Extension of Yeast Chronological Lifespan by Methylamine

Background: Chronological aging of yeast cells is commonly used as a model for aging of human post-mitotic cells. The yeast Saccharomyces cerevisiae grown on glucose in the presence of ammonium sulphate is mainly used in yeast aging research. We have analyzed chronological aging of the yeast Hansenula polymorpha grown at conditions that require primary peroxisome metabolism for growth. Methodology/Principal Findings: The chronological lifespan of H. polymorpha is strongly enhanced when cells are grown on methanol or ethanol, metabolized by peroxisome enzymes, relative to growth on glucose that does not require peroxisomes. The short lifespan of H. polymorpha on glucose is mainly due to medium acidification, whereas most likely ROS do not play an important role. Growth of cells on methanol/methylamine instead of methanol/ammonium sulphate resulted in further lifespan enhancement. This was unrelated to medium acidification. We show that oxidation of methylamine by peroxisomal amine oxidase at carbon starvation conditions is responsible for lifespan extension. The methylamine oxidation product formaldehyde is further oxidized resulting in NADH generation, which contributes to increased ATP generation and reduction of ROS levels in the stationary phase. Conclusion/Significance: We conclude that primary peroxisome metabolism enhanced chronological lifespan of H. polymorpha. Moreover, the possibility to generate NADH at carbon starvation conditions by an organic nitrogen source supports further extension of the lifespan of the cell. Consequently, the interpretation of CLS analyses in yeast should include possible effects on the energy status of the cell.

Water- and nutrient-dependent effects of dietary restriction on Drosophila lifespan

Dietary restriction (DR) is a widely conserved intervention leading to lifespan extension. Despite considerable effort, the mechanisms underlying DR remain poorly understood. In particular, it remains unclear whether DR prolongs life through conserved mechanisms in different species. Here, we show that, in the most common experimental conditions, lifespan extension by DR is abolished by providing Drosophila with ad libitum water, without altering food intake, indicating that DR, as conventionally studied in flies, is fundamentally different from the phenomenon studied in mammals. We characterize an alternative dietary paradigm that elicits robust lifespan extension irrespective of water availability, and thus likely represents a more relevant model for mammalian DR. Our results support the view that protein:carbohydrate ratio is the main dietary determinant of fly lifespan. These findings have broad implications for the study of lifespan and nutrition

Acetyl-L-carnitine supplementation differently influences nutrient partitioning, serum leptin concentration and skeletal muscle mitochondrial respiration in young and old rats.

Variations in energy balance, body composition, and nutrient partitioning induced by acetyl-L-carnitine (ALCAR) supplementation were studied in young (2 mo) and old (24 mo) Wistar rats. Changes in skeletal muscle metabolism as well as in serum free triiodothyronine and leptin levels were also evaluated. Rats were administered 0 (control) or 15 g/L ALCAR in their drinking water for 1 mo. ALCAR treatment significantly decreased body lipid percentage in young rats and significantly increased body protein percentage in old rats. The percentage of metabolizable energy (ME) intake stored as lipid was lower in ALCAR-treated young rats, whereas the percentage of ME intake stored as protein was greater in ALCAR-treated old rats compared with their age-matched controls. In addition, ALCAR supplementation significantly decreased serum leptin levels in old rats. Elevated skeletal muscle respiration was found in old rats treated with ALCAR, due to an increase in mitochondrial protein mass. In conclusion, ALCAR supplementation decreases efficiency of lipid deposition in young rats and increases efficiency of protein deposition in old rats. In addition, ALCAR supplementation partly reduces the leptin resistance that occurs in old rats, and improves ATP production in skeletal muscle mitochondria through an increase in mitochondrial protein content

Direct comparison of methionine restriction with leucine restriction on the metabolic health of C57BL/6J mice

EKL was the recipient of a BBSRC postgraduate studentship. This work was funded by Tenovus Scotland project grant to MD and NM (G13/07) and BBSRC DTG. MD is also supported by the British Heart Foundation (PG/09/048/27675, PG/11/8/28703 and PG/14/43/30889) and Diabetes UK (14/0004853). NM is funded by British Heart Foundation (PG/16/90/32518).Peer reviewedPublisher PD

Lifetime fitness consequences of early-life ecological hardship in a wild mammal population

1. Early-life ecological conditions have major effects on survival and reproduction. Numerous studies in wild systems show fitness benefits of good quality early-life ecological conditions (‘silver spoon’ effects). 2. Recently, however, some studies have reported that poor quality early-life ecological conditions are associated with later-life fitness advantages and that the effect of early-life conditions can be sex-specific. Furthermore, few studies have investigated the effect of the variability of early-life ecological conditions on later-life fitness. 3. Here we test how the mean and variability of early-life ecological conditions affect the longevity and reproduction of males and females using 14 years of data on wild banded mongooses (Mungos mungo). 4. Males that experienced highly variable ecological conditions during development lived longer and had greater lifetime fitness, while those that experienced poor early-life conditions lived longer but at a cost of reduced fertility. In females there were no such effects. 5. Our study suggests that exposure to more variable environments in early life can result in lifetime fitness benefits whereas differences in the mean early-life conditions experienced mediates a life history trade-off between survival and reproduction. It also demonstrates how early-life ecological conditions can produce different selection pressures on males and female

Nutritional Geometry Provides Food for Thought

Dietary Restriction extends lifespan in a diverse range of animals, but this often comes at a cost to reproduction. While a number of molecular pathways integral to these relationships have been characterised, we still do not fully understand whether restriction of specific nutrients or calories is responsible. Two recent studies on insects have offered novel insights into this longstanding issue via the application of Nutritional Geometry. This technique promises to significantly advance our understanding of how nutrition influences reproduction and longevity

Complementary intestinal mucosa and microbiota responses to caloric restriction

The intestine is key for nutrient absorption and for interactions between the microbiota and its host. Therefore, the intestinal response to caloric restriction (CR) is thought to be more complex than that of any other organ. Submitting mice to 25% CR during 14 days induced a polarization of duodenum mucosa cell gene expression characterised by upregulation, and downregulation of the metabolic and immune/inflammatory pathways, respectively. The HNF, PPAR, STAT, and IRF families of transcription factors, particularly the Pparα and Isgf3 genes, were identified as potentially critical players in these processes. The impact of CR on metabolic genes in intestinal mucosa was mimicked by inhibition of the mTOR pathway. Furthermore, multiple duodenum and faecal metabolites were altered in CR mice. These changes were dependent on microbiota and their magnitude corresponded to microbial density. Further experiments using mice with depleted gut bacteria and CR-specific microbiota transfer showed that the gene expression polarization observed in the mucosa of CR mice is independent of the microbiota and its metabolites. The holistic interdisciplinary approach that we applied allowed us to characterize various regulatory aspects of the host and microbiota response to CR

Differences in genome-wide gene expression response in peripheral blood mononuclear cells between young and old men upon caloric restriction

Background: Caloric restriction (CR) is considered to increase lifespan and to prevent various age-related diseases in different nonhuman organisms. Only a limited number of CR studies have been performed on humans, and results put CR as a beneficial tool to decrease risk factors in several age-related diseases. The question remains at what age CR should be implemented to be most effective with respect to healthy aging. The aim of our study was to elucidate the role of age in the transcriptional response to a completely controlled 30 % CR diet on immune cells, as immune response is affected during aging. Ten healthy young men, aged 20–28, and nine healthy old men, aged 64–85, were subjected to a 2-week weight maintenance diet, followed by 3 weeks of 30 % CR. Before and after 30 % CR, the whole genome gene expression in peripheral blood mononuclear cells (PBMCs) was assessed. Results: Expression of 554 genes showed a different response between young and old men upon CR. Gene set enrichment analysis revealed a downregulation of gene sets involved in the immune response in young but not in old men. At baseline, immune response-related genes were higher expressed in old compared to young men. Upstream regulator analyses revealed that most potential regulators were controlling the immune response. Conclusions: Based on the gene expression data, we theorise that a short period of CR is not effective in old men regarding immune-related pathways while it is effective in young men