade-offs [ 7 , 8 ]. Interestingly, tradeoffs occur when a trait cannot increase without a decrease in another one and it has been supposed that beneficial genotypes may pleiotropically generate deleterious effects in phenotypes that trade off with them.…”

Section: Introductionmentioning

confidence: 99%

“…This concept has been proposed for many diseases, such as cancer, neurodegeneration, autoimmune and infectious diseases [ 9 ]. It has been also suggested that an evolutionary approach that relies on models/assumptions of population genetics may help in predicting the genetic background of susceptibility to such diseases [ 6 , 10 – 12 ]. Following this rationale, we have recently investigated the evolutionary history of the Italian population [ 13 ] to obtain prior knowledge essential to carry out the present study.…”

Section: Introductionmentioning

confidence: 99%

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

Giuliani

Sazzini

Pirazzini

et al. 2018

Aging

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…According to this integrated view, aging and ARDs/GSs become part of a continuum [6] where precise boundaries do not exist, and the two extremes are represented by centenarians [12][13][14] and their offspring [15] who largely avoided or postponed most ARDs/GSs and are char-acterized by decelerated aging [16], and patients who suffered one or more severe ARDs/GSs in their 60 s, 70 s, and 80 s and show signs of accelerated aging, respectively [7]. In between these two extremes, there is a continuum of intermediate trajectories representing a sort of gray area.…”

Section: Inflammaging: the State Of The Artmentioning

confidence: 99%