The Genetics of Aging: A Vertebrate Perspective

Singh, Param Priya; Demmitt, Brittany A.; Nath, Ravi D.; Brunet, Anne

doi:10.1016/j.cell.2019.02.038

Cited by 185 publications

(143 citation statements)

References 186 publications

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“…FOXOs play a role in cancer [43], diabetes [44,45] and longevity [46,47], as well as other disease-related processes.…”

Section: Foxo Functionmentioning

confidence: 99%

The FOXO’s Advantages of Being a Family: Considerations on Function and Evolution

Schmitt-Ney

2020

Cells

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The nematode Caenorhabditis elegans possesses a unique (with various isoforms) FOXO transcription factor DAF-16, which is notorious for its role in aging and its regulation by the insulin-PI3K-AKT pathway. In humans, five genes (including a protein-coding pseudogene) encode for FOXO transcription factors that are targeted by the PI3K-AKT axis, such as in C. elegans. This common regulation and highly conserved DNA-binding domain are the pillars of this family. In this review, I will discuss the possible meaning of possessing a group of very similar proteins and how it can generate additional functionality to more complex organisms. I frame this discussion in relation to the much larger super family of Forkhead proteins to which they belong. FOXO members are very often co-expressed in the same cell type. The overlap of function and expression creates a certain redundancy that might be a safeguard against the accidental loss of FOXO function, which could otherwise lead to disease, particularly, cancer. This is one of the points that will be examined in this “family affair” report.

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“…FOXOs play a role in cancer [43], diabetes [44,45] and longevity [46,47], as well as other disease-related processes.…”

Section: Foxo Functionmentioning

confidence: 99%

The FOXO’s Advantages of Being a Family: Considerations on Function and Evolution

Schmitt-Ney

2020

Cells

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“…Investigation of organisms that exhibit extreme longevity, however, may also hold unique promise for identification of anti-ageing defences obtained through evolution. Our own species is an obvious candidate, and comparison among human populations and among individuals within populations-including, for instance, centenarians-has shed tremendous light on genetic and environmental effects on longevity [9]. Some species of bivalves have extreme lifespans-the ocean quahog ( Arctica islandica ), for instance, is notable for living up to 507 years [10].…”

Section: Models For Human Health and Ageingmentioning

confidence: 99%

Rhesus macaques as a tractable physiological model of human ageing

Chiou

Montague

Goldman

et al. 2020

Preprint

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Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from shorter-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research due to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population.

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“…Aging is a complex, multifarious process characterized by changes such as stem cell exhaustion, mitochondrial dysfunction, impaired immune function, reduced autophagy, epigenetic alterations, accumulation of somatic and mitochondrial DNA mutations, aberrant intercellular communication, loss of telomeres, altered nutrient sensing, and impaired protein homeostasis (Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, ; Singh, Demmitt, Nath, & Brunet, ). A large portion of our current, limited understanding of what causes aging comes from lifespan studies in short‐lived model organisms.…”

Section: Introductionmentioning

confidence: 99%

“…With the exception of research showing that caloric restriction improves health and survival in rhesus monkeys (Mattison et al, ), little aging work has been done in longer‐lived organisms. The bulk of our understanding regarding aging comes from genetic experiments in model organisms (Singh et al, ), and we do not yet know how similar or dissimilar human aging is. For example, genome‐wide association studies searching for longevity‐related variants have found a lack of association with many genes known to extend lifespan in simpler animals (de Magalhaes, ).…”

Section: Introductionmentioning

confidence: 99%

The role of lipid metabolism in aging, lifespan regulation, and age‐related disease

2019

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An emerging body of data suggests that lipid metabolism has an important role to play in the aging process. Indeed, a plethora of dietary, pharmacological, genetic, and surgical lipid‐related interventions extend lifespan in nematodes, fruit flies, mice, and rats. For example, the impairment of genes involved in ceramide and sphingolipid synthesis extends lifespan in both worms and flies. The overexpression of fatty acid amide hydrolase or lysosomal lipase prolongs life in Caenorhabditis elegans, while the overexpression of diacylglycerol lipase enhances longevity in both C. elegans and Drosophila melanogaster. The surgical removal of adipose tissue extends lifespan in rats, and increased expression of apolipoprotein D enhances survival in both flies and mice. Mouse lifespan can be additionally extended by the genetic deletion of diacylglycerol acyltransferase 1, treatment with the steroid 17‐α‐estradiol, or a ketogenic diet. Moreover, deletion of the phospholipase A2 receptor improves various healthspan parameters in a progeria mouse model. Genome‐wide association studies have found several lipid‐related variants to be associated with human aging. For example, the epsilon 2 and epsilon 4 alleles of apolipoprotein E are associated with extreme longevity and late‐onset neurodegenerative disease, respectively. In humans, blood triglyceride levels tend to increase, while blood lysophosphatidylcholine levels tend to decrease with age. Specific sphingolipid and phospholipid blood profiles have also been shown to change with age and are associated with exceptional human longevity. These data suggest that lipid‐related interventions may improve human healthspan and that blood lipids likely represent a rich source of human aging biomarkers.

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The Genetics of Aging: A Vertebrate Perspective

Cited by 185 publications

References 186 publications

The FOXO’s Advantages of Being a Family: Considerations on Function and Evolution

The FOXO’s Advantages of Being a Family: Considerations on Function and Evolution

Rhesus macaques as a tractable physiological model of human ageing

The role of lipid metabolism in aging, lifespan regulation, and age‐related disease

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