Molecular genetics of aging in the fly: Is this the end of the beginning?

Helfand, Stephen L.; Rogina, Blanka

doi:10.1002/bies.10225

Cited by 63 publications

(39 citation statements)

References 70 publications

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“…Decreases in physical activity, reproductive status (especially in females), or calorie intake are known to increase life span in the fly (reviewed in ref. 33). Although we did not perform quantitative studies, visual inspection suggested no obvious decrease in physical activity or fertility in the long-lived dSir2-overexpressing flies compared with their matched controls.…”

Section: Increasing Sir2 Expression In Neurons Extends Life Spanmentioning

confidence: 99%

Sir2 mediates longevity in the fly through a pathway related to calorie restriction

Rogina

Helfand²

2004

Proc. Natl. Acad. Sci. U.S.A.

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1,246

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Calorie restriction can extend life span in a variety of species including mammals, flies, nematodes, and yeast. Despite the importance of this nearly universal effect, little is understood about the molecular mechanisms that mediate the life-span-extending effect of calorie restriction in metazoans. Sir2 is known to be involved in life span determination and calorie restriction in yeast mother cells. In nematodes increased Sir2 can extend life span, but a direct link to calorie restriction has not been demonstrated. We now report that Sir2 is directly involved in the calorie-restriction life-span-extending pathway in Drosophila. We demonstrate that an increase in Drosophila Sir2 (dSir2) extends life span, whereas a decrease in dSir2 blocks the life-span-extending effect of calorie reduction or rpd3 mutations. These data lead us to propose a genetic pathway by which calorie restriction extends life span and provides a framework for genetic and pharmacological studies of life span extension in metazoans.aging ͉ life span ͉ Rpd3 ͉ histone deacetylase ͉ Drosophila melanogaster I t has been known for Ϸ70 years that calorie restriction can dramatically extend the life span of rodents (1). In primates calorie restriction causes a number of physiological changes with positive health benefits (2, 3). Although calorie restriction has been the subject of intense investigation, little is understood about the molecular and cellular mechanisms by which a reduction in calorie intake effects life span extension. Recently it has been shown that the calorie-restriction life-span-extending effect is conserved across distant species from yeast to mammals (2,(4)(5)(6)(7)(8)(9)(10)(11)(12). Powerful molecular genetic techniques and the relatively short life span of model organisms such as yeast, nematodes, and flies provide the opportunity to uncover the molecular and cellular mechanisms underlying this universal effect on life span. Indeed, the use of these model organisms has implicated insulinsignaling, nutrient-sensing, and chromosome-remodeling proteins in either triggering calorie restriction or contributing to its life-span-extending effect (13)(14)(15)(16)(17)(18)(19).The Rpd3͞Sir2 histone deacetylases have been implicated in both life span determination and calorie restriction in yeast (15). Rpd3 and Sir2 can effect the activity of a variety of genes and physiological systems by deacetylating histones and other proteins such as p53 (12,20). A decrease in Rpd3 or an increase in Sir2 extends mother cell life span in yeast (11,21), and the effect of Sir2 on yeast life span is linked to calorie restriction (22). A similar mechanism may operate in metazoans, because an increase in Sir2 extends life span in nematodes (23), and a decrease in Rpd3 extends life span in flies (16). The increase in life span associated with decreased Rpd3 in flies is thought to occur through a mechanism related to calorie restriction (16). The finding of an increase in Drosophila Sir2 (dSir2) transcription in both long-lived rpd3 mutant f lies and lon...

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Section: Increasing Sir2 Expression In Neurons Extends Life Spanmentioning

confidence: 99%

Sir2 mediates longevity in the fly through a pathway related to calorie restriction

Rogina

Helfand²

2004

Proc. Natl. Acad. Sci. U.S.A.

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1,246

901

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“…The involvement of ROS in limiting lifespan has been suggested by analyses of transgenic Drosophila, which systematically overexpress both Sod and Cat genes. Some strains of these transgenic flies live up to 30% longer than their natural counterparts, whereas flies carrying only one of these constitutively expressed transgenes do not live longer, suggesting that ROS tox-icity plays an important role in longevity (20,21).…”

Section: Ros Telomeres and Agingmentioning

confidence: 99%

Oxidative stress: molecular perception and transduction of signals triggering antioxidant gene defenses

2005

Braz J Med Biol Res

974

470

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Molecular oxygen (O 2 ) is the premier biological electron acceptor that serves vital roles in fundamental cellular functions. However, with the beneficial properties of O 2 comes the inadvertent formation of reactive oxygen species (ROS) such as superoxide (O 2 •-), hydrogen peroxide, and hydroxyl radical (OH • ). If unabated, ROS pose a serious threat to or cause the death of aerobic cells. To minimize the damaging effects of ROS, aerobic organisms evolved non-enzymatic and enzymatic antioxidant defenses. The latter include catalases, peroxidases, superoxide dismutases, and glutathione S-transferases (GST). Cellular ROS-sensing mechanisms are not well understood, but a number of transcription factors that regulate the expression of antioxidant genes are well characterized in prokaryotes and in yeast. In higher eukaryotes, oxidative stress responses are more complex and modulated by several regulators. In mammalian systems, two classes of transcription factors, nuclear factor κB and activator protein-1, are involved in the oxidative stress response. Antioxidant-specific gene induction, involved in xenobiotic metabolism, is mediated by the "antioxidant responsive element" (ARE) commonly found in the promoter region of such genes. ARE is present in mammalian GST, metallothioneine-I and MnSod genes, but has not been found in plant Gst genes. However, ARE is present in the promoter region of the three maize catalase (Cat) genes. In plants, ROS have been implicated in the damaging effects of various environmental stress conditions. Many plant defense genes are activated in response to these conditions, including the three maize Cat and some of the superoxide dismutase (Sod) genes. Correspondence

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“…It is likely that this first wave of loss is due to direct differentiation of the GSCs without selfrenewing divisions. However, a significant 30% decrease in the number of GSCs is observed in 30-day-old wild type males [33,34]; the median lifespan of a wild type laboratory strain of Drosophila melanogaster is 40 days [36]. The trend continues with a nearly 40% decrease in the number of GSCs by 50 days [34].…”

Section: Effects Of Aging On Germline Stem Cell Number and Activity Imentioning

confidence: 90%

Aging and the Germ Line: Where Mortality and Immortality Meet

Jones

2007

Stem Cell Rev

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Germ cells are highly specialized cells that form gametes, and they are the only cells within an organism that contribute genes to offspring. Germline stem cells (GSCs) sustain gamete production, both oogenesis (egg production) and spermatogenesis (sperm production), in many organisms. Since the genetic information contained within germ cells is passed from generation to generation, the germ line is often referred to as immortal. Therefore, it is possible that germ cells possess unique strategies to protect and transmit the genetic information contained within them indefinitely. However, aging often leads to a dramatic decrease in gamete production and fecundity. In addition, single gene mutations affecting longevity often have a converse effect on reproduction. Recent studies examining age-related changes in GSC number and activity, as well as changes to the stem cell microenvironment, provide insights into the mechanisms underlying the observed reduction in gametogenesis over the lifetime of an organism.

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Molecular genetics of aging in the fly: Is this the end of the beginning?

Cited by 63 publications

References 70 publications

Sir2 mediates longevity in the fly through a pathway related to calorie restriction

Sir2 mediates longevity in the fly through a pathway related to calorie restriction

Oxidative stress: molecular perception and transduction of signals triggering antioxidant gene defenses

Aging and the Germ Line: Where Mortality and Immortality Meet

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