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At Cell Metabolism, we often banter that “all roads lead to metabolism.” Over the years, we have witnessed the spectacular growth and integration of the metabolism field with other disciplines such as cancer biology, microbiology, and neurobiology. The field of immunometabolism is another example of interdisciplinary collaboration between the metabolism and immunology fields. While the concepts of inflammation as a driver of chronic metabolic diseases and of metabolic pathways supporting immune cell differentiation are more or less established, the idea that cellular metabolism affects immune function beyond ATP provision and redox balance is currently being actively pursued. As seen with cancer metabolism, there has been a shift in thinking away from metabolic cycles working as continuous loops and more toward them as dynamic modular components. In this Special Issue on immunometabolism, we chose to focus on a few of the key concepts currently shaping the field.In the opening Perspective of this series, Rathmell and colleagues highlight not only the many metabolic similarities but also critical differences between cancer and immune cells. They point out how these similarities and differences could potentially be exploited to treat cancer and immunological disorders. Next, Prochnicki and Latz turn their attention to a key signaling platform of the immune system, the inflammasome, and discuss how host- and microbial-derived metabolic cues regulate the inflammasome and how inflammasome-mediated metabolic sensing impacts diseases such as obesity, type 2 diabetes, and atherosclerosis. Restifo and colleagues then take us behind the scenes of T cell anti-tumor activity and propose strategies to harness metabolism for improved cancer immunotherapy. They postulate that it may be possible to establish a therapeutic window where metabolic inhibition does not compromise T cell function.On the theme of the gut microbiome, Ghosh and colleagues take stock of the complex interplay among the diverse metabolites produced by bacteria coming either from dietary components, from de novo synthesis, or through modification of existing metabolites in inflammatory diseases. Channeling Aesop, Pearce and colleagues highlight that, in metabolism, “where there is union there is strength” and provide an overview of ancillary pathways, such as those involved in the biosynthesis of polyamines, cholesterol, hexosamines, and nucleotides, which shape the complexity of the immune response. In closing, Netea and colleagues revisit fundamental concepts of myeloid cell metabolism during innate immune responses. They emphasize how different stimuli and/or tissue microenvironments will underlie heterogeneous metabolic response in myeloid cell activation and how a better integration of the molecular inflammatory response will pave the way to precision medicine.While much progress has undoubtedly been made, we are probably only just scratching the tip of the iceberg and foresee much more exciting biology coming on the immunometabolism horizon. The Special Issue cover art, designed by Ayaka Sugiura, pays tribute to the complex and stunning choreography between metabolism and immunology in achieving homeostatic balance; we eagerly await the next dance compositions of immunometabolism.

Despite being in the age of information technology, with a wealth of molecular data at our fingertips, relatively simple clinical parameters such as BMI and fasting glucose are used to diagnose complex metabolic disorders. These clinical markers have stood the test of time and are affordable. However, given that many patients taking top-selling drugs fail to benefit from their prescriptions (Schork, 2015xSchork, N.J. Nature. 2015; 520: 609–611Crossref | PubMed | Scopus (152)See all ReferencesSchork, 2015), we are sharply reminded that a “one size fits most” approach may not always be effective for diagnosing and treating heterogeneous diseases such as the metabolic syndrome. The need for individualized therapies has prompted various countries, including the United States, the United Kingdom, and China, to launch “Precision Medicine” initiatives, recognizing the need to collect and analyze big data from the population at large to ultimately benefit the health of sub-populations and individuals. In the United States, this has paved the way to an all-inclusive research program led by the NIH, “All of Us,” tapping into the rich diversity of the United States population, which promises to collect and analyze lifestyle, environmental, and biological data from one million volunteers in order to cover a wide array of health conditions.The hope of understanding and treating the patient as an individual rather than as part of a generic class has started to materialize. Given their tractability, rare monogenic diseases, such as the extreme hyperphagia and obesity of two patients with proopiomelanocortin deficiency being treated with a melanocortin-4 receptor agonist (Kuhnen et al., 2016xKuhnen, P., Clement, K., Wiegand, S., Blankenstein, O., Gottesdiener, K., Martini, L.L., Mai, K., Blume-Peytavi, U., Gruters, A., and Krude, H. N. Engl. J. Med. 2016; 375: 240–246Crossref | PubMed | Scopus (33)See all ReferencesKuhnen et al., 2016), have seen success stories. Long-term strategies will be aimed at deciphering more complex and heterogeneous pathologies, ranging from cancer to metabolic disorders. In 2011, the National Research Council of the United States called for a “knowledge network,” which layers and connects complex factors, ultimately building a new “taxonomy of disease” from which a patient can be diagnosed through the integration of omics data. The omics include exposomes (exposure-omics), metabolomes, genomes, epigenomes, and microbiomes (NRC, 2011xToward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease. National Research Council. See all ReferencesNRC, 2011). In this Special Issue, we introduce the concept of “Precision Metabolism” and review our quiver of complex factors that need to be integrated to individually target metabolic health and disease.Maggi and colleagues kick off the issue with one of the most basic differences between individuals: sex. In their essay they argue that, with evolutionary pressure driving sex divergence and positive selection on females to adapt their energy metabolism to their reproductive needs, sex differences are intricately weaved into the pathology of metabolic disorders. Focusing on immune-metabolic crosstalk, Elinav and colleagues tackle the complex dynamic equilibrium between diet, host genome, gut microbome, and the immune response from conception through birth to old age. With the march of time, an individual’s metabolism shifts, as does his or her immune state; they propose the intriguing possibility of harnessing the immune system as a means of personalized treatment of some metabolic disorders. Leulier and colleagues review diet, host physiology, and microbiota within an integrative framework from model organisms to humans, and propose a theoretical concept, the nutritional geometry framework, for personalized diet optimization. This concept is applied in a research article in this issue, in which Piper and colleagues (2017)xPiper, M.D., Soultoukis, G., Blanc, E., Mesaros, A., Herbert, S., Juricic, P., He, X., Atanassov, I., Salmonowicz, H., Yang, M. et al. Cell Metab. 2017; 25: 610–621Abstract | Full Text | Full Text PDF | PubMed | Scopus (9)See all References)Piper and colleagues (2017) use the genomic information of an organism to define its dietary amino acid requirements, and show that exome-based designer diets optimize fitness in flies and mice.Although one would intuitively think that understanding the underlying genetic basis for obesity would be helpful, Loos and Janssens take a sobering look at where we are in understanding the polygenic basis of obesity risk. Though we have nearly 200 common genetic variants associated with obesity, we are still coming up short in our predictive capacity compared to traditional parameters, such as family history and childhood obesity. As we are now realizing, however, epigenetics provides an additional layer of complexity on top of our genetics, as our “non-genetic molecular legacy of prior environmental exposures.” Two Perspectives, one by Rando and colleagues, and one by Patti and colleagues, review the complex links between metabolism and epigenetic modifications and multigenerational disease links transmitted through germ cells. Nielsen and colleagues close the issue from a systems perspective, bringing into focus the unprecedented availability of big data for integrative analysis, and take us back to the individual, looking at the immense value of N-of-1 clinical trials with large cohorts.Sixteen years since the publication of the first draft of the human genome, we are watching the arrow of precision medicine fly toward the bull’s-eye of metabolic health.

Otto Warburg is generally credited to be the “father” of cancer metabolism for his seminal discovery of how cancer cells predominantly generate energy through glycolysis rather than oxidative phosphorylation, even in the presence of oxygen. While it was initially thought that the sole function of aerobic glycolysis was to quickly provide ATP for proliferating cancer cells, we have come to realize, over the years, that the situation is much more complex. In a recent Cell Metabolism Perspective, Pavlova and Thompson (2016) highlighted six emerging hallmarks of cancer metabolism, and while not all tumors display all six, more than one hallmark is common: (1) deregulated uptake of glucose and amino acids, (2) opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite-driven gene regulation, and (6) metabolic interactions with the microenvironment.

We all—more or less—think about aging, and our ancestors did too. In Greek mythology, the god of old age, Geras, was often depicted as a shriveled-up old man holding a cane, while the goddess of youth, Hebe, was the young woman keeper of the Fountain of Youth. When we think of aging, even though life expectancy has gone up, it is the increased risk for maladies such as cardiovascular disease, cancer, diabetes, sarcopenia, osteoporosis, and cognitive decline that is more worrisome than the end point.The Authors a Few Years BackView Large Image | View Hi-Res Image | Download PowerPoint SlideWhat makes us age, and can we promote healthy aging? For this Special Issue of Cell Metabolism on Aging, we feature primary research articles and a collection of Crosstalk, Review, Perspective, and Essay articles in aging biology. We hope that this selection will kick-start insightful discussions that we can continue at our upcoming Cell Symposium “Aging and Metabolism” in Spain (July 10–12). We are including a sneak preview of thoughts from the meeting speakers, as well as other leaders in the aging field, in our Voices article.The animal kingdom is full of surprises when it comes to longevity. For example, the naked mole rat, the longest-lived rodent, can live up to 28 years, and the bowhead whale, at 200 years, has the longest lifespan of all animals. Clues into healthy aging may also come from elephants, which carry multiple copies of the tumor-suppressor gene TP53 in their genomes, offering an explanation for their very low cancer rate (Abegglen et al., 2015xPotential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. Abegglen, L.M., Caulin, A.F., Chan, A., Lee, K., Robinson, R., Campbell, M.S., Kiso, W.K., Schmitt, D.L., Waddell, P.J., Bhaskara, S. et al. JAMA. 2015; 314: 1850–1860Crossref | Scopus (19)See all ReferencesAbegglen et al., 2015). Tissue metabolites across 26 mammalian species, representing ten taxonomical orders, were investigated in a Cell Metabolism study in order to identify metabolites correlating with species lifespan (Ma et al., 2015xOrganization of the Mammalian Metabolome according to Organ Function, Lineage Specialization, and Longevity. Ma, S., Yim, S.H., Lee, S.G., Kim, E.B., Lee, S.R., Chang, K.T., Buffenstein, R., Lewis, K.N., Park, T.J., Miller, R.A. et al. Cell Metab. 2015; 22: 332–343Abstract | Full Text | Full Text PDF | PubMed | Scopus (6)See all ReferencesMa et al., 2015). On the other hand, the African turquoise killifish helps us understand the genetics of accelerating aging (Valenzano et al., 2015xThe African turquoise killifish genome provides insights into evolution and genetic architecture of lifespan. Valenzano, D.R., Benayoun, B.A., Singh, P.P., Zhang, E., Etter, P.D., Hu, C.K., Clement-Ziza, M., Willemsen, D., Cui, R., Harel, I. et al. Cell. 2015; 163: 1539–1554Abstract | Full Text | Full Text PDF | PubMed | Scopus (10)See all ReferencesValenzano et al., 2015). In humans, while progeroid syndromes have taught us how specific gene mutations can dramatically shorten lifespan, the basis for exceptional longevity in centenarians has proven to be much more complex, involving numerous genetic variants, reflecting the interaction with environmental factors.Historically, model organisms, including yeast, worms, and fruit flies, have been instrumental in identifying some of the key genes and signaling pathways regulating lifespan. The past decades have witnessed a rejuvenation of the aging field as new molecular targets underlying the biology of aging have emerged, such as sirtuins and mTOR. These fundamental genetic and epigenetic drivers are conserved across the animal kingdom from yeast to humans and have revealed how intricately intertwined metabolism and aging are. Barzilai and colleagues discuss the complexity of the somatotrophic axis in aging in their Review article, while Kennedy and Lamming provide an update on mTOR, a key hub linking metabolism and aging. Using C. elegans as a model in their research article, Kenyon and colleagues explore the link between starvation-induced quiescence, proteostasis, and aging (Roux et al., 2016xProlonged C. elegans Larval Quiescence Induces Signs of Aging that Can Be Reversed by ire-1-Dependent Pathways. Roux, A.E., Langhans, K., Huynh, W., and Kenyon, C. Cell Metab. 2016; 23: 1113–1126Abstract | Full Text | Full Text PDFSee all ReferencesRoux et al., 2016). Steffen and Dillin pick up this topic further and discuss how changes in translation affect proteostasis and longevity, while Wiley and Campisi delve into the connections between metabolism and cellular senescence.Given its multifactorial nature, aging may well be the most complex physiological question. How do genetics, diet, and other lifestyle factors interact to affect longevity? A critical element underlying this trifecta is the influence of sex on biology, as exemplified by the recent NIH mandate to “consider sex as a biological variable” that needs to “be factored into research designs, analyses, and reporting” (NIH notice NOT-OD-15-102, Consideration of Sex as a Biological Variable in NIH-funded Research). Throughout this Special Issue, several authors, such as deCabo and colleagues, who look at the effects of sex and genetics in response to calorie restriction, emphasize how fundamental this point is (Mitchell et al., 2016xEffects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Mitchell, S.J., Madrigal-Matute, J., Scheibye-Knudsen, M., Fang, E., Aon, M., Gonzalez-Reyes, J.A., Cortassa, S., Kaushik, S., Gonzalez-Freire, M., Patel, B. et al. Cell Metab. 2016; 23: 1093–1112Abstract | Full Text | Full Text PDFSee all ReferencesMitchell et al., 2016). In this vein, Fisher and Austad review sex differences in lifespan and conclude that, though more physically limited than men, women are the longer-lived sex. Could the physical limitations be, at least in part, due to skeletal muscle atrophy? Zierath and colleagues offer intriguing answers in their Review about healthy muscle aging. Karsenty and colleagues investigate bone-muscle communication and identify osteocalcin as a strength-promoting hormone that naturally declines with age (Mera et al., 2016xOsteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise. Mera, P., Laue, K., Ferron, M., Confavreux, C., Wei, J., Galan-Diez, M., Lacampagne, A., Mitchell, S.J., Mattison, J.A., Chen, Y. et al. Cell Metab. 2016; 23: 1078–1092Abstract | Full Text | Full Text PDFSee all ReferencesMera et al., 2016). Using a novel mass spectrometry assay, LeBrasseur and colleagues show that the previously thought putative rejuvenating factor, GDF11, does not decrease during aging in humans and, if anything, has a negative health association in older adults with cardiovascular disease (Schafer et al., 2016xQuantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease. Schafer, M.J., Atkinson, E.J., Vanderboom, P.M., Kotajarvi, B., White, T.A., Moore, M.M., Bruce, C.J., Greason, K.L., Suri, R.M., Khosla, S. et al. Cell Metab. 2016; 23: 1207–1215Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesSchafer et al., 2016). Could the “Fountain of Youth” be “just down the street at your nearest neighborhood gym” as posited by Zierath and colleagues? Not so fast, say Longo and Panda in their Perspective, as “everyday dietary choices can clearly accelerate aging” and “increase the incidence of age-related diseases.”The growing number of insights into what makes us age has led some to investigate ways to slow the process down. Considerable pharmaceutical and biotech research efforts are currently being focused in this direction such as Kronos Longevity Research, Proteostasis Therapeutics, and Calico, to name a few, not only looking into novel therapeutics, but also revisiting old ones such as hormonal treatments and antioxidants. The immunosuppressant rapamycin, which is one of the first drugs shown to extend lifespan in a variety of species, including mammals, is currently being tested in a clinical trial for the treatment of Hutchinson-Gilford progeria syndrome. In their Essay, Barzilai and colleagues explain why they chose the anti-diabetic drug metformin for their Targeting Aging with Metformin (TAME) clinical trial of 65+ humans as a paradigm for the evaluation of pharmacological approaches to combat aging. Coming back to diet as a therapy, Elysium Health markets nutritional supplements (nutraceuticals) aimed at boosting NAD levels. Intriguing research in this issue by Chini and colleagues identifies CD38 as the enzyme responsible for the age-related decline in endogenous NAD levels and shows that CD38 can modulate the response to NAD replacement therapies in mice.So it looks like there’s hope for Geras after all; he might soon be able to ditch his cane, spend less time worrying about his health, and post more selfies while skateboarding. Rock on!

Leave all the afternoon for exercise and recreation, which are as necessary as reading. I will rather say more necessary because health is worth more than learning.—Thomas JeffersonTwo years ago, we successfully brought together leaders in the exercise field, including physiologists, clinicians, and molecular biologists, to promote cross-pollination of ideas for the first Cell Symposium on Exercise Metabolism in Amsterdam. When the time came to decide whether or not to repeat the meeting, the “yes” vote was unanimous. We again teamed up with Drs. Juleen Zierath and John Hawley for the second running of the Exercise Metabolism Cell Symposium, this time in Sweden, which has a long tradition in exercise physiology. This Special Issue of Cell Metabolism on the theme of exercise sets the stage for our upcoming symposium in May, starting with a unique cover featuring many of the Cell Symposium speakers and Cell Metabolism editors getting their heart rates up. Besides our Speaker and Editor Voices series, which blends personal stories and research inspiration, you will find a Crosstalk and a Perspective, as well as Reviews and research articles, on exercise.Although we all know that exercise is good for us, promotes healthy aging, improves cognitive function, and staves off a wide range of diseases, the WHO reports that physical inactivity ranks as the fourth leading risk factor for global mortality (http://www.who.int/dietphysicalactivity/pa/en/). In their Crosstalk opinion article, Gibala and Hawley underscore that lack of time is one of the main reasons for delaying going to the gym and discuss the idea that high-intensity interval training might be an effective way of addressing this conundrum. However, despite interval training gaining in popularity, the most effective protocol is still somewhat unclear, as are the underlying molecular mechanisms.In case you are wondering what exercise physiology is, Gabriel and Zierath define it as the “science of studying limits: the limits of elite performance, the limits of the health benefits of exercise, or the limits/barriers to achieving increased population-wide participation in exercise.” Their Perspective highlights how early investigations on the physiological limits of performance have set the stage for modern day exercise scientists to start unraveling the molecular mechanisms of exercise. Cardiac adaptation and fuel selection are, of course, important determinants of performance. Leinwand and colleagues compare an athlete’s physiological heart growth to the pathological hypertrophy observed with hypertension or ischemic heart disease, illustrating how exercise pathways can antagonize pathological pathways. Goodpaster and Sparks argue in their overview of metabolic flexibility in fuel selection that, while targeting metabolic inflexibility in diabetes and obesity is an attractive therapeutic option, “any pharmacologic strategy purporting to mimic exercise would need to impact metabolic flexibility and also induce increases in energy expenditure and demand similar to exercise. This should prove to be challenging, if not impossible.”As the molecular mechanisms underlying exercise emerge, the controversial topic of “exercise in a pill” often comes up. Contrary to Goodpaster’s view on exercise mimetics, a recent Perspective in our journal by Fan and Evans argues that exercise mimetics are already here and discusses their effects on health and as performance-enhancing drugs (Fan and Evans, 2017xFan, W. and Evans, R.M. Cell Metab. 2017; 25: 242–247Abstract | Full Text | Full Text PDF | PubMed | Scopus (3)See all ReferencesFan and Evans, 2017). While it is unlikely that targeting a single pathway would recapitulate the pleiotropic effects of exercise, PPARβ/δ and AMPK have been identified as promising candidates to boost the exercise response. In this issue, the Holloszy group details a two-step process through which PPARβ/δ mediates the adaptive skeletal muscle response to endurance exercise, with an initial early mitochondria maintenance phase, followed by long-term increased mitochondrial biogenesis. Taking advantage of the fact that PPARβ/δ can be pharmacologically targeted, the Evans group shows that PPARβ/δ plays a crucial role in glucose sparing and delays the onset of “hitting the wall,” with agonist-treated mice extending their running time by over 100 min. In turn, Miller and colleagues shed new light on tissue specificity of AMPK by employing a new small-molecule activator of AMPK, which results in a re-wiring of the muscle transcriptome and rapid lowering of glucose levels, independently of AMPK activation in the liver.As the field of exercise makes strides forward, now, more than ever, we need to keep the momentum of exercise research going to better our health. On the heels of the 121st Boston marathon, highlighting endurance, willpower, and perseverance, including the spectacular participation of Kathrine Switzer, the first woman to officially run the Boston Marathon 50 years ago, we could not agree more with Ruth Loos that “the world is a better place after a run.”