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Over 20 years ago, together with seven illustrious colleagues, the author proposed that efforts to postpone the decline and debilitation of aging might most promisingly be pursued by tackling the various lifelong processes of accumulation of damage through a panel of interventions, rather than seeking a magic bullet that would retard them all. A decade later, this approach was embraced in a paper that rapidly became, and is still, by far the most highly cited publication in the biology of aging this century. Here I survey the progress that the field has made in relation to this philosophy and the challenges that remain.

Theses reviewed in this issue include "Engineering Protein Disaggregases to Counter Alpha-Synuclein and Amyloid-Beta Neurotoxicity," "Hyperglycaemia Induced Immunomodulation of Macrophages in Diabetic Vascular Disease," "Microvasculature-on-a-Chip Systems for Human Disease Modeling," "Senescence Surveillance: The Interplay Between the Immune System and Senescent Cells," "The HMG Transcription Factor TOX Induces a Transcriptional and Epigenetic Program of CD8 + T Cell Exhaustion in Chronic Infection and Cancer," and "Zero to One-Translational Advancements in the Field of Xenotransplantation."

Theses reviewed in this issue include "An Aging Tug of War: The Accumulation of the Spontaneous L-Isoaspartate Modification in Proteins vs. Canonical and Novel Maintenance Pathways," "Cellular and Molecular Mechanisms Underpinning Microglial Activation During Remyelination," "Early Detection of Cancer Metastasis at a Synthetic Pre-Metastatic Niche Using Inverse Spectroscopic Optical Coherence Tomography," "Magnetic Stem Cell Spheroid Microrobots and Their In Vivo Applications," "Reprogramming Human Endothelium to Hematopoietic Stem Cells with Adaptive Immune Function," and "Scaffold-Free Three-Dimensional Bioprints Repair Small Intestine Injuries and Integrate Into Native Intestine."

Theses reviewed in this issue include "Developing the Next Generation of Universal Immune Receptors," "From Synthesis to Pathology: A Bottom-Up Approach to Studying the Role of Advanced Glycation End-Products in Diabetes and Aging," "Hybrid Bioactive Nanoparticles for Modulation of Tumor Microenvironment and Enhancing Radiation and Chemotherapy Efficacy," "In Situ Bioprinting of Planar Biomaterials and Tissues," "Novel AAV Engineering Technology: Identification of Improved AAV Variants for Gene Addition and Genome Engineering in Primary Human Cells," and "Substrate Reduction Therapy for Krabbe Disease and a New Murine Model for Cell-Autonomous Expression of Lysosomal Hydrolases."

Theses reviewed in this issue include "Engineering Efficient and Safe In Situ Genome Regulation via CRISPR-Cas9 for Enabling Gene Therapies," "Investigating the Mechanism of LINE-1 Retrotransposition in Human Cells," "Machine Learning Approaches for Prediction of Kidney Transplant Survival," "Novel Obesity Suppressor Function of the Retinoblastoma Protein Uncovers Cyclin-Dependent Kinase 4 as a Therapeutic Target for Diet-Induced Obesity," "Regeneration of Retinal Neurons from Müller Glia in Adult Mice," and "Reprogramming T Cells to Interrogate Intracellular Disease Signatures."

Theses reviewed in this issue include "Characterization and Purification of Putative Stem Cells from the Adult Murine Pancreas," "Inhibition of TLR4 Minimizes Islet Damage due to Sterile Inflammation and Improves Islet Transplant Outcomes," "Liquefaction of the Brain Following Stroke Shares Multiple Characteristics with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism," "Manipulating the Segregation of Human Mitochondrial DNA," "Role of Mitochondria in Plasma Membrane Repair and Pathogenesis of Muscular Dystrophy," and "The Role of Cytosolic Accumulation of Nuclear DNA in Retinal-Pigment Epithelium Dysfunction and Age-Related Macular Degeneration."

Theses reviewed in this issue include "Clearance of Capillary Occlusions Improves Cortical Blood Flow and Cognitive Function in Alzheimer's Mouse Models," "Dermato-Informatic Approaches to Understanding and Improving Lesional Diagnostic Expertise in Cutaneous Oncology," "Furthering the Scope, Understanding, and Application of Proteolysis Targeting Chimera," "Optimization and Application of Synthetic High-Density Lipoprotein (sHDL) System in Atherosclerosis and Glioma Therapy," "Regulatory T Cell Enriching Microparticles for Promoting Tolerance in Vascularized Composite Allotransplantation," and "Tau Prion Strains Induce Distinct Pathological Phenotypes In Vivo ."

Theses reviewed in this issue include "Automated Analysis of Quantitative Image Biomarkers from Low-Dose Chest CT Scans," "Design, Synthesis, and Delivery of a Self-Cleaving Replicon System Yielding Biologically Active MicroRNAs In Vivo ," "Mechanisms of Physiological Amyloidogenesis," "Programming and Reprogramming Neural Cell Types Using Synthetic Transcription Factors," "Targeted Drug Delivery via Exploitation of the Tumor Microenvironment," and "Towards Clinically-Relevant Cell-Transplant-Based Therapies for the Treatment of Liver Diseases."

Theses reviewed in this issue include "Atrophied Thymus, a Tumor Reservoir for Harboring Melanoma Cells," "Evolutionary Adaptations in Developmental Signaling Pathways Underlie Regenerative Scar-Free Wound Repair in African Spiny Mouse (Genus Acomys )," "Integrated Immunoassays on Paper/Polymer Hybrid Microfluidic Devices for Low-Cost Detection of Disease Biomarkers," "RNA Regulation in the Nervous System: CircRNA Expression Changes During Aging, and Function of the Calm1 Extended 3' UTR Isoform," "The Role of Amylin in Alzheimer's Disease," and "Therapeutic Monoclonal Antibodies to Detect and Halt ATTR Cardiac Amyloidosis and Neuropathy."

Theses reviewed in this issue include "Cancer and Stem Cell Extravasation through Angiopellosis," "Human Chimeric Antigen Receptor Macrophages for Cancer Immunotherapy," "Insights on Alzheimer's Disease Etiology from Network Approaches in Healthy Aging," "Myelin and Glial Pathology in Aging and Cognitive Decline: Evidence for Faulty Myelin Clearance in the Rhesus Monkey," "Phosphatidylserine-Based Nanoparticles for Tolerance Induction Toward Therapeutic Proteins," and "Role of Endothelial Cell Stiffening in Choroidal Atrophy Associated with Dry Age-Related Macular Degeneration."

Theses reviewed in this issue include "Downregulation of the Apelinergic Axis Accelerates Aging, Whereas Its Systemic Restoration Improves the Mammalian Healthspan," "Intracellular Delivery of Exogenous Molecules Via an Ultrahigh Throughput Mechanoporation Microdevice," "Intrinsic and Extrinsic Drivers of Treg Fragility in the Tumor Microenvironment," "Lipid Nanoparticles Based Nanomedicine and Liquid Biopsy in Lung Cancer Therapy and Diagnosis," "Stimuli-Responsive Biomaterials for Drug Delivery to Improve Cancer Immunotherapy and Chronic Wound Healing," and "Zebrafish Extracellular Matrix as a Therapeutic Agent for Adult Mammalian Central Nervous System Regeneration."

Theses reviewed in this issue include "Age-Associated Lamin-B1 Reduction in the Thymic Epithelial Cells and Its Role in Thymic Involution," "Brainstem Structural Integrity in the Progression of Alzheimer's Disease," "Challenging Current Paradigms: Increasing the Efficacy of Radiation Therapy with Novel Radiation Schemes," "Cross-Talk Between the Skeletal Muscle Stem Cells and Endothelial Cells," "Design and Synthesis of Enzyme-MOF (Metal-Organic Framework) Composites for Long-Persistent Biomedical Applications," and "Megakaryocyte-Membrane Wrapped Nanoparticles for Targeted Delivery to Hematopoietic Stem Cells."

Theses reviewed in this issue include Characterization and Modeling of Metabolic Stress Responses in Cellular Aging; Engineering Immunity: Enhancing T Cell Vaccines and Combination Immunotherapies for the Treatment of Cancer; Extracellular Inflammatory Signaling from Dysfunctional Telomeres; High-Throughput Microfluidic Labyrinth for the Label-Free Isolation of circulating tumor cells for Single-Cell Gene Expression Profiling; Oxygen Nanobubbles for Ultrasound-guided Targeting of Cancer Hypoxia; and The Eye as a Window to the Alzheimer's Disease Brain.

Background: The role of brown fat in non-shivering thermogenesis and the discovery of brown fat depots in adult humans has made it the subject of intense research interest. A renewable source of brown adipocyte (BA) progenitors would be highly valuable for research and therapy. Directed differentiation of human pluripotent stem (hPS) cells to white or brown adipocytes is limited by lack of cell purity and scalability. Here we describe an alternative approach involving the identification of clonal self-renewing human embryonic progenitor (hEP) cell lines following partial hPS cell differentiation and selection of scalable clones., Methods: We screened a diverse panel of hPS cell-derived clonal hEP cell lines for adipocyte markers following growth in adipocyte differentiation medium. The transcriptome of the human hES-derived clonal embryonic progenitor cell lines E3, C4ELS5.1, NP88, and NP110 representing three class of definitive adipocyte progenitors were compared to the relatively non-adipogenic line E85 and adult-derived BAT and SAT-derived cells using gene expression microarrays, RT-qPCR, metabolic analysis and immunocytochemistry. Differentiation conditions were optimized for maximal UCP1 expression., Results: Many of the differentiated hEP cell lines expressed the adipocyte marker, FAPB4, but only a small subset expressed definitive adipocyte markers including brown adipocyte marker, UCP1. Class I cells (i.e., E3) expressed CITED1, ADIPOQ, and C19orf80 but little to no UCP1. Class II (i.e., C4ELS5.1) expressed CITED1 and UCP1 but little ADIPOQ and LIPASIN. Class III (i.e., NP88, NP110) expressed CITED1, ADIPOQ, C19orf80, and UCP1 in a similar manner as fetal BAT-derived (fBAT) cells. Differentiated NP88 and NP110 lines were closest to fBAT cells morphologically in adiponectin and uncoupling protein expression. But they were more metabolically active than fBAT cells, had higher levels of 3-hydroxybutyrate, and lacked expression of fetal/adult marker, COX7A1. The hEP BA progenitor lines were scalable to 17 passages without loss of differentiation capacity and could be readily rederived., Conclusions: Taken together, these data demonstrate that self-renewing adipocyte progenitor cells can be derived from hES cells and that they are functionally like BAT cells but with unique properties that might be advantageous for basic research and for development of cell-based treatments for metabolic diseases.

Theses reviewed in this issue include "A Thromboresistant Cell-Derived Biomaterial Modification for Vascular Grafts," "Actomyosin Mediated Tension Orchestrates Thermogenic Programs in Adipocytes," "Age-Associated Changes in Intrathymic B Cell Population in Mice," "Endoplasmic Reticulum Stress Is Transmissible Among Cells of the Central Nervous System," "Evaluation of Early Tumor Angiogenesis Using Ultrasound Acoustic Angiography," and "Interactions Between Amyloid-Beta and Microglial Cells."

Theses reviewed in this issue include "Computational Pathology for Quantifying Spatial Heterogeneity in Digital Images of Tissue Sections from Solid Tumors," "Molecular Analysis of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Brain Tissue Identifies Disease Mechanisms Associated with Repetitive DNA Elements," "Neuroprotective Potential of the N-Terminal Beta Amyloid Peptide Fragment in the Neurodegeneration, Synaptic Dysfunction and Memory Deficits in Models of Alzheimer's Disease," "pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent," "Quantitative Approaches for Profiling the T Cell Receptor Repertoire in Human Tissues," and "Regulation and Repair of Neural Stem Cells and the Neurogenic Niche."

Theses reviewed in this issue include "Bowties, Barcodes, and DNA Origami: A Novel Approach for Paired-Chain Immune Receptor Repertoire Analysis," "Development of Canine Chimeric Antigen Receptor T Cell Therapy for Treatment & Translation," "Endocytic Vesicle Rupture in the Pathogenesis and Propagation of Neurodegenerative Proteinopathies," "Exploring Mechanisms of Metastasis Suppression in Metastatic Melanoma," "Polymer and Nucleic Acid Self-Assemblies: Properties and Applications at the Biological Interface," and "Towards a Scalable, Biomimetic, Antibacterial Coating."

Theses reviewed in this issue include "Engineering Cellular Input-Output for the Robust Control of Mammalian Cell-Based Therapies"; "Enzyme-Instructed Self-Assembly (EISA) Selectively Targets Cancer Cells"; "Exploration of helminth-derived immunoregulatory molecules as options for therapeutic intervention in allograft rejection and autoimmune disease"; "Expression of the Medial HOXA genes is indispensible for self-renewal in human hematopoietic stem cells"; "Gamma frequency entrainment attenuates amyloid load and modifies microglia"; and "Heterogeneous Distribution of Microvascular Blood Flow Contributes to Impaired Skeletal Muscle Oxygenation in Diabetes".