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Cancer progression through the lens of age-induced metabolic reprogramming

Nature Reviews Cancer volume 25, pages 801–817 (2025)Cite this article

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Abstract

Ageing is an important risk factor for cancer incidence and augments cancer progression. A shared hallmark of ageing and cancer is metabolic reprogramming, which has been suggested to be not only a cause but also a consequence of ageing. Strikingly, many age-regulated pathways are known to also drive tumour progression, suggesting that metabolic reprogramming connects ageing and tumorigenic processes and shapes whether malignant phenotypes manifest, thrive and evolve. With the rising average age of the world population, understanding how age-related changes in the body influence cancer progression is of paramount importance. In this Perspective, we discuss the metabolic changes that occur with ageing and their potential links with tumour initiation and progression and the development of metastatic disease. Finally, we discuss age-induced metabolic divergences that cause racial disparities and their consequences for the tumorigenic process.

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Fig. 1: Ageing contributes to tumorigenesis via metabolic reprogramming of tissues and systems within the body.
Fig. 2: Age-induced reprogramming of the tumour microenvironment promotes tumorigenesis.
Fig. 3: Systemic metabolic changes in the aged host can promote tumour progression.
Fig. 4: Ageing leads to metabolic alterations in the steps of the metastatic cascade.
Fig. 5: Age-induced metabolic reprogramming influences metastatic organotropism.
Fig. 6: Mitochondrial diversity is at the root of race disparities in cancer and ageing.

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Acknowledgements

We are grateful to members of the Gomes laboratory for the critical discussions on this topic and to J. Cleveland for the critical reading and editing of this Perspective. The Gomes laboratory is supported by the New Innovator Award from the Office of the Director of the National Institutes of Health (DP2AG0776980), an American Cancer Society Research Scholar Award (RSG-22-164-01-MM), the National Institute on Aging (R21AG083720), the National Cancer Institute (R01CA279023), the Florida Health Department Bankhead-Coley Research Program (24B03), the Florida Breast Cancer Research Foundation, the Phi Beta Psi Sorority, and the National Cancer Institute Comprehensive Cancer Center Grant P30 CA076292.

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Authors and Affiliations

  1. Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Felicia Lazure & Ana P. Gomes

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  1. Felicia Lazure
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  2. Ana P. Gomes
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The authors contributed equally to all aspects of the article.

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Correspondence to Ana P. Gomes.

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Glossary

Aerobic glycolysis

A metabolic process whereby cells favour glycolysis over oxidative phosphorylation, by converting glucose into lactate for energy production, even in the presence of oxygen.

Conplastic mouse strains

Mouse strains that have identical genomic DNA but different mitochondrial DNA (mtDNA), often produced by repeatedly backcrossing females carrying the mtDNA of interest with males of the desired nuclear DNA background.

Cryptic promoters

Promoter sequences that are normally hidden by heterochromatin, but which can become uncovered when chromatin is disrupted to initiate transcription, often driving the expression of alternative mRNA transcripts.

Enantiomer

One of a pair of molecules that share the same molecular composition, but which are spatially arranged to be mirror images of each other.

Endoplasmic reticulum (ER) stress

The accumulation of misfolded proteins within the ER caused by reactive oxygen species, hypoxia, various nutrient levels, or other factors that trigger the unfolded protein response to re-establish proteostasis.

Epigenetic erosion

The decline in the stability and/or maintenance of epigenetic marks over time, often observed during ageing.

Folate cycle

A metabolic pathway that utilizes dietary folate to support one-carbon metabolism, fueling nucleotide synthesis and methylation processes.

Haplogroups

Groups of people defined by a set of genetic markers inherited from a common ancestor, usually associated with a specific geographical region.

Haplotypes

Groups of genetic markers, such as single-nucleotide polymorphisms, that are usually inherited as a unit owing to their close proximity on a chromosome or mitochondrial DNA and are used to track genetic variation patterns within populations.

Hyperinsulinaemia

A condition wherein insulin levels in the blood are chronically elevated, often associated with insulin resistance and diabetes.

Hypothalamic–pituitary–adrenal axis

A communication system between the hypothalamus, the pituitary gland of the brain, and the adrenal glands that occurs via hormones to regulate the reaction of the body to stress.

Iron–sulfur cluster

Molecules composed of iron and sulfur found in proteins that are essential for various biological processes such as the functioning of the electron transport chain and various enzymatic activities.

Osteoporosis

A disease defined by reduced bone density often caused by an imbalance between bone formation and resorption and typically associated with older age.

Oxidative phosphorylation

(OXPHOS). The cellular process that harnesses the reduction of oxygen to generate ATP.

Single-nucleotide polymorphisms

(SNPs). DNA point mutations in a single nucleotide, which may or may not lead to phenotypic traits, and are commonly used as markers in population genetics to track inheritance.

Transcriptional elongation

A step during gene expression wherein RNA polymerase II moves along the DNA template to create a nascent RNA transcript.

Tricarboxylic acid cycle

A metabolic pathway that generates electron carriers NADH and flavin adenine dinucleotide (FADH2) by breaking down acetyl-coenzyme A derived from glucose and fatty acids, also known as the Krebs cycle or citric acid cycle.

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Lazure, F., Gomes, A.P. Cancer progression through the lens of age-induced metabolic reprogramming. Nat Rev Cancer 25, 801–817 (2025). https://doi.org/10.1038/s41568-025-00845-4

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