Late-life dietary folate restriction reduces biosynthetic processes without compromising healthspan in mice.

Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual's age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.

Branched-chain amino acid synthesis is coupled to TOR activation early in the cell cycle in yeast.

How cells coordinate their metabolism with division determines the rate of cell proliferation. Dynamic patterns of metabolite synthesis during the cell cycle are unexplored. We report the first isotope tracing analysis in synchronous, growing budding yeast cells. Synthesis of leucine, a branched-chain amino acid (BCAA), increases through the G1 phase of the cell cycle, peaking later during DNA replication. Cells lacking Bat1, a mitochondrial aminotransferase that synthesizes BCAAs, grow slower, are smaller, and are delayed in the G1 phase, phenocopying cells in which the growth-promoting kinase complex TORC1 is moderately inhibited. Loss of Bat1 lowers the levels of BCAAs and reduces TORC1 activity. Exogenous provision of valine and, to a lesser extent, leucine to cells lacking Bat1 promotes cell division. Valine addition also increases TORC1 activity. In wild-type cells, TORC1 activity is dynamic in the cell cycle, starting low in early G1 but increasing later in the cell cycle. These results suggest a link between BCAA synthesis from glucose to TORC1 activation in the G1 phase of the cell cycle.

One-carbon metabolic enzymes are regulated during cell division and make distinct contributions to the metabolome and cell cycle progression in Saccharomyces cerevisiae.

Enzymes of one-carbon (1C) metabolism play pivotal roles in proliferating cells. They are involved in the metabolism of amino acids, nucleotides, and lipids and the supply of all cellular methylations. However, there is limited information about how these enzymes are regulated during cell division and how cell cycle kinetics are affected in several loss-of-function mutants of 1C metabolism. Here, we report that the levels of the S. cerevisiae enzymes Ade17p and Cho2p, involved in the de novo synthesis of purines and phosphatidylcholine (PC), respectively, are cell cycle-regulated. Cells lacking Ade17p, Cho2p, or Shm2p (an enzyme that supplies 1C units from serine) have distinct alterations in size homeostasis and cell cycle kinetics. Loss of Ade17p leads to a specific delay at START, when cells commit to a new round of cell division, while loss of Shm2p has broader effects, reducing growth rate. Furthermore, the inability to synthesize PC de novo in cho2Δ cells delays START and reduces the coherence of nuclear elongation late in the cell cycle. Loss of Cho2p also leads to profound metabolite changes. Besides the expected changes in the lipidome, cho2Δ cells have reduced levels of amino acids, resembling cells shifted to poorer media. These results reveal the different ways that 1C metabolism allocates resources to affect cell proliferation at multiple cell cycle transitions.

Computational studies of ene reactions between aminoborane (F3C)2B[double bond, length as m-dash]N(CH3)2 and substituted propenes: additive effects on barriers and reaction energies.

Systematic computational studies of concerted pericyclic ene-type reactions between aminoborane (F3C)2B[double bond, length as m-dash]N(CH3)2, 1, and substituted propenes (R1a)(R1e)C[double bond, length as m-dash]C(R2)-C(R3a)(R3e)H (R = Me, CF3, F; a = axial position in transition state, e = equatorial position in transition state) show that in all cases but one the reactions are exothermic. The reactions proceed through six-membered cyclic envelope-like transition states except in the case of 1 + C3H(CF3)5. The data allow isolation of substitutional effects on barrier heights; the effects appear to be additive in all cases. Substitution at positions 1a, 1e, and 3a increases barriers, while substitution at positions 2 and 3e has variable impacts. The former observation is ascribed to steric crowding in the transition states, and is particularly prevalent for substitution at positions 1a and 1e. Substitution at position 2 lowers barriers for R = Me, F, possibly due to electronic demands, while raising them for R = CF3 because of 1,3-diaxial repulsions between boron- and carbon-bound CF3 groups. Substitution at position 3e has little impact on the barriers for R = Me, CF3, but significantly raises them for R = F. This seems to arise from charge effects on the position of the transition states.