Cancer has long been acknowledged as an environmental disease, first highlighted in Percivall Pott’s description of chimney sweep’s cancer in 1775. A crucial social determinant of this disease is addressed in a noteworthy article in Lancet Oncology (though access is restricted). While discussions about social determinants may be less fashionable amidst our current MAHA Moment, their importance cannot be denied. More recent studies have convincingly linked smoking, asbestos, and other chemical exposures to cancer development. The area known as Cancer Alley, located along the Mississippi River between Baton Rouge and New Orleans, exemplifies these environmental factors that contribute to cancer risk, particularly for workers in the oil and chemical industries and their families. Despite the opposing claims from the Merchants of Doubt, it is no coincidence that these critics tend to reside in pleasant locales like Great Barrington, rather than in the industrial sacrifice zones across the globe.
Research dating back to the 1960s has provided insights into the molecular and cellular mechanisms behind cancer. The Ames Test has played a vital role in identifying mutagenic substances and has demonstrated that carcinogens often require metabolic activation by liver enzymes (such as cytochrome p450s) to become reactive compounds capable of damaging DNA. For instance, compounds like benzo(apyrene) and other polycyclic aromatic hydrocarbons (PAHs), present in substances like chimney soot, tobacco smoke, and charred foods, are not inherently mutagenic. However, the reactive metabolites formed during their detoxification by the body can result in substantial DNA damage. The multi-step progression of cancer is now well understood, asserting that cancer is typically a long-term, cumulative process.
This understanding has led to the characterization of cancer as a late-onset disease predominantly associated with aging. The prevailing belief suggests that anyone who lives long enough will eventually develop cancer. However, numerous cancers are now being diagnosed much earlier than anticipated, prompting researchers to reconsider the underlying mechanisms of cancer initiation and progression. A pertinent question arises: “Are younger patients experiencing cancer due to accelerated aging?” This question lacks a straightforward answer, yet findings from research spearheaded by Yin Cao at Washington University in St. Louis, published online on June 22, 2026, offer intriguing insights: Tian et al., Biological aging and generational shifts in early-onset cancer risk:
Over the past three decades, early-onset cancers, diagnosed in adults frequently under the age of 50 or 55 years, have emerged as a significant public health concern globally. Between 1990 and 2019, the incidence of cancers diagnosed before the age of 50 increased by 24% worldwide and continues to rise. In the United States, this trend is particularly notable for cancers such as multiple myeloma, colorectal cancer, and uterine cancer. Astonishingly, individuals born in the 1990s are at least four times more likely to develop early-onset colorectal cancer compared to those born in the 1960s. In the US, those born around 1985 have nearly double the risk of uterine cancer compared to individuals born before 1950. Furthermore, cohorts at elevated risk prior to age 50 seem to carry this heightened risk into their early 50s. The proportion of colorectal cancer cases diagnosed before age 55 in the US rose from 11% in 1995 to 20% in 2019, with a similar trend observed in the UK, where the incidence among adults aged 50–54 increased by 0.58% annually between 2008 and 2017. Collectively, these patterns point to the influence of emerging generational risk factors.
A multitude of physiological and environmental factors may contribute to age-related processes such as chronic inflammation, cumulative genetic damage, epigenetic alterations, changes in the tissue microenvironment, and immune system dysregulation, which are all linked to tumor initiation and progression. These factors can interact, reshaping both systemic and organ-specific tissue conditions, thereby enhancing vulnerability to malignant transformation and expediting cancer onset at younger ages. Additionally, as people’s aging patterns may vary across different organ systems, organ-specific aging may affect the risk of early-onset cancer, either independently or alongside systemic aging.
The research utilizes a metric known as PhenoAge, which calculates biological age via a combination of nine clinical biochemistry markers. Individuals whose PhenoAge exceeds their chronological age are considered biologically older than their calendar age. This methodology parallels the established Klemera-Doubal method (KDM), popular within molecular geriatrics, which employs eight clinical biochemistry markers along with two anthropometric measures. Furthermore, metabolic flux changes (metabolomics) serve as indicators of chronological aging, while protein composition analysis (proteomics) can reflect organ-specific aging. Despite Sydney Brenner’s previous dismissal of the “-omic biology” approach, this methodology has proven invaluable in current research.
An outline of the study design can be found in Figure 1. This approach, while somewhat complex, yields valuable data to potentially answer whether younger individuals diagnosed with cancer are biologically older than expected. Alternatively, it’s plausible that these younger patients have endured a higher cumulative burden of cancer-inducing factors compared to previous generations, potentially providing a more comprehensive explanation.
The significance of sample size is crucial for this study’s validity. The UK Biobank includes data from 154,169 participants, while the All of Us Research Program in the United States has 10,262 participants. [2] This substantial sample size is advantageous for obtaining preliminary insights into this area of molecular epidemiology. The findings are compelling, but the authors acknowledge that there is a broader context that extends beyond accelerated aging:
While our findings align with previous studies connecting a larger age gap to cancer risk in older adults, assessing this relationship earlier in life is both biologically significant and, if validated, offers a complementary method to tackle the challenges associated with early-onset cancer causes: accurately identifying all contributing exposures is challenging…Our results indicate that the age gap may be particularly relevant for understanding early-onset cancers with increasing incidence, such as colorectal and uterine cancers, as well as cancers with significant unexplained risks, like lung cancer. In the UK, 67% of young lung cancer patients are diagnosed at stage IV, while in the US, early-onset lung cancer incidence is rising, especially among women, most of whom are non-smokers. Moreover, our analysis revealed that the associations between age gap and early-onset lung, gastrointestinal, and uterine cancers stand independent of telomere length, a recognized biological age marker, suggesting that the age gap encompasses risk factors beyond traditional aging pathways and warrants further mechanistic investigation.
Future mechanistic studies will necessarily involve considerations discussed previously regarding early-onset cancers, particularly colorectal cancer. The various factors contributing to the rise in early-onset cancers likely include chronic inflammation attributed to obesity and increasingly sedentary lifestyles in the Global North. The noted increase in early-onset cancers coincides with shifts in Western dietary habits, where fat calories and cholesterol faced scrutiny and were supplanted by refined carbohydrates (sugar) and ultraprocessed foods. This correlation suggests a systemic, albeit complex, cause for the shifting cancer rates across generations.
This raises a pertinent issue concerning the connection between accelerated biological aging and generational shifts in early-onset cancer risk. In a summary from WUSTL about this research, Dr. Cao stated:
Our ultimate aim is to decipher how modern environments biologically integrate to elevate cancer risk, transforming prevention strategies from broad recommendations into personalized interventions…If we can identify younger individuals at the highest cancer risk while they remain healthy, we can tailor prevention and early detection strategies for those who would benefit most from timely interventions.
However, this assumes that personalized interventions can effectively address systemic population issues. While these strategies are gaining traction, particularly among the MAHA health influencer community, solutions to systemic challenges will require broader initiatives. For instance, at Pheno, the emphasis is on providing individuals tools to manage their health to foster a healthier workforce. Whether such an approach can meaningfully address systemic issues remains to be seen.
Nonetheless, it’s essential to recognize that accelerated biological aging, depending on its definition and measurement, is a crucial piece of the puzzle behind early-onset cancers. The paper Biological aging and generational shifts in early-onset cancer risk is thorough and grounded within the known contexts of cancer initiation and progression.
This topic is too critical to overlook. Although we do not assign homework here, the following open-access papers from Tian et al.’s bibliography are well-written and well-illustrated, providing an opportunity to delve deeper into the present literature surrounding cancer research:
Embracing cancer complexity: Hallmarks of systemic disease (2024). This paper encompasses nearly every aspect of cancer biology.
Accelerating discovery of cancer causes for prevention in the era of rising early-onset cancers (2026). Authored by Lin Cao from WUSTL, this paper situates the prior discussion into a larger context.
Plasma protein-based organ-specific aging and mortality models unveil diseases as accelerated aging of organismal systems (2025). This represents a foundational proof-of-concept for studying organ-specific aging.
Increase of early-onset colorectal cancer: a cohort effect (2026). This paper also situates early-onset cancers within a broader context:
All countries exhibited rising early-onset colorectal cancer incidence across successive birth cohorts since 1960, with individuals born in the 1990s at over four times the risk compared to those born in the 1960s. Cohort effects were evident across all nations, with more dramatic increases observed at younger ages. The past decade saw an estimated annual percentage change ranging from 3.4% in Australia and the United States to 4.5% in England, with particularly steep increases noted before age 40. These trends, especially from ages 20 to 29, indicate that contributing factors likely emerge early in life and accumulate throughout the lifespan.
This cumulative exposure to risk factors leading to colorectal cancer is undeniably systemic and prevalent within affected populations across regions like Australia, Canada, England, and the United States. Addressing and mitigating these risk factors may require as much time as it took for them to manifest.
Interpretation: 17 of 34 cancers exhibited increasing incidence in younger birth cohorts, with nine of these previously showing a decline in older cohorts. These findings bolster the evidence of rising cancer risk among younger generations, underscoring the imperative to identify and address underlying risk factors.
Indeed, a significant shift is underway, akin to current environmental crises, and its roots are undoubtedly ecological. The pressing question is whether we will pay sufficient attention to instigate meaningful change, something that seems increasingly lost to us as a society.
Notes
[1] This refers to an early definition of exposome: “The interactions between the genome and the exposome are real, albeit complex: Discrepancies in the measurement accuracy for genetic and environmental factors have profound implications, particularly in undermining public health advances derived from investments in genomic research and cohort studies. We urgently need methods that provide the same level of precision in assessing environmental exposure as we now possess for genetic analysis. The concept of an exposome, parallel to the genome, may spotlight the critical need for advancements in exposure assessment. Reflecting on my own exposome as a worker exposed to heavy chemicals, I am alarmed by the multitude of exposures I faced.
[2] This contrast highlights the advantages of nations with a universal National Health Service compared to others lacking cohesive systems. Aneurin Bevan, who established the NHS post-WWII, remarked: “The domain where individual commercial interests clash with society’s health values is undoubtedly that of care.” One might also consider the role of large enterprises and public-private partnerships. Bevan, an Old Labour figure, likely could not have envisioned the current Neoliberal landscape.
[3] To understand PhenoAge, one can draw a parallel between phenotype and genotype in biology. While the genotype remains unseen, the phenotype (such as features like hair color, eye color) is measurable. Here, the “age” observed in study participants derives from measurable indicators rather than mere birthdates. (OED: phen-, pheno- Greek: shining, to illuminate, to reveal).
