Genetics of frailty: A longevity perspective.
Ontology highlight
ABSTRACT:
SUBMITTER: Sathyan S
PROVIDER: S-EPMC7729977 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
Publications
Genetics of frailty: A longevity perspective.
Sathyan Sanish S Verghese Joe J
Translational research : the journal of laboratory and clinical medicine 20200319
Frailty is a complex late life phenotype characterized by cumulative declines in multiple physiological systems that increases the risk for disability and mortality. The biological changes associated with aging are risk factors for frailty as well as for complex diseases; whereas longevity is assumed to be an outcome of protective biological mechanisms. Understanding the interplay between biological alterations associated with aging and protective mechanisms associated with longevity in the cont ...[more]
Similar Datasets
Project description:Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may 'buffer' the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.
| S-EPMC3898394 | biostudies-literature
Project description:This article investigates the effect on the mouse frailty index (FI), of factors known to influence lifespan and healthspan in mice: strain (short-lived DBA/2J mice vs long-lived C57BL/6J mice), calorie restriction (CR), and resveratrol treatment. The mouse FI, based on deficit accumulation, was recently validated in C57BL/6J mice by Whitehead JC, Hildebrand BA, Sun M, et al. (A clinical frailty index in aging mice: comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci. 2014;69:621-632) and shares many characteristics of the human FI. FI scores were measured in male and female aged (18 months) ad-libitum fed and CR DBA/2J and C57BL/6J mice, as well as male aged (24 months) C57BL/6J mice ad-libitum fed with or without resveratrol (100 mg/kg/day) in the diet for 6 months. Mean scores of two raters were used, and the raters had excellent inter-rater reliability (ICC = 0.88, 95% CI [0.80, 0.92]). Furthermore, the interventions of CR and resveratrol were associated with a significant reduction in FI scores in C57BL/6J mice, compared to age-matched controls. The short-lived DBA/2J mice also had slightly higher FI scores than the C57BL/6J mice, for the male calorie-restricted groups (DBA/2J FI = 0.16±0.03, C57BL/6J FI = 0.11±0.03, p = .01). This study uses the mouse FI developed by Whitehead JC, Hildebrand BA, Sun M, et al. (A clinical frailty index in aging mice: comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci. 2014;69:621-632) in a different mouse colony and shows that this tool can be applied to quantify the effect of dietary and pharmaceutical interventions on frailty.
| S-EPMC4757961 | biostudies-literature
Project description:Observational studies suggest associations of triglyceride levels with longevity and frailty. This study aimed to test whether the associations are causal. We used data from the Rugao Longevity and Ageing Study, a population-based cohort study performed in Rugao, China. A variant in the APOA5 gene region (rs662799) was used as the genetic instrument. Mendelian randomization (MR) analyses were performed to examine the associations of genetically predicted triglycerides with two ageing phenotypes - longevity ( ≥95 years) and frailty (modified Fried frailty phenotype and Rockwood frailty index). C allele of rs662799 was robustly associated with higher triglyceride levels in the comparison group (β = 0.301 mmol/L per allele, p < 0.001), with an F statistic of 95.3 and R2 = 0.040. However MR analysis did not provide strong evidence for an association between genetically predicted triglyceride levels and probability of longevity (OR: 0.61; 95% CI: 0.35, 1.07 per 1 mmol/L increase in triglycerides). In the ageing arm (70-84 years), genetically predicted triglyceride levels were not associated with the frailty index (β = 0.008; 95% CI: -0.013, 0.029) or the frailty phenotype (OR: 1.91; 95% CI: 0.84, 4.37). In conclusion, there is currently a lack of sufficient evidence to support causal associations of triglyceride levels with longevity and frailty in elderly populations.
| S-EPMC5278549 | biostudies-literature
Project description:Aging negatively impacts vitality and health. Many genetic pathways that regulate aging were discovered in invertebrates. However, the genetics of aging is more complex in vertebrates because of their specialized systems. This Review discusses advances in the genetic regulation of aging in vertebrates from work in mice, humans, and organisms with exceptional lifespans. We highlight challenges for the future, including sex-dependent differences in lifespan and the interplay between genes and environment. We also discuss how the identification of reliable biomarkers of age and development of new vertebrate models can be leveraged for personalized interventions to counter aging and age-related diseases.
| S-EPMC7592626 | biostudies-literature
Project description:Schizophrenia (SZ) is a common disorder that runs in families. It has a relatively high heritability, i.e., inherited factors account for the major proportion of its etiology. The high heritability has motivated gene mapping studies that have improved in sophistication through the past two decades. Belying earlier expectations, it is now becoming increasingly clear that the cause of SZ does not reside in a single mutation, or even in a single gene. Rather, there are multiple DNA variants, not all of which have been identified. Additional risk may be conferred by interactions between individual DNA variants, as well as 'gene-environment' interactions. We review studies that have accounted for a fraction of the heritability. Their relevance to the practising clinician is discussed. We propose that continuing research in DNA variation, in conjunction with rapid ongoing advances in allied fields, will yield dividends from the perspective of diagnosis, treatment prediction through pharmacogenetics, and rational treatment through discoveries in pathogenesis.
| S-EPMC5445022 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component and is characterized by chronic inflammation and the production of anti-nuclear auto-antibodies. In the era of genome-wide association studies (GWASs), elucidating the genetic factors present in SLE has been a very successful endeavor; 28 confirmed disease susceptibility loci have been mapped. In this review, we summarize the current understanding of the genetics of lupus and focus on the strongest associated risk loci found to date (P <1.0 × 10-8). Although these loci account for less than 10% of the genetic heritability and therefore do not account for the bulk of the disease heritability, they do implicate important pathways, which contribute to SLE pathogenesis. Consequently, the main focus of the review is to outline the genetic variants in the known associated loci and then to explore the potential functional consequences of the associated variants. We also highlight the genetic overlap of these loci with other autoimmune diseases, which indicates common pathogenic mechanisms. The importance of developing functional assays will be discussed and each of them will be instrumental in furthering our understanding of these associated variants and loci. Finally, we indicate that performing a larger SLE GWAS and applying a more targeted set of methods, such as the ImmunoChip and next generation sequencing methodology, are important for identifying additional loci and enhancing our understanding of the pathogenesis of SLE.
| S-EPMC3446495 | biostudies-literature
Project description:Despite substantial recent advancements in psychiatric genetic research, progress in identifying the genetic basis of anxiety disorders has been limited. We review the candidate gene and genome-wide literatures in anxiety, which have made limited progress to date. We discuss several reasons for this hindered progress, including small samples sizes, heterogeneity, complicated comorbidity profiles, and blurred lines between normative and pathological anxiety. To address many of these challenges, we suggest a developmental, multivariate framework that can inform and enhance anxiety phenotypes for genetic research. We review the psychiatric and genetic epidemiological evidence that supports such a framework, including the early onset and chronic course of anxiety disorders, shared genetic risk factors among disorders both within and across time, and developmentally dynamic genetic influences. We propose three strategies for developmentally sensitive phenotyping: examination of early temperamental risk factors, use of latent factors to model underlying anxiety liability, and use of developmental trajectories as phenotypes. Expanding the range of phenotypic approaches will be important for advancing studies of the genetic architecture of anxiety disorders.
| S-EPMC3721501 | biostudies-literature
Project description:Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene-environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.
| S-EPMC3410620 | biostudies-literature
Project description:Genetics evolved as a field of science after 1900 with new theories being derived from experiments obtained in fruit flies, bacteria, and viruses. This personal account suggests that the origins of human genetics can best be traced to the years 1949 to 1959. Several genetic scientific advances in genetics in 1949 yielded results directly relating to humans for the first time, except for a few earlier observations. In 1949 the first textbook of human genetics was published, the American Journal of Human Genetics was founded, and in the previous year the American Society of Human Genetics. In 1940 in Britain a textbook entitled Introduction to Medical Genetics served as a foundation for introducing genetic aspects into medicine. The introduction of new methods for analyzing chromosomes and new biochemical assays using cultured cells in 1959 and subsequent years revealed that many human diseases, including cancer, have genetic causes. It became possible to arrive at a precise cause-related genetic diagnosis. As a result the risk of occurrence or re-occurrence of a disease within a family could be assessed correctly. Genetic counseling as a new concept became a basis for improved patient care. Taken together the advances in medically orientated genetic research and patient care since 1949 have resulted in human genetics being both, a basic medical and a basic biological science. Prior to 1949 genetics was not generally viewed in a medical context. Although monogenic human diseases were recognized in 1902, their occurrence and distribution were considered mainly at the population level.
| S-EPMC8298510 | biostudies-literature
Project description:The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an over-expression of anti-inflammatory sequence variants of immune/inflammatory genes. However, as well known, genetic, epigenetic, stochastic and environmental factors seem to have a crucial role in ageing and longevity. Epigenetics is associated with ageing, as demonstrated in many studies. In particular, ageing is associated with a global loss of methylation state. Thus, the aim of future studies will be to analyze the weight of epigenetic changes in ageing and longevity.
| S-EPMC3402998 | biostudies-literature