scholarly journals Human genetic analyses of organelles highlight the nucleus in age-related trait heritability

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Rahul Gupta ◽  
Konrad Karczewski ◽  
Daniel Howrigan ◽  
Benjamin Neale ◽  
Vamsi Mootha, MD
Keyword(s):  
Transcription Factors ◽  
Disease Risk ◽  
Purifying Selection ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Mitochondrial Proteome ◽  
Related Disease ◽  
Age Related ◽  
Genes Encoding ◽  
Open Question ◽  
Related Trait

Most age-related human diseases are accompanied by a decline in cellular organelle integrity, including impaired lysosomal proteostasis and defective mitochondrial oxidative phosphorylation. An open question, however, is the degree to which inherited variation in or near genes encoding each organelle contributes to age-related disease pathogenesis. Here, we evaluate if genetic loci encoding organelle proteomes confer greater-than-expected age-related disease risk. As mitochondrial dysfunction is a 'hallmark' of aging, we begin by assessing nuclear and mitochondrial DNA loci near genes encoding the mitochondrial proteome and surprisingly observe a lack of enrichment across 24 age-related traits. Within nine other organelles, we find no enrichment with one exception: the nucleus, where enrichment emanates from nuclear transcription factors. In agreement, we find that genes encoding several organelles tend to be 'haplosufficient', while we observe strong purifying selection against heterozygous protein-truncating variants impacting the nucleus. Our work identifies common variation near transcription factors as having outsize influence on age-related trait risk, motivating future efforts to determine if and how this inherited variation then contributes to observed age-related organelle deterioration.

scholarly journals Human genetic analyses of organelles highlight the nucleus in age-related trait heritability

2021 ◽  
Author(s):  
Rahul Gupta ◽  
Konrad J. Karczewski ◽  
Daniel Howrigan ◽  
Benjamin M. Neale ◽  
Vamsi K. Mootha
Keyword(s):  
Gene Regulation ◽  
Transcription Factors ◽  
Natural Selection ◽  
Mitochondrial Dysfunction ◽  
Purifying Selection ◽  
Genetic Analyses ◽  
Related Disease ◽  
Age Related ◽  
Open Question ◽  
Related Trait

AbstractAging is associated with defects in many organelles, but an open question is whether the inherited risk for age-related disease is enriched within loci relevant to each organelle. Here, we begin with a focus on mitochondria, as mitochondrial dysfunction is a hallmark of age-related disease. We report a striking lack of enrichment of mitochondria-relevant loci across GWAS for 24 age-related traits. Analyses of nine additional organelles reveal enrichment only for the nucleus, particularly nuclear transcription factors. Consistent with these results, natural selection appears to exert stronger purifying selection against protein-truncating variants for transcription factors compared to mitochondrial pathways, underscoring the importance of inherited variation in gene-regulation in age-related traits.

scholarly journals Flavonoids and age-related disease: Risk, benefits and critical windows

Maturitas ◽  
2010 ◽  
Vol 66 (2) ◽  
pp. 163-171 ◽  
Author(s):  
J.K. Prasain ◽  
S.H. Carlson ◽  
J.M. Wyss
Keyword(s):  
Disease Risk ◽  
Related Disease ◽  
Age Related

Calorie Restriction in Nonhuman Primates: Implications for Age-Related Disease Risk

1998 ◽  
Vol 1 (4) ◽  
pp. 315-326 ◽  
Author(s):  
MARK A. LANE ◽  
ANGELA BLACK ◽  
DONALD K. INGRAM ◽  
GEORGE S. ROTH
Keyword(s):  
Calorie Restriction ◽  
Nonhuman Primates ◽  
Disease Risk ◽  
Related Disease ◽  
Age Related

scholarly journals Physical Activity and Telomere Biology: Exploring the Link with Aging-Related Disease Prevention

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Andrew T. Ludlow ◽  
Stephen M. Roth
Keyword(s):  
Physical Activity ◽  
Physical Inactivity ◽  
Replicative Senescence ◽  
Disease Risk ◽  
Future Research ◽  
Activity Levels ◽  
Related Disease ◽  
Age Related ◽  
A Cell ◽  
Telomere Biology

Physical activity is associated with reduced risk of several age-related diseases as well as with increased longevity in both rodents and humans. Though these associations are well established, evidence of the molecular and cellular factors associated with reduced disease risk and increased longevity resulting from physical activity is sparse. A long-standing hypothesis of aging is the telomere hypothesis: as a cell divides, telomeres shorten resulting eventually in replicative senescence and an aged phenotype. Several reports have recently associated telomeres and telomere-related proteins to diseases associated with physical inactivity and aging including cardiovascular disease, insulin resistance, and hypertension. Interestingly several reports have also shown that longer telomeres are associated with higher physical activity levels, indicating a potential mechanistic link between physical activity, reduced age-related disease risk, and longevity. The primary purpose of this review is to discuss the potential importance of physical activity in telomere biology in the context of inactivity- and age-related diseases. A secondary purpose is to explore potential mechanisms and important avenues for future research in the field of telomeres and diseases associated with physical inactivity and aging.

scholarly journals METABOLIC INTEGRITY – A FACTOR IN AGING AND A PLAYER IN THE MECHANISMS OF CR

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S67-S67
Author(s):  
Rozalyn Anderson
Keyword(s):  
Metabolic Pathways ◽  
Nonhuman Primates ◽  
Disease Risk ◽  
Metabolic Dysfunction ◽  
Aging Research ◽  
Root Cause ◽  
Related Disease ◽  
Metabolic Component ◽  
Age Related ◽  
Metabolic Biomarkers

Abstract An emerging paradigm in aging research identifies metabolic dysfunction as a root cause in age-related disease vulnerability. Several diseases of aging, including diabetes, cancer, and neurodegeneration, have an established metabolic component. Our studies have focused on links between metabolic status and disease vulnerability. Caloric restriction (CR) delays aging and the onset of age-related disease in diverse species, including nonhuman primates. Molecular profiling identifies CR responsive elements in the transcriptome, proteome, and metabolome that are highly enriched for metabolic pathways and in particular mitochondrial processes. These data show that improvements in health and survival are associated with maintenance of system wide metabolic homeostasis and preserved energy metabolism among tissues. Metabolic biomarkers identified in these studies may be clinically relevant for the early identification of elevated disease risk in humans and could even be potential targets for the development of novel strategies to lower disease vulnerability as a function of age.

scholarly journals Deregulation of CRTCs in Aging and Age-Related Disease Risk

2017 ◽  
Vol 33 (5) ◽  
pp. 303-321 ◽  
Author(s):  
Caroline C. Escoubas ◽  
Carlos G. Silva-García ◽  
William B. Mair
Keyword(s):  
Disease Risk ◽  
Related Disease ◽  
Age Related

scholarly journals EPIGENETICS MARKERS OF AGING AND EXPOSURES

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S735-S735
Author(s):  
Joanne Murabito
Keyword(s):  
Dna Methylation ◽  
Cohort Studies ◽  
Disease Risk ◽  
Association Studies ◽  
Methylation Data ◽  
Expression Data ◽  
Cross Sectional ◽  
Related Disease ◽  
Age Related ◽  
Dna Methylation Age

Abstract Widespread changes to the epigenome occur with aging. DNA methylation is one of the most commonly studied epigenetic mechanisms, reflects lifetime exposures that impact aging, and is associated with age-related disease risk. Many longitudinal cohort studies have existing cross-sectional or longitudinal DNA methylation data along with genotype and expression data permitting investigation of relationships between DNA methylation markers, exposures, and disease. The data can be leveraged to conduct large epigenome-wide association studies (EWAS) of aging and age-related disease to identify DNA methylation biomarkers and lead to insights into novel biologic pathways for development of interventions to delay aging. DNA methylation age measures robustly predict chronologic age and associate with both healthspan and lifespan. During the workshop, examples from cohort studies and the CHARGE consortium will be presented.

Summary and Assessment of Studies on Cardiac Aging in Nonhuman Primates

2021 ◽  
Author(s):  
Hillary F Huber ◽  
Peter W Nathanielsz ◽  
Geoffrey D Clarke
Keyword(s):  
Life Course ◽  
Early Life ◽  
Nonhuman Primates ◽  
Disease Risk ◽  
Future Research ◽  
Cardiac Aging ◽  
Related Disease ◽  
Biomarkers Of Aging ◽  
Age Related ◽  
Wide Range

Nonhuman primates (NHP) are important translational models for cardiac aging. To assess progress in this research area and to provide a reference for other investigators, we identified papers indexed in PubMed to determine what species, ages, outcomes, treatments, and approaches have been studied. Since 1983, 33 studies of cardiac aging in NHP have been published.Of these, 27 used species of macaque, 6 baboon, 1 vervet, 1 orangutan, and 1 marmoset (some studies were multispecies).Common research approaches were echocardiography, ECG, and histology of the left ventricle. Only 10 studies performedsex-based analyses. The average age of the oldest macaque studied was 26 y. The reported mean lifespan of macaques incaptivity is around 30 y. The age of the oldest baboon studied was 24 y. Baboons in captivity are reported to live on averageto 21 y. Twelve studies took a “life course” approach, studying animals of a wide range of ages from less than or equal to 10y through the late teens to thirties, and employing analyses designed to show change over time. Keeping NHP into old ageis a major challenge for biomedical research. The ideal design is to start monitoring in early life and to track how cardiacstructure and function change with age. Important issues for future research are an increased focus on life-course approaches, investment in existing life-course NHP cohorts, better reporting of study sample characteristics, more molecular studies to identify genetic risk factors and mechanisms, attention to sex as a biological variable, a move away from descriptive reports to mechanistic studies, development of biomarkers to predict disease risk, and exploration of interventions that are implemented early in life to prevent or delay age-related disease later in life. Reducing exposure to early life adversity, identifying early-life biomarkers of aging and age-related disease, and early treatment can contribute to longer health span.

scholarly journals Deregulation of CRTCs in Aging and Age-Related Disease Risk

2018 ◽  
Vol 34 (4) ◽  
pp. 326
Author(s):  
Caroline C. Escoubas ◽  
Carlos G. Silva-García ◽  
William B. Mair
Keyword(s):  
Disease Risk ◽  
Related Disease ◽  
Age Related
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