Compression of morbidity by interventions that steepen the survival curve

Yifan Yang; Avi Mayo; Tomer Levy; Naveh Raz; Ben Shenhar; Daniel F. Jarosz; Uri Alon

doi:10.1038/s41467-025-57807-5

Compression of morbidity by interventions that steepen the survival curve

Yifan Yang^*, Avi Mayo, Tomer Levy, Naveh Raz, Ben Shenhar, Daniel F. Jarosz, Uri Alon^*

^*Corresponding author for this work

Department of Molecular Cell Biology

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Longevity research aims to extend the healthspan while minimizing the duration of disability and morbidity, known as the sickspan. Most longevity interventions in model organisms extend healthspan, but it is not known whether they compress sickspan relative to the lifespan. Here, we present a theory that predicts which interventions compress relative sickspan, based on the shape of the survival curve. Interventions such as caloric restriction that extend mean lifespan while preserving the shape of the survival curve, are predicted to extend the sickspan proportionally, without compressing it. Conversely, a subset of interventions that extend lifespan and steepen the shape of the survival curve are predicted to compress the relative sickspan. We explain this based on the saturating-removal mathematical model of aging, and present evidence from longitudinal health data in mice, Caenorhabditis elegans and Drosophila melanogaster. We apply this theory to identify potential interventions for compressing the sickspan in mice, and to combinations of longevity interventions. This approach offers potential strategies for compressing morbidity and extending healthspan.

Original language	English
Article number	3340
Journal	Nature Communications
Volume	16
DOIs	https://doi.org/10.1038/s41467-025-57807-5
Publication status	Published Online - 8 Apr 2025

Funding

The authors thank Christos Consoulas, Jeong-Hoon Hahm for sharing original data on Drosophila sickspan and worms’ maximal velocity, respectively, and Nicholas Stroustrup for general discussion and for sharing shortened twilight data in worms. The authors thank Richard Miller for providing feedback and discussions on mice survival curves. The authors also thank Nir Barzilai, Pinchas Cohen, Valery Krizhanovsky, Coleen Murphy, Collin Ewald, Jan Gruber, Sara Hägg and Vadim Gladyshev for general discussion and feedback. The authors also thank Glen Pridham for numerous help on methodology and understanding mice and human frailty; and David S. Glass, Elizabeth Vaisbourd, Alon Bar, and Tomer Milo for editing help. Received funding from European Research Council (ERC) grant agreement No 856487 (UA).

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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title = "Compression of morbidity by interventions that steepen the survival curve",

abstract = "Longevity research aims to extend the healthspan while minimizing the duration of disability and morbidity, known as the sickspan. Most longevity interventions in model organisms extend healthspan, but it is not known whether they compress sickspan relative to the lifespan. Here, we present a theory that predicts which interventions compress relative sickspan, based on the shape of the survival curve. Interventions such as caloric restriction that extend mean lifespan while preserving the shape of the survival curve, are predicted to extend the sickspan proportionally, without compressing it. Conversely, a subset of interventions that extend lifespan and steepen the shape of the survival curve are predicted to compress the relative sickspan. We explain this based on the saturating-removal mathematical model of aging, and present evidence from longitudinal health data in mice, Caenorhabditis elegans and Drosophila melanogaster. We apply this theory to identify potential interventions for compressing the sickspan in mice, and to combinations of longevity interventions. This approach offers potential strategies for compressing morbidity and extending healthspan.",

author = "Yifan Yang and Avi Mayo and Tomer Levy and Naveh Raz and Ben Shenhar and Jarosz, \{Daniel F.\} and Uri Alon",

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AU - Yang, Yifan

AU - Mayo, Avi

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AU - Raz, Naveh

AU - Shenhar, Ben

AU - Jarosz, Daniel F.

AU - Alon, Uri

PY - 2025/4/8

Y1 - 2025/4/8

N2 - Longevity research aims to extend the healthspan while minimizing the duration of disability and morbidity, known as the sickspan. Most longevity interventions in model organisms extend healthspan, but it is not known whether they compress sickspan relative to the lifespan. Here, we present a theory that predicts which interventions compress relative sickspan, based on the shape of the survival curve. Interventions such as caloric restriction that extend mean lifespan while preserving the shape of the survival curve, are predicted to extend the sickspan proportionally, without compressing it. Conversely, a subset of interventions that extend lifespan and steepen the shape of the survival curve are predicted to compress the relative sickspan. We explain this based on the saturating-removal mathematical model of aging, and present evidence from longitudinal health data in mice, Caenorhabditis elegans and Drosophila melanogaster. We apply this theory to identify potential interventions for compressing the sickspan in mice, and to combinations of longevity interventions. This approach offers potential strategies for compressing morbidity and extending healthspan.

AB - Longevity research aims to extend the healthspan while minimizing the duration of disability and morbidity, known as the sickspan. Most longevity interventions in model organisms extend healthspan, but it is not known whether they compress sickspan relative to the lifespan. Here, we present a theory that predicts which interventions compress relative sickspan, based on the shape of the survival curve. Interventions such as caloric restriction that extend mean lifespan while preserving the shape of the survival curve, are predicted to extend the sickspan proportionally, without compressing it. Conversely, a subset of interventions that extend lifespan and steepen the shape of the survival curve are predicted to compress the relative sickspan. We explain this based on the saturating-removal mathematical model of aging, and present evidence from longitudinal health data in mice, Caenorhabditis elegans and Drosophila melanogaster. We apply this theory to identify potential interventions for compressing the sickspan in mice, and to combinations of longevity interventions. This approach offers potential strategies for compressing morbidity and extending healthspan.

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Compression of morbidity by interventions that steepen the survival curve

Abstract

Funding

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