Innovating aging: promises and pitfalls on the road to life extension.

One of the main benefits of the dramatic technological progress over the last two centuries is the enormous increase in human life expectancy, which has now reached record highs. After conquering most childhood diseases and a fair fraction of the diseases that plague adulthood, medical technology is now mainly preoccupied by age-related disorders. Further progress is dependent on circumventing the traditional medical focus on individual diseases and instead targeting aging as a whole as the ultimate cause of the health problems that affect humankind at old age. In principle, a major effort to control the gradual accumulation of molecular and cellular damage - considered by many as the ultimate cause of intrinsic aging - may rapidly lead to interventions for regenerating aged and worn-out tissues and organs. While considered impossible by many, there really is no reason to reject this as scientifically implausible. However, as we posit, it is not only scientific progress that is currently a limiting factor, but societal factors that hinder and may ultimately prevent further progress in testing and adopting the many possible interventions to cure aging.

Zeno's paradox and the faith that technological game-changers are impossible.

In their article in this issue, Olshansky and Carnes [Gerontology 2013;59:85-92] spell out in perhaps the most explicit terms yet a view which they have long espoused: that increases in longevity will inevitably slow down in decades to come, since the rate of biomedical progress that everyone agrees would be necessary to avoid such a slowdown is far too dramatic to be plausible. By doing so, they also betray more explicitly than ever before the flaws in their own logic. It is ironic that these flaws, unlike the work they critique, are actually quite closely analogous to the flaws in Zeno's paradox. Since others are offering their own comments on other parts of the article, I shall restrict my remarks on the article to those passages which refer specifically to my own work, together with the conclusion.

Strategies for engineered negligible senescence.

In this viewpoint, we describe the strategies for engineered negligible senescence (SENS) concept--a simple and appealing model for the design of therapeutic interventions able to meaningfully and persistently reverse the deleterious effects of aging. We go on to outline how current or foreseeable biotechnologies could feasibly be employed to repair every currently identified category of pathogenic damage that accumulates over a human lifespan. Then, briefly, we explain why this goal is not only ethically sound, but can in fact be considered to verge on an ethical obligation. Finally, we review recent progress in some key areas of the SENS platform, including proof-of-concept research sponsored by the SENS Foundation, a charity based in California.

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: 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: 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: 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: 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: 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: 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: 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."

The singularity and the Methuselarity: similarities and differences.

Aging, being a composite of innumerable types of molecular and cellular decay, will be defeated incrementally. I have for some time predicted that this succession of advances will feature a threshold, which I here christen the "Methuselarity," following which there will actually be a progressive decline in the rate of improvement in our anti-aging technology that is required to prevent a rise in our risk of death from age-related causes as we become chronologically older. Various commentators have observed the similarity of this prediction to that made by Good, Vinge, Kurzweil and others concerning technology in general (and, in particular, computer technology), which they have termed the "singularity." In this essay I compare and contrast these two concepts.

Commentary on Some Recent Theses Relevant to Combating Aging: December 2019.

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."

Commentary on Some Recent Theses Relevant to Combating Aging: October 2019.

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."

Commentary on Some Recent Theses Relevant to Combating Aging: August 2019.

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."

Commentary on Some Recent Theses Relevant to Combating Aging: April 2019.

Theses reviewed in this issue include "Alpha-Synuclein Oligomers: Cellular Mechanisms and Aspects of Antibody Treatment," "Cx3cr1/cx3cl1 Axis Drives the Migration and Maturation of Oligodendroglia in the Central Nervous System," "Genome-Wide Expression Profiling of Human Circulating Monocytes and Macrophages Identifies Diagnostic and Prognostic Signatures for Cancer Outcomes," "Lysosomal Oxidation of Low Density Lipoproteins," and "The Senescence-Associated Secretory Phenotype Induced by ID1-p16 Axis Contributes to Sorafenib Resistance in Hepatocellular Carcinoma."

Commentary on Some Recent Theses Relevant to Combating Aging: June 2019.

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."

Commentary on Some Recent Theses Relevant to Combating Aging: February 2019.

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.