One of the more curious aspects of aging is that risk of Alzheimer's disease and risk of cancer is inversely correlated. Why is this the case? Researchers here suggest that cellular senescence may be an important component of this relationship. If cells in a given individual are more than averagely prone to becoming senescent in response to stress and damage, then this may lower the risk of cancer, as precancerous cells will be blocked from replication and removed by the immune system more efficiently. On the other hand, increased cellular senescence in the aging brain will more rapidly drive chronic inflammation and neurological dysfunction, leading to an increased risk of dementia.
Given this, we are fortunately to live in an era in which senolytic drugs to selectively remove senescent cells now exist. Some of them, such as the combination of dasatinib and quercetin, can bypass the blood-brain barrier to destroy senescent cells in brain tissue. This therapy has been shown to reduce chronic inflammation and reverse Alzheimer's pathology in mouse models of the condition. Human trials in Alzheimer's patients are somewhere in the early stages of organization, and we can hope that this strategy will outperform past efforts.
The risk of both neurodegenerative disease and cancer increases with advanced age due to increased damage accumulation and decreased repair capabilities; yet the relative odds of developing one or the other are inversely correlated. Molecular profiling studies have identified disrupted genes, proteins, and signaling pathways shared by neurodegenerative diseases and cancer, but in opposing directions. For example, p53 is upregulated in Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, but downregulated in many cancers. Similarly, mutations of the Parkin gene (PARK2) have been shown to simultaneously contribute both to Parkinson's disease and tumor suppression. A recent study performed transcriptomic analyses of four different tissues from four different species at ages across their lifespan. Across samples, the largest number of shared risk single nucleotide polymorphisms (SNPs) were in the genomic locus containing the long non-coding RNA ANRIL which modulates many cell cycle regulators including CDKN2A/B, which codes for p16INK4A (hereon referred to as p16), one of the best characterized mediators of cellular senescence. Notably, SNPs in this locus were identified in the brain, as well as other tissues analyzed. These results point toward aberrant cell cycle, and in particular senescence, as a key age-associated molecular pathway worth further study.
Cellular senescence has emerged as a hallmark biological process that promotes aging. The pillars of aging, including cellular senescence, are highly interconnected and do not occur in isolation. For example, epigenetic changes, telomere attrition, DNA damage, and mitochondrial dysfunction all may induce cellular senescence, which then contributes to dysfunctional nutrient signaling and proteostasis. Consequences of cellular senescence include stem cell exhaustion and chronic inflammation. Thus, cellular senescence represents an intersection of aging hallmarks. While best studied as an anti-cancer stress response, recent studies highlight its pro-degenerative role in AD and tauopathies. As such, cellular senescence may contribute to the inverse correlation between the risk for developing neurodegeneration and that for cancer.
Bulk tissue analyses, while informative at a macroscopic level, may not capture important changes occurring in single cells. Senescent cell abundance increases with aging, but the relative contribution to a tissue is relatively low and may be missed in bulk analyses. Several laboratories are using single cell technologies to assign cell type specificity to tissue-level observations, but to date these analyses have not included senescent cells in the brain. To maximize generalization and interpretation across studies, in this review we only evaluate studies which investigated cellular senescence with cell type specificity, and not bulk analyses. The present compilation provides evidence on conditions in which cellular senescence may benefit (anti-cancer) or negatively impact (neurodegeneration) brain health. In doing so, this review explores how the cellular senescence stress response may simultaneously distinguish and connect AD and cancer risk.