Unveiling the transcriptional and cellular landscape of age across human tissues

As the aging population grows progressively around the globe, the need to research and develop strategies to healthy aging is ever more critical and takes on new urgency1. Primary hallmarks of aging include cell autonomous changes linked to epigenetic alterations, genomic instability, telomere attrition and loss of proteostasis (protein homeostasis), which are followed by antagonistic responses such as deregulated nutrient sensing, altered mitochondrial function and cellular senescence. In addition, many functions of the immune system show a progressive decline with age, referred as immunosenescence, leading to a higher risk of infection, cancer, and autoimmune diseases2. Although chronological age is the most powerful risk factor for most chronic diseases, the underlying molecular mechanisms that lead to generalized disease susceptibility are largely unknown. In recent years, rapidly developing high-throughput omics have provided a broader insight, with the identification of a number of longevity-relevant loci based on genome-wide association studies (GWAS) and epigenome analyses. Despite this success, APOE, FOXO3 and 5q33.3 are the only identified loci consistently associated with longevity3. Hence, the complexity of the aging phenomenon, influenced by genetic and epigenetic regulation, post-translational regulation, metabolic regulation, host–microbiome interactions, lifestyle, and many other elements, primarily explains the poor understanding of many of the molecular and cellular processes that underlie the progressive loss of healthy physiology.