Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

Pilling, Luke C.; Atkins, Janice L.; Bowman, Kirsty; Jones, Samuel E.; Tyrrell, Jessica; Beaumont, Robin N; Ruth, Katherine S.; Tuke, Marcus A.; Yaghootkar, Hanieh; Wood, Andrew R.; Freathy, Rachel M.; Murray, Anna; Weedon, Michael N.; Xue, Luting; Lunetta, Kathryn L.; Murabito, Joanne M.; Harries, Lorna W.; Robine, Jean-Marie; Brayne, Carol; Kuchel, George A.; Ferrucci, Luigi; Frayling, Timothy M.; Melzer, David

doi:10.18632/aging.100930

Cited by 95 publications

(74 citation statements)

References 39 publications

(74 reference statements)

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“…The lower heritability at younger ages is probably caused by a greater number of accidental deaths at such ages 22 . Environmental factors therefore account for at least 70% of variation in lifespan and an increasing number of studies show that lifestyle, diet, exposure to toxins, including drugs of abuse, can have profound effects on healthspan, longevity and the development of neurodegenerative diseases, although the molecular pathways that underpin effects are mostly unknown.…”

Section: Causes Of Brain Ageing and Neurodegenerationmentioning

confidence: 99%

Ageing, neurodegeneration and brain rejuvenation

Wyss-Coray

2016

Nature

652

483

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Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of the essence of being. Ageing, which is fundamental to neurodegeneration and dementia, affects every organ in the body and seems to be encoded partly in a blood-based signature. Indeed, factors in the circulation have been shown to modulate ageing and to rejuvenate numerous organs, including the brain. The discovery of such factors, the identification of their origins and a deeper understanding of their functions is ushering in a new era in ageing and dementia research.

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Section: Causes Of Brain Ageing and Neurodegenerationmentioning

confidence: 99%

Ageing, neurodegeneration and brain rejuvenation

Wyss-Coray

2016

Nature

652

483

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“…But, discovery in aging research remains in the early stages. Recent GWAS have changed approaches from comparisons of extremely long-lived persons with controls in the normal age range [57,58] to studies of parental lifespan [14,59,60], which allow much larger samples. And new methods are being applied to conduct GWAS of longevity processes in samples of still-living individuals [61].…”

Section: New Developments In Molecular Epidemiology Of Agingmentioning

confidence: 99%

Developments in molecular epidemiology of aging

Hägg

Belsky

Cohen

2019

Emerging Topics in Life Sciences

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The field of molecular epidemiology of aging involves the application of molecular methods to measure aging processes and their genetic determinants in human cohorts. Over the last decade, the field has undergone rapid progress with a dramatic increase in the number of papers published. The aim of this review is to give an overview of the research field, with a specific focus on new developments, opportunities, and challenges.Aging occurs at multiple hierarchical levels. There is increasing consensus that agingrelated changes at the molecular level cause declines in physiological integrity, functional capacity, and ultimately lifespan. Molecular epidemiology studies seek to quantify this process. Telomere length, composite scores integrating clinical biomarkers, and omics clocks are among the most well-studied metrics in molecular epidemiology studies.New developments in the field include bigger data and hypothesis-free analysis together with new modes of collaborations in interdisciplinary teams and open access norms around data sharing. Key challenges facing the field are the lack of a gold standard by which to evaluate molecular measures of aging, inconsistency in which metrics of aging are measured and analyzed across studies, and a need for more longitudinal data necessary to observe change over time.

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“…We used the definition of Pilling et al 15 to define high parental lifespan in participants of the UK Biobank. Only participants between 55 and 69 years were included.…”

Section: Outcomes Ascertainment and Definitionsmentioning

confidence: 99%

Long-Term Exposure to Elevated Lipoprotein(a) Levels, Parental Lifespan and Risk of Mortality

Arsenault

Pelletier

Kaiser

et al. 2019

Preprint

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Background: Elevated Lipoprotein(a) (Lp[a]) levels are associated with a broad range of atherosclerotic cardiovascular diseases (CVD). The impact of high Lp(a) levels on human longevity is however controversial. Our objectives were to determine whether geneticallydetermined Lp(a) levels are associated with parental lifespan and to assess the association between measured and genetically-determined Lp(a) levels and long-term all-cause and cardiovascular mortality. Methods:We determined the association between a genetic risk score of 26 single nucleotide polymorphisms weighted for their impact on Lp(a) levels (wGRS) and parental lifespan (at least one long-lived parent; father still alive and older than 90 or father's age of death ≥90 or mother still alive and older than 93 or mother's age of death ≥93) in 139,362 participants from the UK Biobank. A total of 17,686 participants were considered as having high parental lifespan. We also investigated the association between Lp(a) levels and all-cause and cardiovascular mortality in 18,720 participants from the EPIC-Norfolk study. Results:In the UK Biobank, increases in the wGRS (weighted for a 50 mg/dL increase in Lp(a) levels) were inversely associated with a high parental lifespan (odds ratio=0.92, 95% confidence interval [CI]=0.89-0.94, p=2.7x10 -8 ). During the 20-year follow-up of the EPIC-Norfolk study, 5686 participants died (2412 from CVD-related causes). Compared to participants with Lp(a) levels <50 mg/dL, those with Lp(a) levels ≥50 mg/dL had an increased hazard ratio (HR) for allcause (HR=1.17, 95% CI=1.08-1.27) and cardiovascular (HR=1.54, 95% CI=1.37-1.72) mortality. Compared to individuals with Lp(a) levels below the 50 th percentile of the Lp(a) distribution (in whom event rates were 29.8% and 11.3%, respectively for all-cause and cardiovascular mortality), those with Lp(a) levels equal or above the 95 th percentile of the population distribution (≥70 mg/dL) had HRs of 1.22 (95% CI=1.09-1.37, event rate 37.5%) and 1.71 (95% CI=1.46-2.00, event rate 20.0%), for all-cause mortality and cardiovascular mortality, respectively. Conclusions:Results of this study suggest a potentially causal effect of Lp(a) on human longevity, support the use of parental lifespan as a tool to study the genetic determinants of human longevity, and provide a rationale for a trial of Lp(a)-lowering therapy in individuals with high Lp(a) levels.

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Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

Cited by 95 publications

References 39 publications

Ageing, neurodegeneration and brain rejuvenation

Ageing, neurodegeneration and brain rejuvenation

Developments in molecular epidemiology of aging

Long-Term Exposure to Elevated Lipoprotein(a) Levels, Parental Lifespan and Risk of Mortality

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