Yeast longevity promoted by reversing aging-associated decline in heavy isotope content.
Ontology highlight
ABSTRACT:
SUBMITTER: Li X
PROVIDER: S-EPMC5515009 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Quantitative traits often show large variation caused by multiple genetic factors . One such trait is the chronological lifespan of non-dividing yeast cells, serving as a model for cellular aging. Screens for genetic factors involved in aging typically assay mutants of protein-coding genes. To identify natural genetic variants contributing to cellular aging, we exploited two strains of the fission yeast, Schizosaccharomyces pombe, that differ in chronological lifespan. We generated segregant pools from these strains and subjected them to advanced intercrossing over multiple generations to break up linkage groups. We chronologically aged the intercrossed segregant pool, followed by genome sequencing at different times to detect genetic variants that became reproducibly enriched as a function of age. A region on Chromosome II showed strong positive selection during aging. Based on expected functions, two candidate variants from this region in the long-lived strain were most promising to be causal: small insertions and deletions in the 5'-untranslated regions of ppk31 and SPBC409.08 Ppk31 is an ortholog of Rim15, a conserved kinase controlling cell proliferation in response to nutrients, while SPBC409.08 is a predicted spermine transmembrane transporter. Both Rim15 and the spermine-precursor, spermidine, are implicated in aging as they are involved in autophagy-dependent lifespan extension. Single and double allele replacement suggests that both variants, alone or combined, have subtle effects on cellular longevity. Furthermore, deletion mutants of both ppk31 and SPBC409.08 rescued growth defects caused by spermidine. We propose that Ppk31 and SPBC409.08 may function together to modulate lifespan, thus linking Rim15/Ppk31 with spermidine metabolism.
| S-EPMC6216586 | biostudies-literature
Project description:IntroductionCross-sectional analyses have associated familial longevity with better cognitive function and lower risk of cognitive impairment in comparison with individuals without familial longevity. The extent to which long-lived families also demonstrate slower rates of cognitive aging (i.e., change in cognition over time) is unknown. This study examined longitudinally collected data among 2 generations of the Long Life Family Study (LLFS) to compare rates of cognitive change across relatives and spouse controls.MethodsWe analyzed change in 6 neuropsychological test scores collected approximately 8 years apart among LLFS family members (n = 3,972) versus spouse controls (n = 1,092) using a Bayesian hierarchical model that included age, years of follow-up, sex, education, generation, and field center and all possible pairwise interactions.ResultsAt a mean age of 88 years at enrollment in the older generation and 60 years in the younger generation, LLFS family members performed better than their spouses on the Digit Symbol Substitution Test (DSST) and the Logical Memory test. At follow-up, family members in the younger generation also showed slower decline than spouses on the DSST, whereas rates of change of Digit Span, fluency, and memory were similar between the 2 groups.Discussion/conclusionIndividuals in families with longevity appear to have better cognitive performance than their spouses for cognitive processes including psychomotor processing, episodic memory, and retrieval. Additionally, they demonstrate longer cognitive health spans with a slower decline on a multifactorial test of processing speed, a task requiring the integration of processes including organized visual search, working and incidental memory, and graphomotor ability. Long-lived families may be a valuable cohort for studying resilience to cognitive aging.
| S-EPMC9093735 | biostudies-literature
Project description:Quercetin (QUER) is a natural polyphenolic compound endowed with beneficial properties for human health, with anti-aging effects. However, although this flavonoid is commercially available as a nutraceutical, target molecules/pathways underlying its pro-longevity potential have yet to be fully clarified. Here, we investigated QUER activity in yeast chronological aging, the established model for simulating the aging of postmitotic quiescent mammalian cells. We found that QUER supplementation at the onset of chronological aging, namely at the diauxic shift, significantly increases chronological lifespan (CLS). Consistent with the antioxidant properties of QUER, this extension takes place in concert with a decrease in oxidative stress. In addition, QUER triggers substantial changes in carbon metabolism. Specifically, it promotes an enhancement of a pro-longevity anabolic metabolism toward gluconeogenesis due to improved catabolism of C2 by-products of yeast fermentation and glycerol. The former is attributable to the Sir2-dependent activity of phosphoenolpyruvate carboxykinase and the latter to the L-glycerol 3-phosphate pathway. Such a combined increased supply of gluconeogenesis leads to an increase in the reserve carbohydrate trehalose, ensuring CLS extension. Moreover, QUER supplementation to chronologically aging cells in water alone amplifies their long-lived phenotype. This is associated with intracellular glycerol catabolism and trehalose increase, further indicating a QUER-specific influence on carbon metabolism that results in CLS extension.
| S-EPMC10419316 | biostudies-literature
Project description:The REGγ-20S proteasome is an ubiquitin- and ATP-independent degradation system, targeting selective substrates, possibly helping to regulate aging. The studies we report here demonstrate that aging-associated REGγ decline predisposes to decreasing tau turnover, as in a tauopathy. The REGγ proteasome promotes degradation of human and mouse tau, notably phosphorylated tau and toxic tau oligomers that shuttle between the cytoplasm and nuclei. REGγ-mediated proteasomal degradation of tau was validated in 3- to 12-month-old REGγ KO mice, REGγ KO;PS19 mice, and PS19 mice with forebrain conditional neuron-specific overexpression of REGγ (REGγ OE) and behavioral abnormalities. Coupled with tau accumulation, we found with REGγ-deficiency, neuron loss, dendrite reduction, tau filament accumulation, and microglial activation are much more prominent in the REGγ KO;PS19 than the PS19 model. Moreover, we observed that the degenerative neuronal lesions and aberrant behaviors were alleviated in REGγ OE;PS19 mice. Memory and other behavior analysis substantiate the role of REGγ in prevention of tauopathy-like symptoms. In addition, we investigated the potential mechanism underlying aging-related REGγ decline. This study provides valuable insights into the novel regulatory mechanisms and potential therapeutic targets for tau-related neurodegenerative diseases.
| S-EPMC9647549 | biostudies-literature
Project description:The federal drug administration (FDA)-approved compound rapamycin was the first pharmacological agent shown to extend maximal lifespan in both genders in a mammalian species. A major question then is whether the drug slows mammalian aging or if it has isolated effects on longevity by suppressing cancers, the main cause of death in many mouse strains. Here, we review what is currently known about the effects that pharmacological or genetic mammalian target of rapamycin (mTOR) inhibition have on mammalian aging and longevity. Currently available evidence seems to best fit a model, wherein rapamycin extends lifespan by suppressing cancers. In addition the drug has symptomatic effects on some aging traits, such as age-related cognitive impairments.
| S-EPMC4207939 | biostudies-literature
Project description:The use of "heavy" isotope-labeled arginine for stable isotope labeling by amino acids in cell culture (SILAC) mass spectrometry in the fission yeast Schizosaccharomyces pombe is hindered by the fact that under normal conditions, arginine is extensively catabolized in vivo, resulting in the appearance of "heavy"-isotope label in several other amino acids, most notably proline, but also glutamate, glutamine and lysine. This "arginine conversion problem" significantly impairs quantification of mass spectra. Previously, we developed a method to prevent arginine conversion in fission yeast SILAC, based on deletion of genes involved in arginine catabolism. Here we show that although this method is indeed successful when (13)C6-arginine (Arg-6) is used for labeling, it is less successful when (13)C6(15)N4-arginine (Arg-10), a theoretically preferable label, is used. In particular, we find that with this method, "heavy"-isotope label derived from Arg-10 is observed in amino acids other than arginine, indicating metabolic conversion of Arg-10. Arg-10 conversion, which severely complicates both MS and MS/MS analysis, is further confirmed by the presence of (13)C5(15)N2-arginine (Arg-7) in arginine-containing peptides from Arg-10-labeled cells. We describe how all of the problems associated with the use of Arg-10 can be overcome by a simple modification of our original method. We show that simultaneous deletion of the fission yeast arginase genes car1+ and aru1+ prevents virtually all of the arginine conversion that would otherwise result from the use of Arg-10. This solution should enable a wider use of heavy isotope-labeled amino acids in fission yeast SILAC.
| S-EPMC4468061 | biostudies-literature
Project description:Deficits in chemosensory processing are associated with healthy aging, as well as numerous neurodegenerative disorders, including Alzheimer’s Disease (AD). In many cases, chemosensory deficits are harbingers of neurodegenerative disease, and understanding the mechanistic basis for these changes may provide insight into the fundamental dysfunction associated with aging and neurodegeneration. The fruit fly, Drosophila melanogaster, is a powerful model for studying chemosensation, aging, and aging-related pathologies, yet the effects of aging and neurodegeneration on chemosensation remain largely unexplored in this model, particularly with respect to taste. To determine whether the effects of aging on taste are conserved in flies, we compared the response of flies to different appetitive tastants. Aging impaired response to sugars, but not medium-chain fatty acids that are sensed by a shared population of neurons, revealing modality-specific deficits in taste. Selective expression of the human amyloid beta (Ab) 1-42 peptide bearing the Arctic mutation (E693E) associated with early onset AD in the neurons that sense sugars and fatty acids phenocopies the effects of aging, suggesting that the age-related decline in response is localized to gustatory neurons. Functional imaging of gustatory axon terminals revealed reduced response to sugar, but not fatty acids. Axonal innervation of the fly taste center was largely intact in aged flies, suggesting that reduced sucrose response does not derive from neurodegeneration. Conversely, expression of the amyloid peptide in sweet-sensing taste neurons resulted in reduced innervation of the primary fly taste center. A comparison of transcript expression within the sugar-sensing taste neurons revealed age-related changes in 66 genes, including a reduction in odorant-binding protein class genes that are also expressed in taste sensilla. Together, these findings suggest that deficits in taste detection may result from signaling pathway-specific changes, while different mechanisms underly taste deficits in aged and AD model flies. Overall, this work provides a model to examine cellular deficits in neural function associated with aging and AD.
2024-10-13 | GSE273715 | GEO
Project description:The accumulation of senescent stromal cells in aging tissue changes the local microenvironment from normal to a state similar to chronic inflammation. This inflammatory microenvironment can stimulate the proliferation of epithelial cells containing DNA mutations which can ultimately lead to cancer. Using geriatric skin as a model, we demonstrated that senescent fibroblasts also alter how epithelial keratinocytes respond to genotoxic stress, due to the silencing of IGF-1 expression in geriatric fibroblasts. These data indicate that in addition to promoting epithelial tumor growth, senescent fibroblasts also can promote carcinogenic initiation. We hypothesized that commonly used therapeutic stromal wounding therapies can reduce the percentage of senescent fibroblasts and consequently prevent the formation of keratinocytes proliferating with DNA mutations following acute genotoxic (UVB) stress. Sun-protected skin on the lower back of geriatric human volunteers was wounded by dermabrasion and the skin was allowed to heal for three months. In geriatric skin, we found that dermabrasion wounding decreases the proportion of senescent fibroblasts found in geriatric dermis, increases the expression of IGF-1, and restores the appropriate UVB response to epidermal keratinocytes in geriatric skin. Therefore, dermal rejuvenation therapies may play a significant role in preventing the initiation of skin cancer in geriatric patients.
| S-EPMC3117456 | biostudies-literature
Project description:Abstract Telomere attrition in proliferative tissues is a hallmark feature of human aging. To date, the genetic influence on the rate of telomere attrition is poorly understood. Previously we discovered a variant of the FOXO3 gene that is strongly associated with human longevity, an observation that has been now reproduced in over a dozen independent studies. In the present study, we sought to assess the effect of the longevity associated variant of FOXO3 (rs2802292 - G allele) on the rate of telomere attrition during aging. The results from a cohort of Okinawan-Japanese (N=121), ranging in age from 25 – 94 years, demonstrates carriers of 1 or 2 copies of the longevity-associated G allele of FOXO3 showed markedly reduced rates of telomere loss in peripheral blood leucocytes as compared to carriers of the more common FOXO3 variant (TT – common genotype, m= -33bp/year, P=0.008). Interestingly, telomere shortening was not observed as a function of age for G allele carriers (m= -2bp/year, P>0.1). In an independent study of women (N=6,565) from the Nurses’ Health Study cohort, ranging in age from 40 to 70 years, a similar observation was found. Notably, carriers of the TT or GT FOXO3 genotype showed a significant decline in telomere length with age (m= -15.5 bp/year, P0.1). These results mark the first validated longevity gene variant showing an association with negligible loss of telomere length with age in humans.
| S-EPMC6845095 | biostudies-literature
Project description:IntroductionHealthy aging relies on mitochondrial functioning because this organelle provides energy and diminishes oxidative stress. Single nucleotide polymorphisms (SNPs) in TOMM40, a critical gene that produces the outer membrane protein TOM40 of mitochondria, have been associated with mitochondrial dysfunction and neurodegenerative processes. Yet it is not clear whether or how the mitochondria may impact human longevity. We conducted this review to ascertain which SNPs have been associated with markers of healthy aging.MethodsUsing the PRISMA methodology, we conducted a systematic review on PubMed and Embase databases to identify associations between TOMM40 SNPs and measures of longevity and healthy aging.ResultsTwenty-four articles were selected. The TOMM40 SNPs rs2075650 and rs10524523 were the two most commonly identified and studied SNPs associated with longevity. The outcomes associated with the TOMM40 SNPs were changes in BMI, brain integrity, cognitive functions, altered inflammatory network, vulnerability to vascular risk factors, and longevity.DiscussionsOur systematic review identified multiple TOMM40 SNPs potentially associated with healthy aging. Additional research can help to understand mechanisms in aging, including resilience, prevention of disease, and adaptation to the environment.
| S-EPMC9375314 | biostudies-literature