Aging and Survival: The Genetics of Life Span Extension by Dietary Restriction

Mair, William; Dillin, Andrew

doi:10.1146/annurev.biochem.77.061206.171059

Cited by 551 publications

(530 citation statements)

References 199 publications

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“…The probably best-known example of such lifespan plasticity is dietary restriction (DR), a physiological state of lifespan extension (and typically reduced reproduction) caused by reduced food intake without malnutrition. Remarkably, this DR response of lifespan has been observed, with a few exceptions, in almost every invertebrate and vertebrate species examined so far (6,7,13) .…”

Section: Proceedings Of the Nutrition Societymentioning

confidence: 77%

Plasticity of lifespan: a reaction norm perspective

Flatt

2014

Proc. Nutr. Soc.

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It is a well-appreciated fact that in many organisms the process of ageing reacts highly plastically, so that lifespan increases or decreases when the environment changes. The perhaps best-known example of such lifespan plasticity is dietary restriction (DR), a phenomenon whereby reduced food intake without malnutrition extends lifespan (typically at the expense of reduced fecundity) and which has been documented in numerous species, from invertebrates to mammals. For the evolutionary biologist, DR and other cases of lifespan plasticity are examples of a more general phenomenon called phenotypic plasticity, the ability of a single genotype to produce different phenotypes (e.g. lifespan) in response to changes in the environment (e.g. changes in diet). To analyse phenotypic plasticity, evolutionary biologists (and epidemiologists) often use a conceptual and statistical framework based on reaction norms (genotype-specific response curves) and genotype × environment interactions (G × E; differences in the plastic response among genotypes), concepts that biologists who are working on molecular aspects of ageing are usually not familiar with. Here I briefly discuss what has been learned about lifespan plasticity or, more generally, about plasticity of somatic maintenance and survival ability. In particular, I argue that adopting the conceptual framework of reaction norms and G × E interactions, as used by evolutionary biologists, is crucially important for our understanding of the mechanisms underlying DR and other forms of lifespan or survival plasticity.

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Section: Proceedings Of the Nutrition Societymentioning

confidence: 77%

Plasticity of lifespan: a reaction norm perspective

Flatt

2014

Proc. Nutr. Soc.

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“…For example, resveratrol, which induces a similar gene expression profile to dietary restriction (Pearson et al, 2008), can increase lifespan of mice on a high‐calorie diet, although not in mice on a standard diet (Strong et al, 2013). Rapamycin, directly targets the mTORC1 complex, which plays a central role in nutrient‐sensing network and has an important role in lifespan extension by DR (Mair & Dillin, 2008). Rapamycin extends lifespan by affecting autophagy and the activity of the S6 kinase in flies.…”

Section: Introductionmentioning

confidence: 99%

Gene expression‐based drug repurposing to target aging

et al. 2018

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Aging is the largest risk factor for a variety of noncommunicable diseases. Model organism studies have shown that genetic and chemical perturbations can extend both lifespan and healthspan. Aging is a complex process, with parallel and interacting mechanisms contributing to its aetiology, posing a challenge for the discovery of new pharmacological candidates to ameliorate its effects. In this study, instead of a target‐centric approach, we adopt a systems level drug repurposing methodology to discover drugs that could combat aging in human brain. Using multiple gene expression data sets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterize aging. Then, we compared these changes in gene expression with drug‐perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as antiaging drugs by reversing the detrimental changes that occur during aging, others by mimicking the cellular defence mechanisms. The drugs that we identified included significant number of already identified prolongevity drugs, indicating that the method can discover de novo drugs that meliorate aging. The approach has the advantages that using data from human brain aging data, it focuses on processes relevant in human aging and that it is unbiased, making it possible to discover new targets for aging studies.

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“…We thus decided to evaluate the role of those DR regulators in lifespan extension by calorie restriction, a classic form of dietary restriction in yeast and other organisms (Mair & Dillin, 2008). Specifically, we generated de novo deletion mutants for eight top‐ranked transcription factors and measured their CLS in 2% and 0.5% glucose using the small‐scale outgrowth‐kinetics approach.…”

Section: Resultsmentioning

confidence: 99%

“…Dietary restriction—a reduction in calorie intake without malnutrition, or substitution of the preferred carbon or nitrogen source—extends lifespan in virtually all species studied in the laboratory (Mair & Dillin, 2008). Dietary restriction has been associated with protection against age‐associated disease in mice, including neurodegenerative disorders (Zhu, Guo & Mattson, 1999) and cancer (Yamaza et al., 2010), promoting longer lifespan and healthier aging (Fontana & Partridge, 2015).…”

Section: Introductionmentioning

confidence: 99%

Genomewide mechanisms of chronological longevity by dietary restriction in budding yeast

et al. 2018

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SummaryDietary restriction is arguably the most promising nonpharmacological intervention to extend human life and health span. Yet, only few genetic regulators mediating the cellular response to dietary restriction are known, and the question remains which other regulatory factors are involved. Here, we measured at the genomewide level the chronological lifespan of Saccharomyces cerevisiae gene deletion strains under two nitrogen source regimens, glutamine (nonrestricted) and γ‐aminobutyric acid (restricted). We identified 473 mutants with diminished or enhanced extension of lifespan. Functional analysis of such dietary restriction genes revealed novel processes underlying longevity by the nitrogen source quality, which also allowed us to generate a prioritized catalogue of transcription factors orchestrating the dietary restriction response. Importantly, deletions of transcription factors Msn2, Msn4, Snf6, Tec1, and Ste12 resulted in diminished lifespan extension and defects in cell cycle arrest upon nutrient starvation, suggesting that regulation of the cell cycle is a major mechanism of chronological longevity. We further show that STE12 overexpression is enough to extend lifespan, linking the pheromone/invasive growth pathway with cell survivorship. Our global picture of the genetic players of longevity by dietary restriction highlights intricate regulatory cross‐talks in aging cells.

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Aging and Survival: The Genetics of Life Span Extension by Dietary Restriction

Cited by 551 publications

References 199 publications

Plasticity of lifespan: a reaction norm perspective

Plasticity of lifespan: a reaction norm perspective

Gene expression‐based drug repurposing to target aging

Genomewide mechanisms of chronological longevity by dietary restriction in budding yeast

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