Colonic Aging and Colorectal Cancer: An Unignorable Interplay and Its Translational Implications

Abstract

Colorectal cancer (CRC) incidence increases markedly with age, yet chronological age is an inadequate proxy for the complex biological processes involved. Colon aging, the intrinsic biological aging of the colonic tissue, is emerging as a crucial, active driver of CRC development. This review comprehensively analyzes the interplay between colon aging and CRC pathogenesis by examining fundamental hallmarks of aging-such as altered tissue homeostasis, epigenetic dysregulation, and microenvironmental shifts including chronic inflammation (inflammaging), gut microbiome dysbiosis, and extracellular matrix remodeling-manifest specifically within the aging colon to synergistically foster a pro-tumorigenic environment. Key findings synthesized from the literature highlight the critical roles of impaired colonic stem cell function, epithelial barrier disruption ("leaky gut"), persistent low-grade inflammation, and altered microbial communities and their metabolites in promoting CRC initiation and progression. Translating this mechanistic understanding holds significant promise: insights from colon aging research can inform novel biomarkers for improved early detection and risk stratification, guide the development of personalized preventative strategies and therapeutic interventions targeting aging pathways, and underpin public health initiatives focused on healthy colon aging. Ultimately, recognizing colon aging as a modifiable contributor to CRC offers a powerful avenue to potentially reduce CRC incidence and enhance patient outcomes, particularly in the vulnerable aging population.

Keywords: biological aging; colon aging; colorectal cancer; dysbiosis; early detection; inflammation; microenvironment; prevention; senescence; translational research.

Figure 1

Defining colon aging: beyond chronological time. This figure illustrates the distinction between biological and chronological age in the context of colorectal cancer (CRC) risk. The graph (left panel) displays CRC Risk (Y-axis) plotted against Age (X-axis), comparing the trajectory for expected aging based on chronological age (red line) with that of accelerated biological aging (green line). It highlights that individuals undergoing accelerated biological aging reach a high CRC risk threshold at an earlier chronological age, potentially allowing for earlier detection. The text panel (right) explains that chronological age is simply time elapsed, whereas biological age reflects cumulative molecular damage and functional decline. It also notes that the colon may age at a different rate than other tissues and that accelerated biological aging might underlie early-onset CRC. Key categories of biomarkers used to assess biological aging, such as RNA-seq and methylome data, inflammatory markers, intestinal barrier integrity, and gut microbiome profiles, are listed at the bottom.

Figure 2

Age-related disruption of mouse colonic crypt homeostasis: altered cell fate. In the young mouse colonic crypt, stem cells and Reg4+ cells reside at the base, giving rise to proliferating transit-amplifying (TA) cells, which then differentiate into specialized cell types, including mucus-producing goblet cells, as they migrate up the crypt walls, maintaining tissue homeostasis. The aged mouse colonic crypt illustrates common age-related alterations, characterized by an expansion of the TA cell zone (indicated as “Increase in TA Cells”) and a reduction in the number of mature goblet cells (“Decline in Goblet Cells”). This represents an “Imbalance in Differentiation” and altered cell fate.

Figure 3

Interconnected factors in the aging colonic microenvironment promoting colorectal cancer development. This schematic illustrates the complex interplay of factors within the aging colonic microenvironment that collectively create a pro-tumorigenic ecosystem conducive to colorectal cancer (CRC) development. Key age-related changes depicted include: (1) Gut dysbiosis in the lumen, characterized by a decrease in beneficial bacteria and an increase in pathobionts. (2) Impaired epithelial barrier function (“leaky gut”) due to disrupted tight junctions, allowing translocation of bacterial products. (3) Accumulation of senescent cells (senescent fibroblasts) within the lamina propria that secrete a pro-inflammatory mix of factors known as the senescence-associated secretory phenotype (SASP). (4) A resulting chronic inflammatory environment involving various immune cells. (5) Immune dysregulation, featuring potentially increased M2 macrophages and myeloid-derived suppressor cells (MDSCs) that can suppress cytotoxic T-cell activity, leading to reduced anti-tumor immunity. (6) Remodeling of the extracellular matrix (ECM), including increased collagen deposition and stiffness, which alters cell–ECM interactions. (7) Increased angiogenesis (new blood vessel formation). These interconnected factors—dysbiosis, barrier dysfunction, senescence/SASP, inflammation, immune suppression, and ECM remodeling—contribute synergistically to CRC initiation and progression. Refer to the inset legend for definitions of specific symbols.

Figure 4

Molecular and cellular pathways linking colon aging hallmarks to colorectal cancer development. This diagram illustrates the proposed molecular and cellular pathways connecting general hallmarks of aging (left column) to the initiation and progression of colorectal cancer (CRC, far right). Key aging hallmarks, including genomic instability, telomere attrition, epigenetic alterations, cellular senescence, chronic inflammation, and gut dysbiosis, lead to specific colonic manifestations (middle column) such as altered cell fate, epithelial barrier dysfunction (“leaky gut”), extracellular matrix (ECM) remodeling, immune dysregulation, and an altered microbiome. These age-related changes within the colon subsequently promote pro-tumorigenic effects (right column), including increased cell proliferation, reduced apoptosis, genomic instability, and immune evasion. Together, these effects contribute to the development of CRC.

Figure 5

Translating colon aging insights into colorectal cancer prevention, early detection, and risk stratification. This figure outlines translational applications derived from understanding the interplay between colon aging and colorectal cancer (CRC). Panel A: Biomarker discovery illustrates potential sources and types of colon aging-related biomarkers relevant to CRC risk and detection. These include analyzing the gut microbiome from stool samples, assessing transcriptomic (RNA-seq) and epigenomic (methylome) profiles from colonic biopsies, and performing immune cell profiling from blood samples. Panel B: Improved risk stratification demonstrates how incorporating these novel colon aging biomarkers (from Panel A) with traditional risk factors (such as age, family history, lifestyle, and polyp history) can enhance CRC risk assessment. This improved stratification allows for categorizing individuals into different risk levels (low, moderate, high, ultra-high), guiding personalized management strategies that range from standard screening and enhanced surveillance to frequent monitoring or specific interventional approaches. Panel C: Prevention and intervention strategies highlights potential approaches informed by colon aging research aimed at preventing CRC or intervening in high-risk individuals. These strategies include dietary modifications, microbiome modulation (prebiotics, probiotics, fecal microbiota transplantation), epigenetic interventions, the use of anti-inflammatory therapies, and other potential interventions targeting aging pathways.