Aging increases the risk of endometrial cancer through a combination of molecular, cellular, and hormonal changes that accumulate over time, creating an environment conducive to cancer development in the lining of the uterus. As women age, their endometrial tissue undergoes genetic and epigenetic alterations, hormonal imbalances, and changes in cellular behavior that collectively raise the likelihood of malignant transformation.
One key factor is the **accumulation of genetic mutations and epigenetic changes** in endometrial cells. With age, the normal mechanisms that protect cells from becoming cancerous—such as tumor suppressor genes—can become inactivated. For example, the loss of the PAX2 protein, which normally helps regulate cell growth in the endometrium, becomes more common with age. Studies have shown that PAX2-deficient cell clones, which are early signs of neoplastic change, are rarely found in younger women but appear more frequently in women in their 40s and beyond. This suggests that aging promotes the emergence of these abnormal cell populations that can eventually develop into cancer[1].
Another important aspect is **cellular senescence**, a state where cells stop dividing but do not die. Senescent cells accumulate in tissues as people age and can alter the tissue environment through the secretion of inflammatory molecules and growth factors. While senescence initially acts as a tumor-suppressive mechanism by halting the proliferation of damaged cells, senescent cells can paradoxically promote cancer if they escape growth arrest or influence nearby cells to become malignant. This process involves complex epigenetic remodeling—changes in how genes are turned on or off without altering the DNA sequence—that can silence tumor suppressor genes and activate oncogenic pathways. The chronic inflammation and altered signaling caused by senescent cells create a microenvironment that favors cancer development[2].
Hormonal changes with aging also play a critical role. The endometrium is highly sensitive to estrogen, which stimulates its growth. In premenopausal women, estrogen and progesterone levels fluctuate in a balanced cycle. However, after menopause, estrogen levels decline but can remain relatively unopposed if progesterone is low, especially in women with obesity or other risk factors. This **unopposed estrogen exposure** leads to prolonged stimulation of the endometrial lining, increasing the risk of hyperplasia (excessive cell growth) and subsequent malignant transformation. Aging thus shifts the hormonal milieu in a way that favors endometrial cancer development.
Additionally, aging cells accumulate **random mutations** over time simply due to the natural wear and tear of DNA replication and repair processes. These mutations can affect critical pathways that regulate cell growth and survival. For instance, in sporadic endometrial cancers, mutations often activate the PI3K signaling pathway, which promotes cell proliferation. Interestingly, certain drugs like tamoxifen, used in breast cancer treatment, can mimic this effect by directly activating the PI3K pathway in uterine cells, further increasing cancer risk in aging women who have accumulated mutations[4][5].
The immune system also changes with age, becoming less efficient at identifying and eliminating abnormal cells. This decline in immune surveillance allows mutated or pre-cancerous cells in the endometrium to survive and expand unchecked.
In summary, aging increases the risk of endometrial cancer through a multifaceted process involving:
– **Accumulation of genetic and epigenetic alterations** that disable tumor suppressor genes and activate oncogenes.
– **Emergence of abnormal cell clones** such as PAX2-deficient cells that represent early neoplastic changes.
– **Cellular senescence and associated inflammatory changes** that alter the tissue environment to favor malignancy.
– **Hormonal imbalances**, particularly unopposed estrogen exposure after menopause, that stimulate excessive endometrial growth.
– **Accumulation of random mutations** in critical growth pathways like PI3K.
– **Decline in immun