Reducing signs of aging and increasing lifespan by drug synergy

Huang, Xinhe; Liu, Jun; Withers, Bradley R.; Samide, Aaron; Leggas, Markos; Dickson, Robert C.

doi:10.1111/acel.12090

Cited by 22 publications

(19 citation statements)

References 42 publications

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“…We found a wide range of concentrations that could produce a synergistic increase in CLS and data for one combination are shown in Fig. 3B[74]. Drug synergy was accessed by using three commonly used mathematical models and all verified that synergy was achieved.…”

Section: Roles For Sphingolipids In Modulating Lifespan In Model Nmentioning

confidence: 68%

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Sphingolipids and lifespan regulation

Huang

Withers

Dickson

2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Diseases including cancer, type 2 diabetes, cardiovascular and immune dysfunction and neurodegeneration become more prevalent as we age, and combined with the increase in average human lifespan, place an ever increasing burden on the health care system. In this chapter we focus on finding ways of modulating sphingolipids to prevent the development of age-associated diseases or delay their onset, both of which could improve health in elderly, fragile people. Reducing the incidence of or delaying the onset of diseases of aging has blossomed in the past decade because of advances in understanding signal transduction pathways and cellular processes, especially in model organisms, that are largely conserved in most eukaryotes and that can be modulated to reduce signs of aging and increase health span. In model organisms such interventions must also increase lifespan to be considered significant, but this is not a requirement for use in humans. The most encouraging interventions in model organisms involve lowering the concentration of one or more sphingolipid so as to reduce the activity of key signaling pathways, one of the most promising being the Target of Rapamycin Complex 1 (TORC1) protein kinase pathway. Other potential ways in which modulating sphingolipids may contribute to improving the health profile of the elderly is by reducing oxidative stresses, inflammatory responses and growth factor signaling. Lastly, perhaps the most interesting way to modulate sphingolipids and promote longevity is by lowering the activity of serine palmitoyltransferase, the first enzyme in the de novo sphingolipid biosynthesis pathway. Available data in yeasts and rodents are encouraging and as we gain insights into molecular mechanisms the strategies for improving human health by modulating sphingolipids will become more apparent.

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Section: Roles For Sphingolipids In Modulating Lifespan In Model Nmentioning

confidence: 68%

“…The p value for the lifespan increase is computed using the area under the viability curves. Reproduced with permission [74]…”

Section: Figmentioning

confidence: 99%

Sphingolipids and lifespan regulation

Huang

Withers

Dickson

2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…The fact that the prolonged life span of ypc1∆ cells was not seen in a previous study (Powers et al ., ) is probably due to the fact that cells were aged in very different types of media (synthetic complete vs. water; Longo et al ., ). A recent report also found a much higher increase of the CLS in the BY genetic background when cells were transferred to water rather than kept in synthetic complete medium (Huang et al ., ). Interestingly, this increase of the CLS was induced by a combined treatment with myriocin plus rapamycin, a treatment that is predicted to curb the drastic increase of LCBs occurring during chronological aging (Lester et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of yeast mutants lacking alkaline ceramidasesYPC1andYDC1

et al. 2014

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Humans and yeast possess alkaline ceramidases located in the early secretory pathway. Single deletions of the highly homologous yeast alkaline ceramidases YPC1 and YDC1 have very little genetic interactions or phenotypes. Here, we performed chemical-genetic screens to find deletions/conditions that would alter the growth of ypc1∆ydc1∆ double mutants. These screens were essentially negative, demonstrating that ceramidase activity is not required for cell growth even under genetic stresses. A previously reported protein targeting defect of ypc1∆ could not be reproduced and reported abnormalities in sphingolipid biosynthesis detected by metabolic labeling do not alter the mass spectrometric lipid profile of ypc1∆ydc1∆ cells. Ceramides of ypc1∆ydc1∆ remained normal even in presence of aureobasidin A, an inhibitor of inositolphosphorylceramide synthase. Moreover, in caloric restriction conditions Ypc1p reduces chronological life span. A novel finding is that, when working backwards as a ceramide synthase in vivo, Ypc1p prefers C24 and C26 fatty acids as substrates, whereas it prefers C16:0, when solubilized in detergent and working in vitro. Therefore, its physiological activity may not only concern the minor ceramides containing C14 and C16. Intriguingly, so far the sole discernable benefit of conserving YPC1 for yeast resides with its ability to convey relative resistance toward H2O2.

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“…These two assays have been widely used to evaluate age-dependent genome instability in yeast [8, 22, 60, 61]. …”

Section: Resultsmentioning

confidence: 99%

Tethering telomerase to telomeres increases genome instability and promotes chronological aging in yeast

Liu

Peng

et al. 2016

Aging

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Chronological aging of the yeast Saccharomyces cerevisiae is attributed to multi-faceted traits especially those involving genome instability, and has been considered to be an aging model for post-mitotic cells in higher organisms. Telomeres are the physical ends of eukaryotic chromosomes, and are essential for genome integrity and stability. It remains elusive whether dysregulated telomerase activity affects chronological aging. We employed the CDC13-EST2 fusion gene, which tethers telomerase to telomeres, to examine the effect of constitutively active telomerase on chronological lifespan (CLS). The expression of Cdc13-Est2 fusion protein resulted in overlong telomeres (2 to 4 folds longer than normal telomeres), and long telomeres were stably maintained during long-term chronological aging. Accordingly, genome instability, manifested by accumulation of extra-chromosomal rDNA circle species, age-dependent CAN1 marker-gene mutation frequency and gross chromosomal rearrangement frequency, was significantly elevated. Importantly, inactivation of Sch9, a downstream kinase of the target of rapamycin complex 1 (TORC1), suppressed both the genome instability and accelerated chronological aging mediated by CDC13-EST2 expression. Interestingly, loss of the CDC13-EST2 fusion gene in the cells with overlong telomeres restored the regular CLS. Altogether, these data suggest that constitutively active telomerase is detrimental to the maintenance of genome stability, and promotes chronological aging in yeast.

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Reducing signs of aging and increasing lifespan by drug synergy

Cited by 22 publications

References 42 publications

Sphingolipids and lifespan regulation

Sphingolipids and lifespan regulation

Characterization of yeast mutants lacking alkaline ceramidasesYPC1andYDC1

Tethering telomerase to telomeres increases genome instability and promotes chronological aging in yeast

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