Compression of morbidity by interventions that steepen the survival curve

Abstract

Longevity research aims to enhance the period of healthy life, known as the healthspan, while minimizing the duration of disability and morbidity, known as the sickspan. Various interventions extend lifespan in model organisms, but it is not known which of these are likely to compress the relative sickspan. Here, we present a theory that predicts which interventions effectively compress the sickspan. The theory is based on the shape of the survival curve - the fraction of organisms surviving as a function of age. Interventions that lengthen mean lifespan while preserving the shape of the survival curve, known as scaling, are hypothesized to extend the sickspan proportionally, without compressing it. Such interventions include caloric restriction and most other known longevity interventions. Conversely, a small subset of interventions that extend lifespan and alter the shape of the survival curve, particularly by steepening it, are predicted to compress the sickspan. We provide intuitive explanations for this theory and demonstrate its origin from the saturated removal model, a recent mathematical aging model calibrated in mice. We discuss specific longevity interventions in mice that steepen the survival curves, including senolytics, ketogenic diet, and agents that reduce glucose spikes and protect blood vessels, as potential candidates for compressing the sickspan. This hypothesis offers insights into the potential strategies for achieving compressed morbidity and extending healthspan.