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Caloric restriction (CR) is the leading non-pharmacological intervention to delay induced and spontaneous tumors in pre-clinical models. These effects of CR are largely attributed to canonical inhibition of pro-growth pathways. However, our recent data suggest that CR impairs primary tumor growth and cancer progression in the murine 4T1 model of triple negative breast cancer (TNBC), at least in part, through reduced frequency of the myeloid-derived suppressor cells (MDSC). In the present study, we sought to determine whether injection of excess MDSCs could block regression in 4T1 tumor growth and metastatic spread in BALB/cJ female mice undergoing daily CR. Our findings show that MDSC injection impeded CR-mediated protection against tumor growth without increasing lung metastatic burden. Overall, these results reveal that CR can slow cancer progression by affecting immune suppressive cells. Impact statement: Inoculation of MDSCs from donor mice effectively impedes the ability of calorie restriction to protect against primary tumor growth without impacting lung metastatic burden in recipient animals. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00635-y.

Diet composition, calories, and fasting times contribute to the maintenance of health. However, the impact of very low-calorie intake (VLCI) achieved with either standard laboratory chow (SD) or a plant-based fasting mimicking diet (FMD) is not fully understood. Here, using middle-aged male mice we show that 5 months of short 4:10 VLCI cycles lead to decreases in both fat and lean mass, accompanied by improved physical performance and glucoregulation, and greater metabolic flexibility independent of diet composition. A long-lasting metabolomic reprograming in serum and liver is observed in mice on VLCI cycles with SD, but not FMD. Further, when challenged with an obesogenic diet, cycles of VLCI do not prevent diet-induced obesity nor do they elicit a long-lasting metabolic memory, despite achieving modest metabolic flexibility. Our results highlight the importance of diet composition in mediating the metabolic benefits of short cycles of VLCI., Understanding the contribution of diet composition, calories and length of fasting in health maintenance is still challenging. Here the authors compare the effects of cycles of intermittent very low calorie intake achieved with a plant-based fasting mimicking diet or standard laboratory chow to provide insights into the role played by diet composition in mediating the metabolic benefits of short cycles of very low-calorie intake in mice.

An identifying feature of Quercus agrifolia Nee (Fagaceae) is the presence of hair tufts on lower leaf surfaces. In other plant species, hair tufts act as domatia for arthropods such as mites, which in turn feed on leaf fungi or small herbivores and possibly benefit plant health. However, this mutualistic relationship remains untested in Q. agrifolia. In this study two primary questions were addressed within a natural stand of Q. agrifolia in San Luis Obispo, CA: 1) Do hair tufts act as domatia for mites? and 2) Does the removal of hair tufts impact mite abundance, herbivory or fungal pathogens on leaves? In an observational study of 377 leaves from 20 trees, we found a significant association between the presence of hair tufts and the presence of mites. When we experimentally removed hair tufts, we found a significant reduction in mites, yet there was no impact on leaf herbivory or necrosis. We conclude leaf hair tufts on Q. agrifolia serve as domatia for mites, but we found no evidence that mites reduce herbivory or fungal pathogens. Thus, while mites likely benefit from housing provided by hair tufts on Q. agrifolia, it is unclear that the tree benefits from the mites, i.e., whether this is a mutually beneficial relationship.

Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer. However, due to CR’s stringency, dietary alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR., Caloric restriction (CR) has been shown as an effective intervention to reduce tumorigenesis, but alternative less stringent dietary interventions have also been considered. Here, the authors show that in a murine model of breast cancer CR has a larger effect on preventing tumorigenesis and metastasis compared to periodic caloric cycling.

Urban areas provide animals with both a unique set of challenges and resources. One of the novel resources available in urban areas is an abundance of human food waste. Although it is known that many urban-dwelling animals are consuming human food waste at some level, there is not a good understanding of the nutrients provided by this novel resource. Given that human food waste is unlikely to resemble an animal’s natural diet, there could be health consequences for an animal consuming human food waste. In some animals, nutritional imbalances can also lead to behavioral changes, making it important to understand more precisely what they are eating. To answer the question of what nutrients were available in urban food waste, we surveyed food waste in the Philadelphia–Camden urban matrix. We found that human food waste contained ∼1000% more carbohydrates than other nutrient types. Given the impact that carbohydrate-rich diets can have on human health, there may be important consequences for the animals in urban environments that consume this food waste. Therefore, it is possible that human food subsidies have cascading consequences for entire communities and their ecosystem services in cities.

Cancer is a leading cause of mortality, with its incidence only expected to rise with an increasingly aging population. Dietary interventions, primarily caloric restriction (CR), lower cellular energy metabolism and have long been utilized to slow the aging process and protect against age-related diseases, including cancer. However, due to the stringency of CR, dietary alternatives that offer the same beneficial outcomes in cancer prevention and longevity have become increasingly attractive. Periodic cycles (4 days twice a month) of low caloric intake followed by a standard ad libitum (AL) diet was previously shown to promote health-span in mice and humans and protect against primary tumorigenesis and enhanced the effects of chemotherapy. The aim of our study was to compare the tumorigenic potential of 4T1 cells, a murine model of stage IV breast cancer, in young and aged female BALB/c mice fed either periodic cycles of low caloric diets versus chronic 20% CR. Compared to AL controls, we found a significant delay in primary tumor growth in mice regardless of diet composition by the 4:10 cycles of very low caloric intake. However, unlike in CR, CR-alternative diets were not protective against lung metastases in the absence of chemotherapy. Our study sheds light into the underlying differences of calorie-based interventions in the absence of chemotherapy.

The aging process is sexually dimorphic, with males having higher occurrence rates of cancer and facing a greater risk of mortality. Sexual dimorphism in the response to cellular damage may account for distinct phenotypic changes with age as they relate to the accumulation of cellular damage leading to cancer. Cellular senescence triggers permanent cell cycle arrest in order to protect against malignant growth. However, organismal senescence increases with age and is associated with the release of pro-inflammatory signals (cytokines, chemokines, and proteases) known as the ‘senescence-associated-secretory-phenotype’ (SASP) that, if unchecked, accelerates tissue damage and creates a microenvironment ripe for cancer development. In this study, we hypothesized that sexual disparities in mortality and cancer prevalence stems from differences in the rate of accumulation of senescent cells in mice. Male and female C57BL/6J mice were fed ad libitum or subjected to 30% calorie restriction, a nutritional intervention known to delay the onset of various cancers and prevent senescent cell accumulation. Primary skin fibroblasts were collected longitudinally to allow measurement of cell proliferation, wound healing and the release of SASP factors. The results indicate that when compared to males, fibroblasts of CR-fed females showed significant improvements in cell growth rate, wound healing and SASP markers vs. AL controls. Work is underway to determine how sex influences cellular protective pathways. Thus, like other cell processes, cellular senescence is unequal between males and females and CR delays the emergence of the senescence phenotype.

The last decade has seen a dramatic rise in the development of new cellular therapeutics in a wide range of indications. There have been acceptable safety profi les reported in early studies using blood-derived and adherent stem cell products, but also an inconsistent effi cacy record. Further expansion has been hindered in part by a lack of capital (both private and public) and delayed entry into the cell therapy space by large healthcare and pharmaceutical companies, those members of the industry most reliably able to initiate and maintain advanced-phase clinical trials. With recognition that the International Society for Cellular Therapy (ISCT) is uniquely positioned to serve the global translational regenerative medicine research community as a network hub for scientifi c standards and policy, the ISCT commissioned the establishment of an Industry Task Force (ITF) to address current and future roles for industry. The objectives of the ITF were to gather information and prioritize efforts for a new Commercialization Committee (CC) and to construct innovative platforms that would foster constructive and synergistic collaborations between industry and ISCT. Recommendations and conclusions of the ITF included that the new CC: (1) foster new relationships with therapeutic and stem cell societies, (2) foster educational workshops and forums to cross-educate and standardize practices, (3) create industry subcommittees to address priority initiatives, with clear benchmarks and global implementation, and (4) establish a framework for a greater industry community within ISCT, opening doors for industry to share the new vision for commercialization of cell therapy, emphasizing the regenerative medicine space.

Novocell, Inc. is a stem cell engineering company creating, delivering and commercializing cell and drug therapies for diabetes and other chronic diseases. The use of human embryonic stem cells provides a scalable source of any differentiated lineage that has potential for cell replacement therapy, as well as tools for drug discovery to create regenerative medicines.

Dopaminergic neurons of human origin have many potential research applications such as in vitro studies on biochemical pathways related to neuronal disorders, and potentially direct cell replacement for therapeutic use. Dopaminergic neurons with apparently normal properties can be produced from embryonic stem cells from mice and sub-human primates by the simple procedure of coculturing with the PA6 stromal cell line. Recently, we have demonstrated that this coculture system can induce dopaminergic differentiation in human embryonic stem cells, and the human embryonic stem cell-derived dopaminergic cells exhibit biochemical and functional properties of mature dopaminergic neurons.