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Modelling the ageing dependence of cancer evolutionary trajectories

Nature Reviews Cancer volume 25, pages 757–780 (2025)Cite this article

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Abstract

Ageing is the single most important prognostic factor for cancer development. Despite this knowledge, experimental models of cancer have historically omitted incorporating the impact of age on cancer initiation, progression and treatment outcomes. Ageing interacts with other lifestyle factors, including cigarette smoking, obesity and physical activity, but these intersections are rarely studied in experimental models. Given that cancer-related mortality rates increase with age, there is a growing emphasis on modelling ageing-associated mutational and microenvironmental changes in cancer research. In this Review, we provide guidance on the technological advancements and experimental strategies that have increased our ability to model how ageing impacts various stages of cancer evolution, from mutation-driven clonal expansions, to pre-malignant lesions, and then to progression to more malignant phenotypes and metastasis, and responses to therapies. We discuss the benefits and limitations of methods and models used. The wider adoption of age-appropriate models of cancer will enable the development of improved approaches for the detection, prevention and therapeutic intervention of human cancers.

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Fig. 1: Overview of ageing-associated changes that contribute to the evolution of cancers.
Fig. 2: Methods for tissue isolation and mutation detection provide distinct insights into mutational landscapes.
Fig. 3: Shared features between humans and animal models used to study accelerated ageing or anti-ageing strategies.

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Acknowledgements

The authors thank M. De Dominici for his careful review of this manuscript. The authors also thank M. Tipton and A. A. Henry for the original figures they created for this work. Funding to support this article was provided by the National Institutes of Health (NIH) grants R01AG066544 (J.D.), U01CA271830 (J.D.), NIH grant R01AI172452 (C.J.H.), the Courtenay C. and Lucy Patten Davis Endowed Chair in Lung Cancer Research (J.D.), and the David F. and Margaret Turley Grohne Endowed Chair in Translational Cancer Research (C.J.H.).

Author information

Authors and Affiliations

  1. The Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Curtis J. Henry & James DeGregori

  2. The Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    James DeGregori

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  1. Curtis J. Henry
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  2. James DeGregori
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The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Curtis J. Henry or James DeGregori.

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Competing interests

J.D. is the editor in chief of the journal Aging And Cancer and a member of the scientific advisory boards for the International Center for Aging and Cancer (Hainan, China) and for the biotech company Mitotherapeutix. C.J.H. declares no competing interests.

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Nature Reviews Cancer thanks João Pedro de Magalhães and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Base editing

A derivative of CRISPR technology that allows for the generation of precise single-nucleotide variants. This gene-editing technology specifically makes single base substitutions (for example, converting an adenine (A) to a guanine (G) nucleotide).

Cellular senescence

A process whereby cells can permanently exit the cell cycle but remain viable in response to damage or oncogenic stress; can be tumour-suppressive or tumour-promoting.

Chemopreventative agent

The use of natural, biological or synthetic agents to inhibit cancer initiation or progression.

Drift

The random distribution of alleles over generations.

Epigenetic changes

Heritable changes without alteration of the DNA sequence, such as through altered methylation of DNA or modifications of chromatin-associated histones.

Fitness

The relative ability of a (epi)genotype to contribute to subsequent generations.

Glutaminolysis

The metabolic utilization of glutamine to produce ATP, lactate, glutamate, α-ketoglutarate and ammonia in cells.

Healthspan

The number of years alive without debilitating pathologies.

Hormone replacement therapy

(HRT). Treatment involving the replacement of hormones that decline with age, such as in women post-menopause.

Hypogonadism

A condition wherein the gonads produce little or no hormones.

Immunosenescence

Reduced or altered functionality of the immune system in older ages.

Lifespan

The number of years an organism lives.

Microbiome

The community of microorganisms living within a tissue.

Mutations

Changes to the DNA sequence, from single-nucleotide variants to chromosomal rearrangements.

Organoid

A 3D tissue culture model of an organ made from stem cells or tumour cells.

Pentose phosphate pathway

A cellular metabolic pathway that primarily produces NADPH and ribose-5-phosphate, a precursor for nucleotide synthesis.

Prime editing

A derivative of CRISPR technology that allows for the generation of precise single-nucleotide variants. Compared to base editing, this gene-editing technology enables a wider range of edits, including substitutions, insertions and deletions.

Selection

Changes in the frequency of a phenotype within a population based on its effect on fitness.

Senolytics

Agents used to deplete senescent cells, often in mouse models.

Single-nucleotide variants

(SNVs). Mutations that change a single base pair in DNA.

Soma

All body parts of an organism with the exception of the reproductive organs.

Telomerase

An enzyme that maintains telomeres.

Telomeres

Repetitive sequences at the end of chromosomes that alleviate the end-replication problem and prevent the triggering of a DNA damage response.

Unique molecular identifiers

(UMIs). Short random sequences experimentally attached to fragments of DNA that enable assignment of all amplified progeny DNAs to their original parent DNA.

Variant allele frequency

(VAF). The proportion of alleles that are variant (that is, mutated).

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Henry, C.J., DeGregori, J. Modelling the ageing dependence of cancer evolutionary trajectories. Nat Rev Cancer 25, 757–780 (2025). https://doi.org/10.1038/s41568-025-00838-3

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