Fight Aging!

Senescent cells are created throughout the body at all stages of life, largely when somatic cells reach the Hayflick limit on replication. Senescent cells cease replication and begin to energetically produce pro-growth, pro-inflammatory factors, attracting the attention of the immune system and otherwise changing the behavior of surrounding cells. Cell stress and mutational damage can induce senescence, and in this case senescence is a mechanism that acts to limit the risk of cancer. Tissue injury also produces senescent cells, and here they help to coordinate the activities of the many different cell types that become involved in the complex process of regeneration.

In youth, senescent cells are promptly destroyed, either through programmed cell death mechanisms, or by attracting the attention of immune cells. In later life, the immune system becomes less efficient in its task of clearing senescent cells. This leads to a growing burden of lingering senescent cells. While the signals generated by senescent cells are useful in the short-term, when sustained over the long-term they become disruptive to tissue structure and function, contributing to the chronic inflammation of aging. Researchers are coming to see the inflammation of aging as an important mechanism in the aging of the brain and the onset of neurodegenerative conditions, and so attention is turning, slowly, to whether clearance of senescent cells is a viable treatment for Alzheimer's disease, Parkinson's disease, and other paths to dementia.

Cellular senescence in brain aging and cognitive decline

The mechanisms underlying brain aging have garnered significant attention due to the significant number of patients suffering from dementia and Alzheimer's disease (AD). The cost of managing these patients exceeds that of cancer and cardiovascular disease patients combined. Importantly, however, cognitive decline is observable in individuals without AD or overt neurodegenerative changes. Age-related mild cognitive impairment (MCI) and late-onset AD can be mechanistically explained by processes governing biological aging. Currently, 12 biological aging hallmarks have been identified: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, altered nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, altered intracellular communication, cellular senescence, disabled macroautophagy, chronic inflammation (i.e., inflammaging), and gut microbiome dysbiosis. The geroscience hypothesis posits that age-related diseases arise from the cumulative effects of these biological aging hallmarks and that targeting them constitutes an avenue to ameliorate age-related diseases.

Cellular senescence describes a state of cell cycle arrest accompanied by characteristic morphological, cellular, and molecular changes. Studies using pharmacological targeting of senescent cells (SCs), transplanting SCs, and transgenic mouse models have demonstrated a causal relationship between SC accumulation and age-related tissue dysfunction, with addition of SCs being shown to accelerate aging phenotypes on the one hand and clearance being shown to alleviate them on the other. In the brain, SCs become more abundant with aging in mice, which is associated with cognitive decline, and their depletion mitigates neuroinflammation and delays cognitive decline.

This review explores the association between cellular senescence and age-related cognitive decline. We also discuss how cellular senescence may underlie cognitive decline in different patient populations that exhibit a premature brain aging phenotype. These patients include cancer survivors, traumatic brain injury (TBI) patients, obese individuals, obstructive sleep apnea (OSA) patients, and chronic kidney disease (CKD) patients. Understanding the role of senescence in cognitive decline is essential, especially considering the rapidly evolving field of senotherapeutics. Targeting SCs could mitigate early brain aging and reduce a significant burden on patients, healthcare systems, and society.