Missing Therapeutic Capabilities for Longevity and Health Engineering

Missing Therapeutic Capabilities for Longevity and Health Engineering: A Translational Agenda for Finite-Course Rejuvenation and Amplification of Physiological Adaptation Contemporary medicine has achieved substantial progress in preventing disease, controlling risk factors, and extending survival. However, many forms of accumulated tissue damage, age-related structural deterioration, and loss of physiological reserve remain incompletely reversible. Existing treatments often suppress ongoing injury without fully restoring previously damaged tissues to a younger functional state. This research perspective identifies and systematically evaluates therapeutic capabilities whose development could enable a qualitative advance in longevity science and health engineering. The proposed framework distinguishes three categories: Class R — Finite-Course Repair and Rejuvenation: Interventions that reverse established pathological damage or restore lost biological functions, producing clinically meaningful benefits that persist without continuous maintenance administration of the repair agent. Class A — Physiological Adaptation Amplification: Interventions that enhance the retained biological benefits of exercise, rehabilitation, learning, or other defined adaptive stimuli. Unlike Class R, continuous pharmacological administration may be acceptable. Class E — Adaptation-Enabling Interventions: Treatments that remove physiological constraints preventing individuals from effectively participating in beneficial adaptive activities. The manuscript evaluates 23 therapeutic programs, comprising 18 repair domains, four adaptation-enhancement programs, and one adaptation-enabling case. Major research areas include selective cleavage of glucosepane crosslinks, arterial elastin regeneration, vascular and valvular decalcification, reversal of established fibrosis, atherosclerotic plaque resolution, lysosomal waste and lipofuscin clearance, amyloid removal, selective senolysis, mitochondrial quality restoration, thymic regeneration, clonal hematopoiesis, pancreatic beta-cell regeneration, neural repair, latent viral reservoir eradication, restoration of age-related chronotropic reserve, and controlled cellular reprogramming. Adaptation-oriented programs address PPARδ/AMPK signaling, hydrogen sulfide signaling, endothelial nitric oxide synthase recoupling, and pharmacological reopening of learning-related plasticity. For each program, the review examines clinical relevance, limitations of endogenous repair and existing medical interventions, mechanistic evidence, translational feasibility, safety constraints, and experiments required to demonstrate genuine therapeutic benefit. Special emphasis is placed on distinguishing structural repair from disease suppression, persistent rejuvenation from ongoing drug action, and enhanced physiological adaptation from transient performance improvements. The manuscript proposes operational criteria, experimental designs, and evidence-based development priorities, while incorporating negative clinical findings and important translational limitations. Central thesis: A major future advance in longevity and health engineering may arise not merely from better suppression of age-associated disease, but from the development of therapies that remove accumulated damage, restore lost tissue function, or substantially increase the beneficial adaptations achievable through physiological interventions. This is a hypothesis-generating, non-systematic research perspective. The proposed capabilities vary substantially in technological maturity, and their inclusion does not imply established clinical efficacy, safety, or demonstrated human lifespan extension. Evidence cutoff: October 31, 2026. Document type: Research preprint / Translational research perspective.