Combining rejuvenation interventions in rodents: a milestone in biomedical gerontology whose time has come.

INTRODUCTION: Longevity research has matured to the point where significantly postponing age-related decline in physical and mental function is now achievable in the laboratory and foreseeable in the clinic. The most promising strategies involve rejuvenation, i.e. reducing biological age, not merely slowing its progression. AREAS COVERED: We discuss therapeutic strategies for rejuvenation and results achieved thus far, with a focus on in vivo studies. We discuss the implications of interventions which act on mean or maximum lifespan and those showing effects in accelerated disease models. While the focus is on work conducted in mice, we also highlight notable insights in the field from studies in other model organisms. EXPERT OPINION: Rejuvenation was originally proposed as easier than slowing aging because it targets initially inert changes to tissue structure and composition, rather than trying to disentangle processes that both create aging damage and maintain life. While recent studies support this hypothesis, a true test requires a panel of rejuvenation interventions targeting multiple damage categories simultaneously. Considerations of cost, profitability, and academic significance have dampened enthusiasm for such work, but it is vital. Now is the time for the field to take this key step toward the medical control of aging.

The Divide-and-Conquer Approach to Delaying Age-Related Functional Decline: Where Are We Now?

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.

Commentary on Some Recent Theses Relevant to Combating Aging: June 2021.

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."

Commentary on Some Recent Theses Relevant to Combating Aging: April 2021.

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."

Commentary on Some Recent Theses Relevant to Combating Aging: February 2021.

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."

Commentary on Some Recent Theses Relevant to Combating Aging: December 2020.

Theses reviewed in this issue include "Advances on Chip-In-Cell Wireless Platform for Continuous Monitoring of Physiological Parameters in Single Cells," "Design and Delivery of Synthetic mRNA by a Peptide Nanoparticle," "Inflammation Alters Endothelial Progenitor Cell-derived Exosome Contents and Therapeutic Effect on Myocardial Repair," "Partial Reprogramming: A Shortcut to Rejuvenation," "Renal Angioplasty and Therapeutic Angiogenesis for Renovascular Disease: A Novel Treatment Strategy," and "Targeted EDTA Chelation Therapy with Albumin Nanoparticles to Reverse Arterial Calcification and Restore Vascular Health in Chronic Kidney Disease."

Commentary on Some Recent Theses Relevant to Combating Aging: October 2020.

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."

Commentary on Some Recent Theses Relevant to Combating Aging: August 2020.

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."

Commentary on Some Recent Theses Relevant to Combating Aging: June 2020.

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."

Commentary on Some Recent Theses Relevant to Combating Aging: April 2020.

Theses reviewed in this issue include "Advanced Imaging Technologies for Combined Biomedical Ultrasound and Photoacoustic Imaging," "Engineering Bispecific Chimeric Antigen Receptors to Improve the Efficacy of Adoptive T-Cell Therapy," "Il-36 Gamma Promotes Anti-Tumor Immunity Through Therapeutic Induction of Tumor-Associated Tertiary Lymphoid Structures," "Investigating the Role of Matrix Vesicles During Aortic Valve Interstitial Cell Calcification," "Local Delivery of Cyclosporine and Erythropoietin Promotes Functional Recovery in a Rodent Model of Stroke Injury by Endogenous Tissue Repair," and "Targeting Primary Cilia-Mediated Mechanotransduction to Promote Whole Bone Formation."

Commentary on Some Recent Theses Relevant to Combating Aging: February 2020.

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."