Most look at cancer and aging as separate; that is, cancer is a disease of the aged, thus cancer is downstream of aging. Stated another way, cancer is a byproduct of aging. The central idea here is that aging and cancer are linked, but nothing more.
Cancer is not simply a downstream effect of aging. This is a reductionist fallacy built on sequential thinking. The reductionist fallacy occurs when a complex issue is broken down into compartments for understanding, but is never reassembled into the whole, leading to conclusions about the parts, not the whole, which creates a false interpretation and understanding. The holistic and emerging evidence actually supports the idea that both aging and cancer are co-expressions of immune system failure.
Cancer as a systems failure is a new emerging paradigm in cancer. No longer is cancer seen as an isolated gene-hit theory, whether in causation or targeted treatment. Instead, cancer is the result of closely linked simultaneous system failures. The future of cancer care will incorporate strategies for treating system failures.
Four horsemen of the apocalypse —> Dysbiosis
I have previously written and spoken on the Four Horsemen of the cancer apocalypse:
• Ultra-processed foods
• Glyphosate and other pesticides
• Antibiotic overuse
• Obesity
These same four horsemen of the apocalypse can equally apply to aging.
Dysbiosis:
• Not simply loss of particular bacteria, but Loss of diversity
• Altered metabolism (decreased SCFAs and decreased Bile acids)
• Dysbiosis durability (the current ecological environment outside and inside the body ensures dysbiosis durability)
• Pathobionts (loss of microbiota homeostasis leaves a void that outright pathogenic or potentially pathogenic bacteria fill)
• Gut epithelial barrier breakdown (also known as ‘leaky gut’)
✧ Dysbiosis and leaky gut are virtually impossible to separate. They are one and the same. Dysbiosis begets a leaky gut in the motion to aging and cancer; as the left step begets a right step in movement.
✧ Increased intestinal permeability
✧ Increased LPS and endotoxin transfer (metabolic endotoxemia)
▪︎ Drives systemic metabolic dysfunction
• The result is chronic immune activation.
◦ ↑ TLR4 signaling
◦ ↑ NF-κB
◦ ↑ IL-6
◦ ↑ TNF-α
◦ ↑ IL-1β
Dysbiosis —> Immunosenescence
• Chronic immune activation resulting from dysbiosis drives immune exhaustion and repair/remodeling.
• Remodeling triggers replicative stress, accelerating cell senescence.
• The result is immunosenescence.
• Immunosenescence is defined as the cessation of immune cell replication and activation due to hyperactivation and dysfunction. Though replication and remodeling stop, senescence-associated secretory phenotype production continues, driving ongoing growth factor and pro-inflammatory cytokine signaling.
Immunosenescence —> SASP —> inflammaging —> chronic inflammation —> immune remodeling —> immunosenesence
Though the sequence presented is accurate, the complexity requires further explanation, as chronic immune activation is not the only driver. Persistent, chronic immune activation and inflammation drive immune exhaustion and immune remodeling. The result is a sum that contributes to immunosenescence.
Immunosenescence:
• ↓ naive T cells
• ↓ TCR diversity reducing immune cell adaptability
• ↑ immune exhaustion markers (PD-1, TIM-3, and TIGIT) impairing immunosurveillance
• ↑ MDSC and Tregs
• ↑ IL-10 and TGF-beta
• ↓ NK and CD8 cytotoxicity
Senescent cells, whether immune or non-immune, promote a senescent-associated secretory phenotype. Although not replicating, senescent cells promote pro-inflammatory signals, such as IL-6, IL-1β, and TNF-α, which create a loop of inflammation and cell senescence.
The accelerated aging that accompanies this loop promotes systemic inflammaging. The result is increased cell and tissue damage. This repair stress impairs the repair and remodeling capacity at the micro (cell) and macro (tissue and body as a whole) levels, creating another loop that promotes and accelerates the parallel vectors pushing immunosenescence.
Immunosenescence is the central node of disease that begins with dysbiosis, which manifests in parallel outcomes as aging and cancer.
References:
https://app.researchrabbit.ai/folder-shares/7ecc6d04-7601-4d38-b2f4-778d351542c8
