Ageing is a fundamental driver of cancer, with more than 90% of cancers arising in individuals over 50 years of age, and as such is the number one risk factor for cancer development (Siegel et al. CA Cancer J. Clin. 71, 7–33; 2021). It is accompanied by a decrease in physiological resilience, impaired immune function and an increase in frailty that creates a landscape susceptible to tumorigenesis. Importantly, cancer itself as well as cancer treatment can affect the fundamental ageing processes, leaving survivors of cancer in accelerated aged states, as highlighted by Demaria in a Comment in this issue. This establishes a circular feedback loop that exacerbates frailty, impairs organ function and increases vulnerability to other cancers and chronic diseases. As ageing is associated with a time-dependent accumulation in cellular damage, and cancer arises from such damage, the incidence of cancer is expected to rise with our currently ageing global population. The healthcare burden and the associated financial and economic burdens that this will place on society are far from trivial. Studying cancer within the context of ageing is therefore essential — not only to better understand tumour biology, but also to improve cancer prevention, treatment, patient quality of life and long-term outcomes for survivors. As such, we have organized this Focus, spread over two issues, in recognition of the mounting research looking at the interplay between cancer and ageing, and the unique challenges to studying and treating age-related cancers.

Although ageing involves the accumulation of genetic alterations that drive clonal expansions and tumorigenesis, many mutations in oncogenes and tumour suppressor genes are essential but not sufficient on their own to initiate cancer. In their Review, Easwaran and Weeraratna highlight how ageing-induced epigenetic changes in the cancer cell of origin and in other cells within the tissue microenvironment contribute to tumour initiation and progression.

Senescence, the state in which cells are no longer dividing but remain metabolically active, is intertwined with the process of ageing. As a physiological stress response to various forms of damage — such as DNA damage, oxidative stress or oncogenic signalling — senescence has a dual role: it protects against malignant transformation but also contributes to tissue dysfunction and chronic inflammation with age. In their Review that focuses on the role of senescent fibroblasts within the tumour microenvironment, Ye, Melam and Stewart highlight this dynamic and complex relationship, emphasizing the pro-tumorigenic and immunosuppressive role of senescent stromal cells in established cancers.

Moreover, senescence is closely linked to immunosenescence, the age-associated decline in immune function, which reduces immune fitness and further drives a pro-inflammatory state known as inflammaging. The haematopoietic system exhibits changes with age, leading to myeloid bias and alterations in clonal haematopoiesis, impairing immune defence and creating a systemic environment permissive to malignancies, as addressed in a Review by McAllister and colleagues.

Metabolic changes are also prevalent in ageing tissues, interacting with genetic and epigenetic driver mutations to promote or suppress cancer. This is highlighted in the Perspective by Lazure and Gomes, in which they propose that metabolic changes induced by ageing alter cell fate, function and identity that can ultimately increase cancer risk.

Although ageing and cancer commonly occur across metazoans, the rates of both vary substantially across species. In his Perspective, de Magalhães argues that to prevent cancer in young people, natural selection must favour the evolution of cancer resistance mechanisms over processes that maintain health later in life. This would suggest that anti-ageing interventions may increase cancer risk if they target processes evolved to suppress cancer, highlighting the need for careful evaluation of such therapeutic approaches.

Finally, experimental models routinely used for cancer studies often do not consider the age of the host and therefore are not able to capture the aforementioned age-related changes to tissues. In their Review, Henry and DeGregori outline possible solutions for this, highlighting both the strengths and limitations of the models and tools currently in use, and advocate for the widespread implementation of age-controlled models and tools to improve clinical translation. An example of such an approach is ImAge, an imaging-based approach to capture age-related trajectories of chromatin and epigenetic marks in single nuclei, described by Ninomiya in their Tools of the Trade article.

Together, this Focus highlights that although it is clear that ageing can create a tumour-permissive environment, progress continues to be needed and made on understanding the contributions of ageing to cancer. This work will ultimately lead to the identification of biomarkers for ageing-related risks as highlighted in a Comment by LaBarge and Binder, with earlier cancer diagnoses, new drug targets, age-tailored treatments, and improved quality of life and outcomes for patients with cancer.