Suggestions from Geroscience for the Genetics of Age-Related Diseases

Franceschi, Claudio; Garagnani, Paolo

doi:10.1371/journal.pgen.1006399

Cited by 20 publications

(15 citation statements)

References 10 publications

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“…This concept particularly implies that “small” genetic effects (often expected in GWAS of age-related phenotypes) can be due to a complex superposition of large effects rather than small penetrance. Then, just relaying on large samples in GWAS of age-related phenotypes without dissecting the natural-selection–free genetic heterogeneity is inefficient because increasing the sample size will also increase heterogeneity [ 28 ]. The current study supports this concept by highlighting strong impact of antagonistic heterogeneity, which is counter-intuitive in medical genetics but natural within the evolutionary framework.…”

Section: Discussionmentioning

confidence: 99%

Strong impact of natural-selection–free heterogeneity in genetics of age-related phenotypes

Kulminski

Huang

Loika

et al. 2018

Aging

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A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection–free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection–free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection–free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

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Section: Discussionmentioning

confidence: 99%

Strong impact of natural-selection–free heterogeneity in genetics of age-related phenotypes

Kulminski

Huang

Loika

et al. 2018

Aging

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“…157 Moreover, this approach underestimates the relationship between genes and the environmental changes that occur generations after generations, so that genes that impact on longevity may be different in different birth cohort (Figure 8). Industrial progress, improvements in living conditions, changes in nutrition, and other transformations in the human environment (including the emerging obesogenic environment) may have different survival effects on individuals with similar or different genotypes, as previously hypothesized 137 and recently supported 137,158 .This scenario is further complicated by the fact that for certain genes GxE interactions change with age 159 . APOE and CHRNA3/5 (nicotinic acetylcholine receptor) are the genes identified and replicated in the highest number of study on parental lifespan.…”

Section: Parental Lifespan: a Different Approach In Gwas Studiesmentioning

confidence: 91%

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

Giuliani

Garagnani

Franceschi

2018

Circulation Research

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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.

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“…Within this perspective, particular attention has to be devoted to the genetics of each individual which is the complex result of the interaction between nuclear and mitochondrial genetics (stable with the exception of somatic mutations) and microbiomes’s genetics (malleable and adaptative to the environment), focusing on GM for its capability to be modified by basic habits such as nutrition. In particular, we predict that it will be useful to combine the abovementioned integrated biomarkers’ assessment with established and new genetic risk factors for ARDs, taking into account some criticalities related to population genetics and demographic birth cohorts ( 225 ).…”

Section: Markers Of Biological Agementioning

confidence: 99%

The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates

et al. 2018

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Geroscience, the new interdisciplinary field that aims to understand the relationship between aging and chronic age-related diseases (ARDs) and geriatric syndromes (GSs), is based on epidemiological evidence and experimental data that aging is the major risk factor for such pathologies and assumes that aging and ARDs/GSs share a common set of basic biological mechanisms. A consequence is that the primary target of medicine is to combat aging instead of any single ARD/GSs one by one, as favored by the fragmentation into hundreds of specialties and sub-specialties. If the same molecular and cellular mechanisms underpin both aging and ARDs/GSs, a major question emerges: which is the difference, if any, between aging and ARDs/GSs? The hypothesis that ARDs and GSs such as frailty can be conceptualized as accelerated aging will be discussed by analyzing in particular frailty, sarcopenia, chronic obstructive pulmonary disease, cancer, neurodegenerative diseases such as Alzheimer and Parkinson as well as Down syndrome as an example of progeroid syndrome. According to this integrated view, aging and ARDs/GSs become part of a continuum where precise boundaries do not exist and the two extremes are represented by centenarians, who largely avoided or postponed most ARDs/GSs and are characterized by decelerated aging, and patients who suffered one or more severe ARDs in their 60s, 70s, and 80s and show signs of accelerated aging, respectively. In between these two extremes, there is a continuum of intermediate trajectories representing a sort of gray area. Thus, clinically different, classical ARDs/GSs are, indeed, the result of peculiar combinations of alterations regarding the same, limited set of basic mechanisms shared with the aging process. Whether an individual will follow a trajectory of accelerated or decelerated aging will depend on his/her genetic background interacting lifelong with environmental and lifestyle factors. If ARDs and GSs are manifestations of accelerated aging, it is urgent to identify markers capable of distinguishing between biological and chronological age to identify subjects at higher risk of developing ARDs and GSs. To this aim, we propose the use of DNA methylation, N-glycans profiling, and gut microbiota composition to complement the available disease-specific markers.

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Suggestions from Geroscience for the Genetics of Age-Related Diseases

Cited by 20 publications

References 10 publications

Strong impact of natural-selection–free heterogeneity in genetics of age-related phenotypes

Strong impact of natural-selection–free heterogeneity in genetics of age-related phenotypes

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

The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates

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