Autophagy and aging: Maintaining the proteome through exercise and caloric restriction

Accumulation of dysfunctional and damaged cellular proteins and organelles occurs during aging, resulting in a disruption of cellular homeostasis and progressive degeneration and increases the risk of cell death. Moderating the accrual of these defunct components is likely a key in the promotion of longevity. While exercise is known to promote healthy aging and mitigate age‐related pathologies, the molecular underpinnings of this phenomenon remain largely unclear. However, recent evidences suggest that exercise modulates the proteome. Similarly, caloric restriction (CR), a known promoter of lifespan, is understood to augment intracellular protein quality. Autophagy is an evolutionary conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This housekeeping system has been reliably linked to the aging process. Moreover, autophagic activity declines during aging. The target of rapamycin complex 1 (TORC1), a central kinase involved in protein translation, is a negative regulator of autophagy, and inhibition of TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production of cellular proteins which may otherwise contribute to the deleterious accumulation observed in aging. TORC1 may also exert its effects in an autophagy‐dependent manner. Exercise and CR result in a concomitant downregulation of TORC1 activity and upregulation of autophagy in a number of tissues. Moreover, exercise‐induced TORC1 and autophagy signaling share common pathways with that of CR. Therefore, the longevity effects of exercise and CR may stem from the maintenance of the proteome by balancing the synthesis and recycling of intracellular proteins and thus may represent practical means to promote longevity.     

The Association of Serum Leptin with Mortality in Older Adults

Objective

Elevated levels of serum leptin are associated with increased adiposity and production of pro-inflammatory cytokines. Both cytokines and body adiposity have been shown to predict cardiovascular events and mortality. The primary objective of the present study is to explore the associations between serum leptin and all-cause mortality and mortality from cardiovascular disease (CVD) over a span of 10 years, controlling for body adiposity and proinflammatory cytokines.

Methods

The Health, Aging and Body Composition (Health ABC) study is a prospective cohort of 3,075 older adults aged 70 to 79 years. This analysis includes 2,919 men and women with complete serum leptin and vital status data. Data on all-cause mortality and incident cardiovascular events (including Coronary Heart Disease and Congestive Heart Failure) were collected over 10 years of follow-up (mean 8.4 years).

Results

Women with leptin in quartile 2 and 3 were at lower risk of all-cause mortality, and those with leptin in quartile 2 were at lower risk of mortality from CVD as compared to women with lowest leptin values when adjusted for age, race, site, years of education, alcohol use, smoking, and physical activity. When these associations were additionally adjusted for body fat, C-reactive protein and pro-inflammatory cytokines, women with leptin values in quartile 3 were at lower risk of all-cause mortality and women with leptin in quartile 2 and 3 were at lower risk of mortality from CVD than women with lowest leptin values. These associations were not significant among men after adjusting for body fat and cytokines.

Conclusions

The present study suggests that moderately elevated concentrations of serum leptin are independently associated with lower risk of all-cause mortality and CVD-related mortality among older women. Among men, serum leptin is not associated with reduced risk of all-cause and CVD mortality after controlling for body fat and cytokines.     

Evaluation of pyrolysis chars derived from marine macroalgae silage as soil amendments

Pyrolysis char residues from ensiled macroalgae were examined to determine their potential as growth promoters on germinating and transplanted seedlings. Macroalgae was harvested in May, July and August from beach collections, containing predominantly Laminaria digitata and Laminaria hyperborea; naturally seeded mussel lines dominated by Saccharina latissima; and lines seeded with cultivated L. digitata. Material was ensiled, pressed to pellets and underwent pyrolysis using a thermo‐catalytic reforming (TCR) process, with and without additional steam. The chars generated were then assessed through proximate and ultimate analysis. Seasonal changes had the prevalent impact on char composition, though using mixed beach‐harvested material gave a greater variability in elements than when using the offshore collections. Applying the char at 5% (v/v)/2% (w/w) into germination or seedling soils was universally negative for the plants, inhibiting or delaying all parameters assessed with no clear advantage in harvesting date, species or TCR processing methodology. In germinating lettuce seeds, soil containing the pyrolysis chars caused a longer germination time, poorer germination, fewer true leaves to be produced, a lower average plant health score and a lower final biomass yield. For transplanted ryegrass seedlings, there were lower plant survival rates, with surviving plants producing fewer leaves and tillers, lower biomass yields when cut and less regrowth after cutting. As water from the char‐contained plant pots inhibited the lettuce char control, one further observation was that run‐off water from the pyrolysis char released compounds which detrimentally affected cultivated plant growth. This study clearly shows that pyrolysed macroalgae char does not fit the standard assumption that chars can be used as soil amendments at 2% (w/w) addition levels. As the bioeconomy expands in the future, the end use of residues and wastes from bioprocessing will become a genuine global issue, requiring consideration and demonstration rather than hypothesized use.     

Estimated plant richness pattern across northwest South America provides similar support for the species-energy and spatial heterogeneity hypotheses

Explaining geographic variation in plant species richness at broad spatial scales has long been a major challenge. Many hypotheses have been proposed during the last 200 yr, but recent work has focused on a few major alternatives. Among these, two hypotheses contend that plant species richness reflects 1) variation in energy and water availability among sampling units (the species-energy hypothesis) and 2) habitat and topographic heterogeneity within sampling units (the spatial heterogeneity hypothesis). We used a large botanical database and regression models to simultaneously confront the predictions from both hypotheses against an estimate of vascular plant richness across northwest South America. This estimate provided similar support for both hypotheses, a result that may be seen as contrasting with the notion that variation in energy and water availability among sampling units is the main determinant of plant species richness. We discuss potential explanations for this apparent discrepancy. Regression models that incorporated the relative contributions of both hypotheses predicted that the highest plant species richness in northwest South America is found in topographically complex areas. In contrast to several of the most recent mapping efforts, lowland Amazonia was predicted to be a plant richness trough in the study region. We suggest that diverging portrayals of plant richness across northwest South America result from differences in estimates of the relative importance of the species-energy and the spatial heterogeneity hypotheses.     

SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids

Increased metabolism is a requirement for tumor cell proliferation. To understand the dependence of tumor cells on fatty acid metabolism, we evaluated various nodes of the fatty acid synthesis pathway. Using RNAi we have demonstrated that depletion of fatty-acid synthesis pathway enzymes SCD1, FASN, or ACC1 in HCT116 colon cancer cells results in cytotoxicity that is reversible by addition of exogenous fatty acids. This conditional phenotype is most pronounced when SCD1 is depleted. We used this fatty-acid rescue strategy to characterize several small-molecule inhibitors of fatty acid synthesis, including identification of TOFA as a potent SCD1 inhibitor, representing a previously undescribed activity for this compound. Reference FASN and ACC inhibitors show cytotoxicity that is less pronounced than that of TOFA, and fatty-acid rescue profiles consistent with their proposed enzyme targets. Two reference SCD1 inhibitors show low-nanomolar cytotoxicity that is offset by at least two orders of magnitude by exogenous oleate. One of these inhibitors slows growth of HCT116 xenograft tumors. Our data outline an effective strategy for interrogation of on-mechanism potency and pathway-node-specificity of fatty acid synthesis inhibitors, establish an unambiguous link between fatty acid synthesis and cancer cell survival, and point toward SCD1 as a key target in this pathway.     

Hollow-fiber ultrafiltration for simultaneous recovery of viruses, bacteria and parasites from reclaimed water

Hollow-fiber ultrafiltration (UF) is a technique that has been reported to be effective for recovering a diverse array of microbes from water, and may also be potentially useful for microbial monitoring of effluent from water reclamation facilities. However, few data are available to indicate the potential limitations and efficacy of the UF technique for treated wastewater. In this study, recovery efficiencies were determined for various options available for performing the tangential-flow UF technique, including hollow-fiber ultrafilter (i.e., dialyzer) type, ultrafilter pre-treatment (i.e., blocking), and elution. MS2 and ΦX174 bacteriophages, Clostridium perfringens spores, Escherichia coli, and Cryptosporidium parvum oocysts were seeded into 10-L reclaimed water samples to evaluate UF options. Then a single UF protocol was established and studied using seeded and non-seeded 100-L samples from two water reclamation facilities in Georgia, USA. Baxter Exeltra Plus 210 and Fresenius F200NR dialyzers were found to provide significantly higher microbial recovery than Minntech HPH 1400 hemoconcentrators. The selected final UF method incorporated use of a non-blocked ultrafilter for UF followed by elution using a surfactant-based solution. For 10-L samples, this method achieved recovery efficiencies of greater than 50% recovery of seeded viruses, bacteria, and parasites. There was no significant difference in overall microbial recovery efficiency when the method was applied to 10- and 100-L samples. In addition, detection levels for pathogens in seeded 100-L reclaimed water samples were 1000 PFU HAV, 10,000 GI norovirus particles, < 500 Salmonella and < 200 Cryptosporidium oocysts. These data demonstrate that UF can be an effective technique for recovering diverse microbes in reclaimed water to monitor and improve effluent water quality in wastewater treatment plants.     

Bir1 Is Required for the Tension Checkpoint

The Saccharomyces cerevisiae chromosomal passenger proteins Ipl1 (Aurora B) and Sli15 (INCENP) are required for the tension checkpoint, but the role of the third passenger, Bir1, is controversial. We have isolated a temperature-sensitive mutant (bir1-107) in the essential C-terminal region of Bir1 known to be required for binding to Sli15. This allele reveals a checkpoint function for Bir1. The mutant displays a biorientation defect, a defective checkpoint response to lack of tension, and an inability to detach mutant kinetochores. Ipl1 localizes to aberrant foci when Bir1 localization is disrupted in the bir1-107 mutant. Thus, one checkpoint role of Bir1 is to properly localize Ipl1 and allow detachment of kinetochores. Quantitative analysis indicates that the chromosomal passengers colocalize with kinetochores in G1 but localize between kinetochores that are under tension. Bir1 localization to kinetochores is maintained in an mcd1-1 mutant in the absence of tension. Our results suggest that the establishment of tension removes Ipl1, Bir1, and Sli15, and their kinetochore detachment activity, from the vicinity of kinetochores and allows cells to proceed through the tension checkpoint.