Inflammaging is driven by upregulation of innate immune receptors and systemic interferon signaling and is ameliorated by dietary restriction

Aging is characterized by a chronic low-grade inflammation known as inflammaging in multiple tissues, representing a risk factor for age-related diseases. Dietary restriction (DR) is the best-known non-invasive method to ameliorate aging in many organisms. However, the molecular mechanism and the signaling pathways that drive inflammaging across different tissues and how they are modulated by DR are not yet understood. Here we identify a multi-tissue gene network regulating inflammaging. This network is characterized by chromatin opening and upregulation in the transcription of innate immune system receptors and by activation of interferon signaling through interferon regulatory factors, inflammatory cytokines, and Stat1-mediated transcription. DR ameliorates aging-induced alterations of chromatin accessibility and RNA transcription of the inflammaging gene network while failing to rescue those alterations on the rest of the genome. Our results present a comprehensive understanding of the molecular network regulating inflammation in aging and DR and provide anti-inflammaging therapeutic targets

Region-Specific Proteome Changes of the Intestinal Epithelium during Aging and Dietary Restriction

© 2020 The Author(s) The small intestine is responsible for nutrient absorption and one of the most important interfaces between the environment and the body. During aging, changes of the epithelium lead to food malabsorption and reduced barrier function, thus increasing disease risk. The drivers of these alterations remain poorly understood. Here, we compare the proteomes of intestinal crypts from mice across different anatomical regions and ages. We find that aging alters epithelial immunity, metabolism, and cell proliferation and is accompanied by region-dependent skewing in the cellular composition of the epithelium. Of note, short-term dietary restriction followed by refeeding partially restores the epithelium by promoting stem cell differentiation toward the secretory lineage. We identify Hmgcs2 (3-hydroxy-3-methylglutaryl-coenzyme A [CoA] synthetase 2), the rate-limiting enzyme for ketogenesis, as a modulator of stem cell differentiation that responds to dietary changes, and we provide an atlas of region- and age-dependent proteome changes of the small intestine

Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging

Dietary restriction (DR) improves health, delays tissue aging, and elongates survival in flies and worms. However, studies on laboratory mice and nonhuman primates revealed ambiguous effects of DR on lifespan despite improvements in health parameters. In this study, we analyzed consequences of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function. DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR increased HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging. In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. The study shows that DR-dependent suppression of growth factors and interleukins mediates these divergent effects caused by DR. Supplementation of insulin-like growth factor 1 partially reverted the DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the impairment of B lymphopoiesis exposed to DR. Together, these findings delineate positive and negative effects of long-term DR on HSC functionality involving distinct stress and growth signaling pathways. Experimental dietary restriction (DR) is based on a 10–30% reduction in food intake without leading to malnutrition (Omodei and Fontana, 2011). DR has been intensively studied and was shown to elongate the lifespan of Caenorhabditis elegans, Drosophila melanogaster, and rats (Fontana et al., 2010). Studies on inbred laboratory mice revealed that DR elongates lifespan in some mouse strains, whereas in others, the effects of DR were neutral or even resulted in lifespan shortening compared with ad libitum (AL)–fed controls (Harper et al., 2006). In long-lived nonhuman primates, two studies reported on the consequences of long-term DR on overall lifespan (Colman et al., 2009; Mattison et al., 2012). In both studies, DR did not result in a significant elongation of the lifespan compared with AL controls when all primates were included in the analysis (Colman et al., 2009; Mattison et al., 2012). These results stand in contrast to multiple studies having unambiguously documented beneficial effects of DR on health parameters and disease prevention in both murine models and primates, including suppression of cancer development, memory loss, hearing impairments, type 2 diabetes, hypertension, and heart disease (Shimokawa et al., 1993; Mattson, 2005; Cohen et al., 2009; Colman et al., 2009; Omodei and Fontana, 2011; Mattison et al., 2012). To better understand the effects of DR on health and lifespan, it is important to characterize the cellular consequences of DR at the level of adult tissue stem cells. Adult stem cells exist in many mammalian organs and tissues. Given that stem cells play essential roles in the maintenance of tissue homeostasis and tissue regeneration after damage, it is believed that age-related changes in stem cell function impact tissue aging (Dorshkind et al., 2009; Jones and Rando, 2011; Goldberg et al., 2015). Indeed, age-related declines in stem cell functionality occur in various tissues (Liu and Rando, 2011). However, the effects of DR on stem cell functionality and aging remain to be characterized in greater detail. It was reported that DR enhances muscle stem cell maintenance and activity to regenerate damaged muscle (Cerletti et al., 2012). In addition, it was shown that DR augments stem cell activity in the intestinal epithelium by stimulating mammalian target of rapamycin complex 1 (mTORC1) signaling in the Paneth cells that form a niche for intestinal stem cells (Yilmaz et al., 2012). In the hematopoietic system, DR ameliorated aging-associated increases in the self-renewal of phenotypic hematopoietic stem cells (HSCs) with reduced functionality as well as defects in the clearance of nonproliferative (senescent) and damaged T lymphocytes (Spaulding et al., 1997a; Chen et al., 1998, 2003; Ertl et al., 2008). However, DR-fed mice exhibited an enhanced susceptibility to infections indicative of impaired immune functions (Peck et al., 1992; Gardner, 2005; Kristan, 2007; Goldberg et al., 2015). Mechanistically, the effects of DR on HSC functionality remain incompletely understood but are influenced by genetic factors (Ertl et al., 2008). In this study, we analyzed the short- and long-term effects of adult-onset 30% DR on the capacity of HSCs and progenitor cells in maintaining hematopoietic repopulation and B lymphopoiesis in C57BL/6J mice. The study provides the first experimental evidence that long-term DR alters the lymphoid cell differentiation potential of HSCs and progenitor cells, resulting in immune defects in the context of prolonged bacterial infection. However, long-term DR from young adulthood to midlife improves the maintenance of the repopulation capacity of HSCs by enhancing stem cell quiescence. The study identifies distinct stress signaling factors (IL-6 and IL-7) and growth factors (insulin-like growth factor 1 [IGF1]) that contribute to both the positive and adverse effects of DR on HSC functionality