Among Gerontogens, Heavy Metals Are a Class of Their Own: A Review of the Evidence for Cellular Senescence

Abstract

Advancements in modern medicine have improved the quality of life across the globe and increased the average lifespan of our population by multiple decades. Current estimates predict by 2030, 12% of the global population will reach a geriatric age and live another 3–4 decades. This swelling geriatric population will place critical stress on healthcare infrastructures due to accompanying increases in age-related diseases and comorbidities. While much research focused on long-lived individuals seeks to answer questions regarding how to age healthier, there is a deficit in research investigating what aspects of our lives accelerate or exacerbate aging. In particular, heavy metals are recognized as a significant threat to human health with links to a plethora of age-related diseases, and have widespread human exposures from occupational, medical, or environmental settings. We believe heavy metals ought to be classified as a class of gerontogens (i.e., chemicals that accelerate biological aging in cells and tissues). Gerontogens may be best studied through their effects on the “Hallmarks of Aging”, nine physiological hallmarks demonstrated to occur in aged cells, tissues, and bodies. Evidence suggests that cellular senescence—a permanent growth arrest in cells—is one of the most pertinent hallmarks of aging and is a useful indicator of aging in tissues. Here, we discuss the roles of heavy metals in brain aging. We briefly discuss brain aging in general, then expand upon observations for heavy metals contributing to age-related neurodegenerative disorders. We particularly emphasize the roles and observations of cellular senescence in neurodegenerative diseases. Finally, we discuss the observations for heavy metals inducing cellular senescence. The glaring lack of knowledge about gerontogens and gerontogenic mechanisms necessitates greater research in the field, especially in the context of the global aging crisis.

Heavy Metal Exposure: Molecular Pathways, Clinical Implications, and Protective Strategies

“…Senolytic drugs that induce apoptosis in senescent cells effectively protect against heavy metal toxicity [222]. Senolytic drugs are classified as BCL family inhibitors, PI3K/AKT inhibitors, or FOXO regulators [223,224].…”

Gerontogen as the Toxicology of Aging<strong> </strong>

“…Currently, there has been a review of heavy metals that have been shown to induce senescence, both in vitro and in vivo, including arsenic and iron [42]. Arsenic (As) is a toxicant commonly found in air, water, and soil and can enter the body through various routes.…”

“…Arsenic (As) is a toxicant commonly found in air, water, and soil and can enter the body through various routes. Exposure to arsenic can increase ROS production which causes DNA damage and affects the DNA repair process [7,41,42]. Okamura et al showed that exposure to sodium arsenite 5 and 7.5 μg for 144 hours caused the occurrence of senescence in the human stellate cell line, which is characterized by changes in cell morphology, increased SA-β-Gal, increased expression of p21, increased marker of DNA damage (γ-H2AX), and decreased expression of lamin B1.…”