For decades, cancer was framed as the ultimate genetic disease, driven by the steady accrual of mutations as the inevitable consequence of the accumulation of biological noise. But that view now feels incomplete.

Cancer now appears less like a purely cell-autonomous failure and more like a systems-level breakdown. This is also seen – in a remarkably similar fashion – by the ageing process itself, which in many ways, is the master accumulator of biological noise. During ageing, cells lose functional precision, genomes acquire scars, and once-coordinated systems begin to drift. It is in this context where altered metabolism of the host, and the microbial ecosystems that inhabit it, converge to shape disease risk.

Nowhere is this interplay in the holobiont – made of up of the host and its microbes – more striking than in the intestine.

Shared biology

Colorectal cancer (CRC), one of the most common malignancies of ageing, offers a compelling lens through which to look at this.

At its genetic core lies the adenomatous polyposis coli (APC) tumour suppressor, one of the gatekeepers of epithelial homeostasis whose loss initiates tumour formation in both familial and sporadic disease. Yet, APC mutation alone is not a death warrant. Many individuals harbour oncogenic mutations for years without developing malignancy. It’s clear then that additional layers of biology – which are driven by the holobiont in interaction with its external environment – govern whether a tumour truly emerges.

Age is the orchestrator of holobiont biology applying pressure on both host physiology as well as microbial. Over time, the colonic epithelium accumulates mitochondrial defects driven by mutations in mitochondrial DNA. These mutations, particularly in genes encoding components of the electron transport chain, impair oxidative phosphorylation and reshape cellular metabolism. Intriguingly, similar mitochondrial alterations are not only a hallmark of ageing tissue but are also enriched in colorectal tumours, hinting at a shared biology between aged cells and cancer cells. Likewise, as time goes by, the well-established homeostatic relationship between the host with its microbes starts to fall apart, with microbiomes drifting away with consequential shifts in its functional properties.

This raises a provocative possibility: what if age-associated mitochondrial and microbial dysfunction are not merely bystanders, but active participants in tumour initiation?

Experimental evidence is beginning to support this idea. In models where mitochondrial fidelity is compromised, metabolic rewiring accelerates tumour development in APC-deficient intestines. The implications are profound. Rather than viewing mitochondrial dysfunction as a downstream consequence of cancer, we may need to consider it as a driver that preconditions tissue landscapes in ways that favour malignant transformation.

Shift in perspective

But the story does not end within the host cells. Remember, the intestine is not just a tissue: it’s an entire ecosystem. The gut microbiome, long appreciated for its key roles in energy homeostasis and immunity, is now emerging as a key architect of cancer risk.

In the context of APC-driven tumorigenesis, microbial communities may act as co-conspirators. For example, certain strains of Escherichia coli or Bacteroides fragilis produce genotoxins that directly damage host DNA, initiating cancer. Further, metabolites produced by dysfunctional microbiota such as secondary bile acids exacerbate oxidative stress and inflammation. These microbial outputs do not act in isolation, they intersect with host processes like mitochondrial function, immune signalling, and epithelial turnover. And, importantly, this relationship is not static – it’s dynamic in an age-dependent manner. So, it could well be the case that metabolites produced by microbiota that are beneficial during early life turn “sour” when mitochondrial, immune and intestinal fitness is compromised.

What makes this view particularly compelling is its alignment with the biology of ageing. Chronic low-grade inflammation, or “inflammageing,” shifts immune tone and thus cancer surveillance. Intestinal barrier function declines while microbial composition drifts creating a doom loop of inflammation. Mitochondria falter. Each of these hits alone may be tolerable, but together, they may tip the balance towards disease. In this view, cancer is less of a singular event and more an emergent property of a destabilised system that occurs with age.

This shift in perspective opens new avenues for intervention. If microbial metabolites can maintain health as well as promote tumour initiation in a context-dependent manner, could they also be manipulated in a timely fashion to prevent it? If mitochondrial dysfunction sensitises tissues to transformation, could metabolic correction restore resilience? And crucially, could we identify individuals at risk not only through their genome, but through the combined signatures of their microbiome and metabolic state?

The prospect of microbiome-informed precision oncology is particularly tantalising. Unlike the human genome, the microbiome is dynamic and, in principle, modifiable. These approaches would represent a fundamental shift from treating established cancer to managing the ecosystems that give rise to it and thus, prevent it.

This vision comes with significant challenges. The microbiome is complex, personalised, environmentally-dependent, and deeply intertwined with host physiology – as such, interventions risk unintended consequences. Yet the direction of travel is clear; as our understanding of the holobiont deepens, the boundaries between ageing, metabolism, immunity, and microbiology are falling apart creating an opportunity to treat disease.

For CRC this means a greater appreciation that risk is not only written in our DNA, or our age, but is also shaped by ecosystems we inhabit and those that live within us.