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Editorial: No Trp, no B: surprising connectivity of diet, microbiome, aging, and adaptive immunity

Ben Franklin quipped: “In this world nothing can be said to be certain, except death and taxes”; whereas today’s polymaths might shudder in attempts to explain modern politics, interest abounds in current efforts that are starting to move the needle on lifespan. Modern medicine and public health practices have contributed an increase in life expectancy of .2-fold in the United States since Franklin’s era, as well as an increase of ;8 y in the past 50 y and a 44% increase in the number of U.S. centenarians from 2000 to 2014 [1]. Can specific interventions that target aging push this progress even further? Insights from biomedical research as to the molecular basis of aging have been used to generate treatments designed to slow aging or increase healthspan (i.e., healthy “golden years”). For example, clinical trials of nicotinamide mononucleotide are underway [2], and metformin, used to treat diabetes, is being tested in the Targeting Aging with Metformin study [3]. CR as an anti-aging intervention predates testing of these compounds and has been studied extensively in rodents and other model organisms. Clinical studies are in progress [4], but the jury is still out as to whether CR might be effective for humans. The featured paper (“Tryptophan restriction arrests B cell development and enhances microbial diversity in WT and prematurely aging Ercc12/D7 mice”) by van Beek et al. [5] reduces the complexity of CR interventions by feeding mice a diet only lacking Trp, as TR also delays aging of mice. This study breaks new ground by evaluating the consequences of TR for B cell development. Aging, in general, increases morbidity, disability, and mortality, as a result of infectious disease [6]. For example, influenza infections are responsible for significant morbidity and mortality each year, with the highest infection rates found in the elderly. Unfortunately, the efficacy of influenza vaccines in the elderly is limited [7], at least in part, as a result of reduced humoral immune responses [8, 9]. In mice, the most pronounced change in the B cell compartment is the reduction in numbers of pre-B cells in aged mice; we and others [10] found that aged mice can have as few as 10% of the number of pre-B cells found in young mice, as well as some loss of pro-B cells. Inefficient transition of cells from the pro-B to pre-B cell stage of development, coupled with HSC impairment, may be critical to the reduced number of pre-B cells in aged mice (reviewed in ref. [10]). Strategies to counter the aging immune system should bolster B cell production to supply naive B cells that can respond to vaccines and new pathogens. Van Beek et al. [5] asked whether TR ameliorates the decline in B cell generation with age. Given that TR for 20 mo is most likely not feasible, the authors first established that mice deficient for the DNA repair enzyme Ercc1, in addition to premature aging phenotypes already found in these mice, also have reduced numbers of B cell progenitors at 16 wk of age. TR not only fails to reverse the Ercc1dependent defect in B cell generation, it also potentiates the loss of pro-B and preB cells in the mutant mice and profoundly depletes these and immature bone marrow B cells in wild-type mice. This is the first direct assessment of B cell development in dietary-restricted mice, and this surprising result can serve as a cautionary tale for CR as an aging intervention, especially so, given that mice in a clean animal facility might respond to CR with lifespan extension without any real requirement for a functional immune system. It would be interesting to ask whether CR and TR affect B cell development equivalently and whether this effect impacts the susceptibility to infectious diseases. van Beek et al. [5] also found that splenic T cells are reduced after TR, hinting at wider-spread effects on the immune system. Therefore, it would be important to examine HSC activity and early lymphocyte progenitors from these mice and also whether the bone marrow and thymic microenvironments are disrupted (Fig. 1). Along these lines, a recent study found that dietary restriction impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes [11]. Furthermore, we wonder whether Trp is directly