br Conclusions Outstanding Questions and Future Directions

Conclusions, Outstanding Questions, and Future Directions To resolve these and other questions future directions must include synergistic collaborative efforts focused on aligning insights from human and laboratory aging studies. Development of advanced computational approaches such as meta-analyses and machine learning will enhance derivation of biological insights from large datasets. These insights can then be tested using genetic and pharmacological approaches in rodent studies to identify new effective interventions to delay aging. Extension of these studies to nonhuman lysophospholipid receptor will allow translation of biological insights. Caloric restriction research will also have a role to play, where interdisciplinary approaches can be brought to bear to determine the molecular details of CR\'s mechanisms and thereby identify the most promising candidate factors for targeted intervention (Fig. 3). There is tremendous interest among the public at large in discovering what influences the way we age and if the burden of age-related disease really is an inevitability of the aging process. Working together, researchers engaged in the multiple facets of aging biology are on track to have a profound impact on clinical approaches to healthy human aging.
Search Strategy and Selection Criteria
Acknowledgments This work was supported by NIH/NIA grants AG047358 and AG040178 and awards from the Glenn Foundation for Medical Research and the American Federation for Aging Research. The work was conducted with the use of resources and facilities at the William S Middleton Memorial Veterans Hospital, WI. The authors declare no conflict of interest.
Gastric cancer (GC) and colorectal cancer (CRC) are two of the most common human malignancies worldwide, ranking 5th and 3rd in incidence, and 3rd and 4th in mortality, respectively, in 2012 (). Over the last decade, a significant progress in CRC treatment resulted in improved patient survival and quality of life, whereas for GC such progress has not been apparent in the same extent. Thus, a more profound knowledge of the molecular alterations underlying neoplastic transformation and progression in GC and CRC is key for developing new tools for risk stratification and novel therapeutic strategies. The canonical Wnt pathway has been implicated both in gastric and colorectal carcinogenesis. In the stomach, Helicobacter pylori-driven carcinogenesis promotes nuclear β-catenin accumulation, fostering cell proliferation (). On the other hand, the vast majority of CRCs (about 80%) displays Wnt pathway deregulation due to mutations, that render β-catenin free to translocate to the nucleus and activate its target genes (). Overall, Wnt deregulation results in uncontrolled proliferation and impaired cell differentiation, setting the stage for neoplastic transformation. Both genetic and epigenetic events are implicated in gastrointestinal carcinogenesis, although the role of genetic aberrations has been more extensively and thoroughly investigated. Nevertheless, epigenetic deregulation, including aberrant DNA methylation patterns as well as histone onco modifications and altered chromatin remodeling, is being increasingly recognized as major contributor to cancer initiation and progression. In this setting, the study by Liang and co-workers () addresses the very interesting, but seldom explored, link between cancer genetics and epigenetics. This study is focused on the altered expression of histone H3–H4 chaperone ASF1A as a prognostic biomarker in GC and CRC, as well as its impact in cancer cell biology. In a small panel of GC and CRC cell lines, ASF1A was found overexpressed at protein level and this observation was confirmed in primary tumors, using immunohistochemistry. Interestingly, ASF1A expression gradually increased from normal to metaplastic to neoplastic tissues, suggesting a role in tumorigenesis. In CRC, higher ASF1A expression levels associated with worse overall survival. Functional studies demonstrated that ASF1A promotes cell cycle progression, clonogenicity, stemness and invasiveness, and these effects are likely mediated through its interaction with β-catenin, stimulating expression of its target genes, including , , - and . Remarkably, an inverse correlation between ASF1A and E-Cadherin expression was disclosed, intermediated by β-catenin in an inhibitory loop involving ZEB1. Finally, in vivo experiments demonstrated that ASF1A overexpression promote tumor growth and metastasis. The authors conclude that in addition to its potential as prognostic biomarker, ASF1A might also constitute a therapeutic target ().