L-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative. This Review summarizes the physiological and pathophysiological roles of Trp metabolism, highlighting the vast opportunities and challenges for drug development in multiple diseases.

Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond

A diet deficient in the amino acid methionine has previously been shown to extend lifespan in several stocks of inbred rats. We report here that a methionine-deficient (Meth-R) diet also increases maximal lifespan in (BALB/cJ x C57BL/6 J)F1 mice. Compared with controls, Meth-R mice have significantly lower levels of serum IGF-I, insulin, glucose and thyroid hormone. Meth-R mice also have higher levels of liver mRNA for MIF (macrophage migration inhibition factor), known to be higher in several other mouse models of extended longevity. Meth-R mice are significantly slower to develop lens turbidity and to show age-related changes in T-cell subsets. They are also dramatically more resistant to oxidative liver cell injury induced by injection of toxic doses of acetaminophen. The spectrum of terminal illnesses in the Meth-R group is similar to that seen in control mice. Studies of the cellular and molecular biology of methionine-deprived mice may, in parallel to studies of calorie-restricted mice, provide insights into the way in which nutritional factors modulate longevity and late-life illnesses.

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Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance

Dietary energy restriction has been a widely used means of experimentally extending mammalian life span. We report here that lifelong reduction in the concentration of a single dietary component, the essential amino acid L-methionine, from 0.86 to 0.17% of the diet results in a 30% longer life span of male Fischer 344 rats. Methionine restriction completely abolished growth, although food intake was actually greater on a body weight basis. Studies of energy consumption in early life indicated that the energy intake of 0.17% methionine-fed animals was near normal for animals of their size, although consumption per animal was below that of the much larger 0.86% methionine-fed rats. Increasing the energy intake of rats fed 0.17% methionine failed to increase their rate of growth, whereas restricting 0.85% methionine-fed rats to the food intake of 0.17% methionine-fed animals did not materially reduce growth, indicating that food restriction was not a factor in life span extension in these experiments. The biochemically well-defined pathways of methionine metabolism and utilization offer the potential for uncovering the precise mechanism(s) underlying this specific dietary restriction-related extension of life span.

Low Methionine Ingestion by Rats Extends Life Span

Some mammalian aging processes involve effects of steroids on the brain and pituitary. An ovary-dependent, neuroendocrine aging syndrome of laboratory rats and mice is described in this article. Th...

Ovarian and Steroidal Influences on Neuroendocrine Aging Processes in Female Rodents

Nutritional control of aging

Patho-physiologic findings after chronic tryptophan deficiency in rats: A model for delayed growth and aging

Histology and survival in age-delayed low-tryptophan-fed rats

An artificial plasma-like substance having at least one water soluble polysaccharide oncotic agent selected from the group consisting of high molecular weight hydroxyethyl starch, low molecular weight hydroxyethyl starch, dextran 40 and dextran 70, and albumin which is buffered by lactate and has a pre-administration pH of between 5 and 6.5 is disclosed. Also disclosed is an artificial plasma-like solution having at least two water soluble polysaccharide oncotic agents one of which is eliminated from the circulation slowly and the other of which is eliminated from the circulation quickly. Supplimentation of the plasma-like solution with certain ions is described. A system for administration of the plasma-like solution to a subject wherein the system comprises a first and second solution each having particular buffers is described. The plasma-like solution including cryoprotective adducts is also disclosed. The use of the plasma-like solution in organ transplant, novel chemotherapy procedures, and tissue, organ and organism cryopreservation are also disclosed.

Plasma expander and blood substitute

From a larger study seeking to develop indexes of physiological aging, the present experiment was designed 1) to test thermoregulatory capacity in the aging and old rat subjected to 3 minutes of whole-body ice water immersion, and 2) using this index of physiological age, to determine whether tryptophan deficiency from time of weaning can retard the onset of senescence. Results indicate a progressive prolongation of temperature recovery time from young to middle age to old, and tryptophan-deficient animals restored to commercial diet at middle age show the thermoregulatory capacity of young adults. The implications of tryptophan deficiency with respect to brain development, serotonin metabolism, and temperature regulation are also discussed in terms of the possibility of intervening with the aging process.—Segall, P. E. and P. S. Tlmiras. Age-related changes in thermoregulatory capacity of tryptophan-deficient rats. Federation Proc. 34: 83–85, 1975.

Age-related changes in thermoregulatory capacity of tryptophan-deficient rats

The present invention relates to the field of compositions of matter, disclosing compositions of matter which as aqueous solutions, may be used to perfuse a living or non-living subject in need of perfusion. The solutions according to the invention are typified by an aqueous solution comprising a polysaccharide oncotic agent, a physiologically compatible buffer, a simple hexose sugar, dissolved chloride salts of calcium, sodium and magnesium, and a dissolved organic salt of sodium. The solutions according to the invention are effective substitutes for blood. In addition the solution according to the invention may be used to preserve the biological integrity of the organs of a mammalian donor organism as shown by superior anatomical integrity of cryopreserved organs and tissues of subjects perfused with the solution of the invention. The solutions may be used for a number of purposes including maintaining a partially or substantially completely exsanguinated subject at temperatures substantially below those normally maintained by a mammal. The solutions may be used in conjunction with hyperbaric environments to maintain such partially or completed exsanguinated subjects alive without infusing blood back into the subject. Methods for using the solutions for these purposes are disclosed.

Paul E. Segall

Papers

Patho-physiologic findings after chronic tryptophan deficiency in rats: A model for delayed growth and aging

Histology and survival in age-delayed low-tryptophan-fed rats

Plasma expander and blood substitute

Age-related changes in thermoregulatory capacity of tryptophan-deficient rats

Method of perfusing a primate